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Austin, Melissa A. "Genetic Epidemiology of Dyslipidaemia and Atherosclerosis." Annals of Medicine 28, no. 5 (January 1996): 459–63. http://dx.doi.org/10.3109/07853899608999108.
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Berberich, Amanda J., and Robert A. Hegele. "The role of genetic testing in dyslipidaemia." Pathology 51, no. 2 (February 2019): 184–92. http://dx.doi.org/10.1016/j.pathol.2018.10.014.
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Marais, A. David. "Dietary lipid modification for mild and severe dyslipidaemias." Proceedings of the Nutrition Society 72, no. 3 (May 17, 2013): 337–41. http://dx.doi.org/10.1017/s0029665113001298.
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The aim of this review is to place a historical perspective on linking dyslipidaemia with atherosclerosis and emphasises previous knowledge about the impact on the lipoprotein profile and health in persons with mild dyslipidaemia and in those with defined genetic disorders. CVD is becoming the leading cause of death and disability in developed and developing countries and is strongly related to lifestyle factors that influence plasma lipoprotein concentrations. It is established that risk of complications from atherosclerosis increases with increasing LDL and decreasing HDL and that there is potentiation of risk when these and other risk factors co-exist. High-fat diets used for losing body mass may increase risk through dyslipidaemia. Pharmaceutical modulation of the lipoproteins has lowered risk powerfully but residual risk persists, possibly relating to existing disease as well as progression relating in many instances to dietary lipids. The impact of various dietary lipids is reviewed as they relate to the conventional lipoprotein profile in persons who do not have significant metabolic defects, as well as the impact on inherited metabolic disease such as familial hypercholesterolaemia, hypertriglyceridaemia and phytosterolaemia. For most persons with dyslipidaemias a significant benefit will be seen on the lipid profile by adopting a low saturated fat diet with less cholesterol intake.
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Chekanova, Valeriya, Nazanin Abolhassani, Julien Vaucher, and Pedro Marques-Vidal. "Association of clinical and genetic risk factors with management of dyslipidaemia: analysis of repeated cross-sectional studies in the general population of Lausanne, Switzerland." BMJ Open 13, no. 2 (February 2023): e065409. http://dx.doi.org/10.1136/bmjopen-2022-065409.
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ObjectivesTo assess the importance of clinical and genetic factors in management of dyslipidaemia in the general population.DesignRepeated cross-sectional studies (2003–2006; 2009–2012 and 2014–2017) from a population-based cohort.SettingSingle centre in Lausanne, Switzerland.Participants617 (42.6% women, mean±SD: 61.6±8.5 years), 844 (48.5% women, 64.5±8.8 years) and 798 (50.3% women, 68.1±9.2) participants of the baseline, first and second follow-ups receiving any type of lipid-lowering drug. Participants were excluded if they had missing information regarding lipid levels, covariates or genetic data.Primary and secondary outcome measuresManagement of dyslipidaemia was assessed according to European or Swiss guidelines. Genetic risk scores (GRSs) for lipid levels were computed based on the existing literature.ResultsPrevalence of adequately controlled dyslipidaemia was 52%, 45% and 46% at baseline, first and second follow-ups, respectively. On multivariable analysis, when compared with intermediate or low-risk individuals, participants at very high cardiovascular risk had an OR for dyslipidaemia control of 0.11 (95% CI: 0.06 to 0.18), 0.12 (0.08 to 0.19) and 0.38 (0.25 to 0.59) at baseline, first and second follow-ups, respectively. Use of newer generation or higher potency statins was associated with better control: OR of 1.90 (1.18 to 3.05) and 3.62 (1.65 to 7.92) for second and third generations compared with first in the first follow-up, with the corresponding values in the second follow-up being 1.90 (1.08 to 3.36) and 2.18 (1.05 to 4.51). No differences in GRSs were found between controlled and inadequately controlled subjects. Similar findings were obtained using Swiss guidelines.ConclusionManagement of dyslipidaemia is suboptimal in Switzerland. The effectiveness of high potency statins is hampered by low posology. The use of GRSs in the management of dyslipidaemia is not recommended.
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Tokgozoglu, Lale, Carl Orringer, Henry N. Ginsberg, and Alberico L. Catapano. "The year in cardiovascular medicine 2021: dyslipidaemia." European Heart Journal 43, no. 8 (February 3, 2022): 807–17. http://dx.doi.org/10.1093/eurheartj/ehab875.
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Abstract The past year was an exciting time for clinical lipidology when we learnt more about existing therapies as well as therapies targeting novel pathways discovered through genetic studies. LDL cholesterol remained the main target and a variety of drugs to lower LDL cholesterol through different mechanisms were explored. Emerging evidence on the atherogenity of triglyceride-rich lipoproteins led to renewed interest in lowering them with new treatments. Lp(a) was back in focus with evidence on causality and new targeted therapeutics which dramatically lower Lp(a) levels. We will be able to personalise lipid lowering therapy further with this enriched armamentarium once we have the results of the cardiovascular outcome studies with some of these new agents.
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Klug, E. Q., F. J. Raal, A. D. Marais, C. M. Smuts, C. Shamroth, D. Jankelow, D. J. Blom, and D. A. Webb. "Klug E, Raal FJ, Marais AD, et al. South African Dyslipidaemia Guideline Consensus Statement 2018 Update: A joint statement from the South African Heart Association (SA Heart) and the Lipid and Atherosclerosis Society of Southern Africa (LASSA). S Afr Med J 2018;108(11b):973-1000." South African Medical Journal 108, no. 11 (November 1, 2018): 973–1000. http://dx.doi.org/10.7196/samj.2018.v108i11.13383.
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South Africa (SA) is home to a heterogeneous population with a wide range of cardiovascular risk factors. Cholesterol reduction in combination with aggressive management of modifiable risk factors, including nutrition, physical activity, blood pressure and smoking, can help to reduce and prevent morbidity and mortality in individuals who are at increased risk of cardiovascular events. This updated consensus guide to management of dyslipidaemia in SA is based on the updated European Society of Cardiology and European Atherosclerosis Society dyslipidaemia guidelines published in 2016. For individuals who are not considered to be at high or very high cardiovascular risk, the decision whether to treat and which interventional strategy to use is based on a cardiovascular risk score calculated using total cholesterol, high-density lipoprotein cholesterol (HDL-C), gender, age and smoking status. The cardiovascular risk score refers to the 10-year risk of any cardiovascular event and includes 4 categories of risk (low, moderate, high and very high). People with established cardiovascular disease, diabetes mellitus, chronic kidney disease and genetic or severe dyslipidaemias are considered to already be at high or very high risk and do not require risk scoring. Therapeutic lifestyle change is the mainstay of management for all patients. The need for and intensity of drug therapy is determined according to baseline low-density lipoprotein (LDL-C) levels and the target LDL-C concentration appropriate to the individual. LDL-C treatment targets are based on pre-treatment risk and are as follows: <3 mmol/L in low- and moderate risk cases; <2.5 mmol/L and a reduction of at least 50% if the baseline concentration is 2.5 - 5.2 mmol/L in high-risk cases; and <1.8 mmol/L and a reduction of at least 50% if the baseline concentration is 1.8 - 3.5 mmol/L in very high-risk cases. A statin is usually recommended first-line; the specific agent is based on the required degree of cholesterol reduction, comorbidities and co-prescribed medication. Special attention should be paid to children with a family history of genetic or severe dyslipidaemia, who should be screened for dyslipidaemia from 8 years of age. In SA, HIV infection is not considered to be a significant cardiovascular risk factor and treatment recommendations for HIV-positive individuals are the same as for the general population, with careful choice of pharmacotherapy to avoid potential adverse drug-drug interactions. The benefit of statins in individuals older than 70 years is uncertain and clinical judgement should be used to guide treatment decisions and to avoid side-effects and overmedication in this group.
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Nicholls, Stephen J. "Management of Severe Dyslipidaemia: Role of PCSK9 Inhibitors." European Cardiology Review 13, no. 1 (2018): 9. http://dx.doi.org/10.15420/ecr.2018.3.2.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulation of LDL receptors on the hepatocyte surface and therefore is essential for effective removal of LDL particles from circulation. Genetic and biochemical studies have established that altered PCSK9 functionality influences both LDL cholesterol levels and cardiovascular risk. This has prompted development of inhibitory strategies targeting PCSK9. Study of monoclonal PCSK9 antibodies has progressed to the clinic, where they have been found to lower LDL cholesterol levels and reduce cardiovascular event rates in large, clinical outcome trials. The use of PCSK9 inhibitors in the setting of dyslipidaemia is reviewed.
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E. Toms, Tracey, Deborah P. Symmons, and George D. Kitas. "Dyslipidaemia in Rheumatoid Arthritis: The Role of Inflammation, Drugs, Lifestyle and Genetic Factors." Current Vascular Pharmacology 8, no. 3 (May 1, 2010): 301–26. http://dx.doi.org/10.2174/157016110791112269.
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Toms, Tracey E. "Dyslipidaemia in Rheumatoid Arthritis: The Role of Inflammation, Drugs, Lifestyle and Genetic Factors." Current Vascular Pharmacology 999, no. 999 (December 15, 2009): 1–13. http://dx.doi.org/10.2174/1570209197581151611.
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Slanovic-Kuzmanović, Zorana, Ivan Kos, and Ana-Marija Domijan. "Endocrine, Lifestyle, and Genetic Factors in the Development of Metabolic Syndrome." Archives of Industrial Hygiene and Toxicology 64, no. 4 (December 1, 2013): 581–91. http://dx.doi.org/10.2478/10004-1254-64-2013-2327.
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Abstract Metabolic syndrome (MetS) is a chronic, multi-component disease characterised by central obesity, hyperglycaemia, dyslipidaemia, and hypertension. Since MetS leads to type 2 diabetes, cardiovascular disease, development of certain cancers, and eventually to premature death, it is not surprising that it draws the attention of scientists around the world. The aetiopathology of MetS is complex and still not fully understood. This review focuses on the role of endocrine factors such as cortisol and insulin in the development of MetS. It also takes a look at some of the contributing lifestyle and genetic factors as well as at the current knowledge about its treatment.
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Fanlo-Maresma, Marta, Virginia Esteve-Luque, Xavier Pintó, Ariadna Padró-Miquel, Emili Corbella, and Beatriz Candás-Estébanez. "Study of common hypertriglyceridaemia genetic variants and subclinical atherosclerosis in a group of women with SLE and a control group." Lupus Science & Medicine 9, no. 1 (August 2022): e000774. http://dx.doi.org/10.1136/lupus-2022-000774.
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ObjectiveSLE is associated with increased cardiovascular risk (CVR). High serum concentrations of triglyceride-rich lipoproteins and apolipoprotein B-rich particles constitute the characteristic dyslipidaemia of SLE.MethodsA cross-sectional study was conducted to study the relationship between genetic variants involved in polygenic hypertriglyceridaemia, subclinical atherosclerosis and lipoprotein abnormalities. 73 women with SLE and 73 control women age-matched with the case group were recruited (age range 30–75 years). Serum analysis, subclinical atherosclerosis screening studies for the detection of plaque, and genetic analysis of the APOE, ZPR1, APOA5 and GCKR genes were performed.ResultsTriglyceride concentrations and the prevalence of hypertension, dyslipidaemia and carotid atherosclerosis were higher in women with SLE than in the control group. Multivariate logistic regression showed that CC homozygosity for the GCKR rs1260326 gene (OR=0.111, 95% CI 0.015 to 0.804, p=0.030) and an increase of 1 mmol/L in triglyceride concentrations were associated with a greater risk of carotid plaque in women with SLE (OR=7.576, 95% CI 2.415 to 23.767, p=0.001).ConclusionsGCKR CC homozygosity (rs1260326) and serum triglyceride concentrations are independently associated with subclinical carotid atherosclerosis in women with SLE. Subclinical carotid atherosclerosis is also more prevalent in these women compared with the control group. The study of GCKR rs1260326 gene variants may contribute to more precise assessment of CVR and modulation of the intensity of lipid-lowering treatment in patients with SLE.
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Mori, Krishna Shantilal, Karthik Balachandran, Adyne Reena Asirvatham, and Shriraam Mahadevan. "‘H-syndrome’: a multisystem genetic disorder with cutaneous clues." BMJ Case Reports 14, no. 5 (May 2021): e238973. http://dx.doi.org/10.1136/bcr-2020-238973.
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We present a case of a 25-year-old man who came to our Endocrine Clinic for evaluation of short stature. He had a history of sensorineural hearing loss, hypertrichosis and hyperpigmentation with the thickening of the skin below the hip, gynecomastia and autoimmune haemolytic anaemia. Investigations showed that he had hypergonadotropic hypogonadism. His phenotype was consistent with that of a rare autosomal recessive genodermatosis of ‘H-syndrome’. The diagnosis was confirmed by genetic analysis using next-generation sequencing which showed a homozygous mutation in the SLC29A3 gene (variant: c.1330G>T (p.Glu444Ter)) which was confirmed by Sanger sequencing. This is a rare syndrome with around 100 cases reported in world literature. Though the skin manifestations are pathognomonic of the H-syndrome, it has myriad presentations like short stature, insulin-dependent diabetes mellitus, hypogonadism, hypothyroidism, dyslipidaemia, cardiac anomalies and sensorineural hearing loss. We report this case to highlight the constellation of features of this rare syndrome and bring awareness among the physicians to be vigilant about this syndrome.
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Toms, Tracey E., Vasileios F. Panoulas, Jacqueline P. Smith, Karen M. J. Douglas, Giorgos S. Metsios, Antonios Stavropoulos-Kalinoglou, and George D. Kitas. "Rheumatoid arthritis susceptibility genes associate with lipid levels in patients with rheumatoid arthritis." Annals of the Rheumatic Diseases 70, no. 6 (March 11, 2011): 1025–32. http://dx.doi.org/10.1136/ard.2010.144634.
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IntroductionRheumatoid arthritis (RA), a systemic inflammatory disease with complex genetic aetiology, associates with excess cardiovascular morbidity and mortality. Dyslipidaemia, a major cardiovascular risk factor has been reported to predate the onset of RA, thus suggesting a potential genetic link between the two conditions. The authors assessed whether RA susceptibility genes associate with the presence of dyslipidaemia in RA patients.Methods400 well-characterised RA patients were included in this cross-sectional study. Fasting lipid profile (total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), triglycerides, apolipoproteins (ApoA and ApoB) and lipoprotein (a)) and four RA susceptibility genes (PTPN22, TRAF1/C5, STAT4 and human leucocyte antigen shared epitope (HLA-SE)) were assessed and associations were sought in both univariate and multivariate analyses.ResultsFollowing adjustment for age, sex and erythrocyte sedimentation rate, the G allele of TRAF1/C5 associated with lower total cholesterol (p=0.010), LDL (p=0.022) and ApoB (p=0.014); one or more copies of the shared epitope associated with lower ApoA (p=0.035) and higher ApoB:ApoA ratio (p=0.047); while STAT4 TT homozygotes had higher lipoprotein (a) (p=0.004).ConclusionsRA susceptibility genes (TRAF1/C5, STAT4 and HLA-DRB1-SE) may be involved in the regulation of lipid metabolism in RA patients, thus contributing to cardiovascular disease (CVD) risk and adverse outcome. If these findings are replicated, such genotyping could be used to identify and target for prevention those RA patients most at risk of CVD. It will also be interesting to study the association of these genes with lipid levels in the general population and identify mechanisms to explain the link.
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Phipps, Meaghan, and Julia Wattacheril. "Non-alcoholic fatty liver disease (NAFLD) in non-obese individuals." Frontline Gastroenterology 11, no. 6 (December 13, 2019): 478–83. http://dx.doi.org/10.1136/flgastro-2018-101119.
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Individuals with non-alcoholic fatty liver disease (NAFLD) who lack classical risk factors also have the ability to develop nonalcoholic steatohepatitis (NASH) and progression to more advanced liver disease. The pathophysiology and risk factors for the development of NAFLD in non-obese persons are not fully understood but seem to be closely related to insulin resistance, atherogenic dyslipidaemia and alterations in body composition, with some patients harbouring predisposing genetic polymorphisms. In normal-weight individuals, also called ‘lean’, there is limited potential for effective lifestyle change in disease management. Additionally, biological mechanisms underlying the development of NASH in non-obese individuals may reveal novel targets for intervention. In this review, the authors discuss the clinical, histological and genetic features and risk factors for non-obese NAFLD and highlight gaps in knowledge and areas for future research.
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Ma, Doris, Jessica F. Romine, and Michael Hardcastle. "Cutaneous xanthoma causing hypercalcaemia in a cat." Journal of Feline Medicine and Surgery Open Reports 8, no. 1 (January 2022): 205511692210820. http://dx.doi.org/10.1177/20551169221082050.
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Case summary A 5-year-old male neutered cat weighing 3.56 kg presented owing to the development of two masses over the dorsal cervical and cranial thoracic areas, as well as weight loss, inappetence and vomiting. Diagnostic tests revealed a grossly lipaemic sample with hypercholesterolaemia (440 mg/dl; reference interval [RI] 90.0–205.0), hypercalcaemia (>16.0 mg/dl [RI 8.0–11.8]) and urine specific gravity 1.022 (RI ⩾1.035). When re-presented 9 months later, fasted blood analyses revealed elevated ionised calcium (1.87 mmol/l [RI 1.11–1.38]), persistently elevated total calcium, normal phosphate and persistent minimally concentrated urine with calcium oxalate dihydrate crystals. Ultrasound-guided fine-needle aspiration of the masses produced blood-tinged purulent fluid with negative culture results. Excisional biopsies of both masses were undertaken, and histopathology was consistent with cutaneous xanthoma. No organisms were identified with special staining, and deep-tissue culture did not grow bacteria or fungi. Postoperatively, repeat fasted biochemical analysis revealed persistent hypercholesterolaemia with normal triglycerides, and normalisation of ionised and total calcium levels. Based on these findings, a diagnosis of cutaneous xanthoma causing hypercalcaemia due to primary dyslipidaemia was made. The cat was reported to be significantly improved in comfort and energy levels postoperatively and a transition to a fat-restricted diet was instituted. Eight months after xanthoma removal no recurrence was reported. Relevance and novel information To our knowledge, this is the first report of cutaneous xanthoma and associated granulomatous inflammation causing hypercalcaemia due to dyslipidaemia in a cat. Familial hypercholesterolaemia is an example of a primary condition that could cause dyslipidaemia in cats, and further studies are warranted to better describe the genetic characteristics. Xanthoma formation and the resultant granulomatous inflammation should be considered in cases of hypercalcaemia.
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Tanyanyiwa, Donald Moshen, Philani Ernest Buthelezi, Collet Dandara, and Sandeep Amrat Bhana. "ApoE genetic variation is associated with differential susceptibility to dyslipidaemia and type 2 diabetes in black Africans." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.00624.
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Chan, L., and K. Kobayashi. "Molecular basis and promise of genetic therapy for diabetic dyslipidaemia: studies in an animal model of diabetes." Diabetologia 40 (June 20, 1997): S155—S156. http://dx.doi.org/10.1007/s001250051436.
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Costache, Irina Iuliana, Florin Mitu, Razan Al Namat, Iuliu Ivanov, Roxana Popescu, Ovidiu Mitu, Alexandru Dan Costache, and Ana Clara Aprotosoaie. "Is There a Link Between Clopidogrel Resistance and Common Risk Factors for Atherosclerosis in Patients with Acute Coronary Syndrome?" Revista de Chimie 68, no. 11 (December 15, 2017): 2726–30. http://dx.doi.org/10.37358/rc.17.11.5963.
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The antiplatelet effect of clopidogrel prodrug is characterized by a wide inter-individual variability that has a significant clinical relevance. Among varios factors that are involved in the occurrence of clopidogrel resistance, the genetic polymorphisms play a key role. The aim of the present study was to investigate the impact of some risk factors for atherosclerosis on the antiplatelet effect of clopidogrel in patients with acute coronary syndrome and the possible correlation with metabolizer phenotype of patients based on CYP2C19 polymorfisms. We found a statistically significant correlation (p value [ 0.05) between smoking or dyslipidaemia and the presence of ultrarapid metabolizer phenotype for clopidogrel in our research population.
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Verma, Anita, Sanjay Shete, Gururaj Doddoli, Ritu Prasad, and Ranjeet Singh Bhogal. "Short-term combined therapy of yoga, ayurveda and naturopathy for dyslipidaemia: a case report." Integrative Medicine Case Reports 4, no. 1 (2023): 26. http://dx.doi.org/10.38205/imcr.040126.
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Hyperlipidemia is a condition which comprises several acquired and genetic disorders that cause elevated lipid levels in the body. The elevated lipids may further lead to various health complications such as arteriosclerosis, cardiovascular disease, cerebrovascular and peripheral vascular diseases. A 41-year-old male, non-alcoholic, non-smoking, vegetarian, and self-employed patient reported with chronic abnormally high level of lipids. The patient was assessed on day 1, day 18 and after completion of 25 days of Ayurveda and naturopathy therapy for hyperlipidemia. In spite of suffering from hyperlipidemia, the patient was not having any associated complaints; therefore he was prescribed an integrated therapy of yoga, Ayurveda and Naturopathy. The results of present case report showed substantial reduction in cholesterol and triglycerides levels with three weeks of yoga, Ayurveda, and Naturopathy treatment. The patient was not prescribed any concomitant allopathic medications during the treatment period. The case study concluded that combined alternative therapies of yoga, Ayurveda and Naturopathy have helped in substantial reduction of abnormal levels of lipids in a short duration of three weeks.
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Rašiová, Mária, Martin Koščo, Ľubomír Špak, Matej Moščovič, Jozef Židzik, Eva Slabá, Viera Habalová, Ľudmila Farkašová, Marek Hudák, and Ivan Tkáč. "Higher preprocedural fibrinogen levels are associated with aneurysm sac regression after EVAR." Vasa 48, no. 4 (July 1, 2019): 347–54. http://dx.doi.org/10.1024/0301-1526/a000783.
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Summary. Background: The aim of our study was to determine the diameter of the aneurysm sac 24 months after endovascular abdominal aortic aneurysm repair (EVAR); to identify factors associated with sac regression, and to determine the impact of sac regression on all-cause mortality during long-term follow-up. Patients and methods: We conducted a retrospective review of prospectively collected data from patients treated with EVAR between January, 2010 and July, 2016. Sac regression was defined as at least 5 mm decrease in aneurysm diameter in relation to the preprocedural diameter seen on computed tomography angiography. Sociodemographic information, comorbidities, treatment, laboratory parameters, selected anatomical and genetic factors were all analysed to determine their impact on sac regression. Results: During the study period, 124 patients with mean age of 71.2 ± 7.2 years met the inclusion criteria. Sac regression was found in 45.2% of patients. Higher preprocedural fibrinogen was found in patients with sac regression in comparison with patients with stable sac or sac expansion (3.84 g/l vs 3.47 g/l; p = 0.028). In multivariate analysis after adjustment for age, hypertension, sex, smoking, dyslipidaemia, volume and percentage of intraluminal thrombus higher fibrinogen was associated with an increased probability of sac regression (OR 2.47; 95% CI 1.29–4.72; p = 0.006). Persistent type II endoleak was associated with significantly lower probability of sac regression in univariate and multivariate analysis after adjustment for age, hypertension, sex, smoking and dyslipidaemia (OR 0.26; 95% CI 0.10–0.66; p = 0.004). Higher age was a significant predictor of sac regression in multivariate analysis after adjustment for hypertension, sex, smoking and dyslipidaemia (OR 1.07; 95% CI 1.02–1.14; p = 0.012). No difference was found between patient subgroups with and without sac regression in all-cause mortality during follow-up. Conclusions: Higher preprocedural fibrinogen, absence of persistent type II endoleak and higher age were predictive factors of aneurysm sac regression post-EVAR.
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OKUNO, SHIRO, TAKESHI K. WATANABE, TOSHIHIDE ONO, KEIKO OGA, AYAKO MIZOGUCHI-MIYAKITA, YUKI YAMASAKI, YOSHIHIRO GOTO, et al. "Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain." Genetical Research 77, no. 2 (April 2001): 183–90. http://dx.doi.org/10.1017/s0016672301004918.
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Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.
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Wuni, Ramatu, Evelyn Adela Nathania, Ashok K. Ayyappa, Nagarajan Lakshmipriya, Kandaswamy Ramya, Rajagopal Gayathri, Gunasekaran Geetha, et al. "Impact of Lipid Genetic Risk Score and Saturated Fatty Acid Intake on Central Obesity in an Asian Indian Population." Nutrients 14, no. 13 (June 29, 2022): 2713. http://dx.doi.org/10.3390/nu14132713.
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Abnormalities in lipid metabolism have been linked to the development of obesity. We used a nutrigenetic approach to establish a link between lipids and obesity in Asian Indians, who are known to have a high prevalence of central obesity and dyslipidaemia. A sample of 497 Asian Indian individuals (260 with type 2 diabetes and 237 with normal glucose tolerance) (mean age: 44 ± 10 years) were randomly chosen from the Chennai Urban Rural Epidemiological Study (CURES). Dietary intake was assessed using a previously validated questionnaire. A genetic risk score (GRS) was constructed based on cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genetic variants. There was a significant interaction between GRS and saturated fatty acid (SFA) intake on waist circumference (WC) (Pinteraction = 0.006). Individuals with a low SFA intake (≤23.2 g/day), despite carrying ≥2 risk alleles, had a smaller WC compared to individuals carrying <2 risk alleles (Beta = −0.01 cm; p = 0.03). For those individuals carrying ≥2 risk alleles, a high SFA intake (>23.2 g/day) was significantly associated with a larger WC than a low SFA intake (≤23.2 g/day) (Beta = 0.02 cm, p = 0.02). There were no significant interactions between GRS and other dietary factors on any of the measured outcomes. We conclude that a diet low in SFA might help reduce the genetic risk of central obesity confirmed by CETP and LPL genetic variants. Conversely, a high SFA diet increases the genetic risk of central obesity in Asian Indians.
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Vitale, Salvatore Giovanni, Antonio Simone Laganà, Angela Nigro, Valentina Lucia La Rosa, Paola Rossetti, Agnese Maria Chiara Rapisarda, Sandro La Vignera, et al. "Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions." PPAR Research 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/6517313.
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The prevalence of obesity and metabolic diseases (such as type 2 diabetes mellitus, dyslipidaemia, and cardiovascular diseases) has increased in the last decade, in both industrialized and developing countries. This also coincided with our observation of a similar increase in the prevalence of cancers. The aetiology of these diseases is very complex and involves genetic, nutritional, and environmental factors. Much evidence indicates the central role undertaken by peroxisome proliferator-activated receptors (PPARs) in the development of these disorders. Due to the fact that their ligands could become crucial in future target-therapies, PPARs have therefore become the focal point of much research. Based on this evidence, this narrative review was written with the purpose of outlining the effects of PPARs, their actions, and their prospective uses in metabolic diseases and cancers.
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Schellack, Natalie, Gustav Schellack, and E. Bronkhorst. "The role of proprotein convertase subtilisin/kexin type 9 inhibitors in managing cardiovascular risk." South African Family Practice 58, no. 1 (January 1, 2016): 4. http://dx.doi.org/10.4102/safp.v58i1.4439.
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Hypercholesterolaemia and dyslipidaemia, marked by decreased levels of high-density lipoprotein and elevated levels of lowdensity lipoprotein (LDL), increase the risk of cardiovascular disease. Familial hypercholesterolaemia (FH), diagnosed based on the clinical features seen in patients with a positive family history, constitutes a heritable disorder involving a single gene. FH can exist in either the heterozygous or homozygous form, and may be differentiated based on clinical features and genetic studies. A novel drug target, proprotein convertase subtilisin/kexin type 9 (PCSK9), has resulted in the development and subsequent approval of new, targeted monoclonal antibodies in the treatment of FH. Targeting PCSK9 with monoclonal antibodies, i.e. evolocumab and alirocumab, inhibits the degradation of LDL receptors, and against a background of optimised statin therapy, increases the life expectancy of patients with hypercholesterolaemia by reducing the incidence and severity of coronary artery disease.
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Groop, Leif. "Genetics of the metabolic syndrome." British Journal of Nutrition 83, S1 (June 2000): S39—S48. http://dx.doi.org/10.1017/s0007114500000945.
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The clustering of cardiovascular risk factors such as abdominal obesity, hypertension, dyslipidaemia and glucose intolerance in the same persons has been called the metabolic or insulin-resistance syndrome. In 1998 WHO proposed a unifying definition for the syndrome and chose to call it the metabolic syndrome rather than the insulin-resistance syndrome. Although insulin resistance has been considered as a common denominator for the different components of the syndrome, there is still debate as to whether it is pathogenically involved in all of the different components of the syndrome. Clustering of the syndrome in families suggests a genetic component. It is plausible that so-called thrifty genes, which have ensured optimal storage of energy during periods of fasting, could contribute to the phenotype of the metabolic syndrome. Common variants in a number of candidate genes influencing fat and glucose metabolism can probably, together with environmental triggers, increase susceptibility to the syndrome. Among these, the genes for β3-adrenergic receptor, hormone-sensitive lipase, lipoprotein lipase, IRS-1, PC-1, skeletal muscle glycogen synthase, etc. appear to increase the risk of the metabolic syndrome. In addition, novel genes may be identified by genome-wide searches.
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Zhou, Jun-Yu, Mi Young Song, and Sunmin Park. "Carbohydrate and sodium intake and physical activity interact with genetic risk scores of four genetic variants mainly related to lipid metabolism to modulate metabolic syndrome risk in Korean middle-aged adults." British Journal of Nutrition 122, no. 8 (September 23, 2019): 919–27. http://dx.doi.org/10.1017/s0007114519001752.
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AbstractMetabolic syndrome (MetS) risk is influenced by genetic and environmental factors. The present study explored genetic risk scores (GRS) of genetic variants that influence the MetS and the effect of interactions between GRS and nutrient intake on MetS risk. The genetic variants that influence MetS risk were selected by genome-wide association study after adjusting for age, sex, area of residence and BMI in 8840 middle-aged adults. GRS were calculated by summing the risk alleles of the selected SNP and divided into low (0–1), medium (2–3) and high (4–7) risk groups, and the relationships between the MetS and GRS were determined by logistic regression after adjusting covariates involved in MetS risk. We also analysed the interaction between GRS and lifestyles. Four genetic variants (APOA5_rs651821, EFCAB4B_rs4766165, ZNF259_rs2160669 and APOBEC1_rs10845640) were selected because they increased MetS risk after adjusting for covariates. Individuals with medium-GRS and high-GRS alleles had a higher MetS risk by 1·48- and 2·23-fold, respectively, compared with those with low-GRS after adjusting for covariates. The increase in MetS risk was mainly related to serum TAG and HDL-cholesterol concentrations. The GRS had an interaction with carbohydrate (CHO) and Na intakes and daily physical activities for MetS risk. In conclusion, Asian middle-aged adults with high-GRS alleles were at increased MetS risk mainly due to dyslipidaemia. High daily physical activity (≥1 h moderate activity per d) reduced the MetS risk but a low-CHO diet (<65 % of total energy intake) increased the risk in carriers with high-GRS alleles. Low Na intake (<1·6 g Na intake/4 MJ) did not decrease its risk.
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Osman, Wael M., Herbert F. Jelinek, Guan K. Tay, Ahsan H. Khandoker, Kinda Khalaf, Wael Almahmeed, Mohamed H. Hassan, and Habiba S. Alsafar. "Clinical and genetic associations of renal function and diabetic kidney disease in the United Arab Emirates: a cross-sectional study." BMJ Open 8, no. 12 (December 2018): e020759. http://dx.doi.org/10.1136/bmjopen-2017-020759.
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ObjectivesWithin the Emirati population, risk factors and genetic predisposition to diabetic kidney disease (DKD) have not yet been investigated. The aim of this research was to determine potential clinical, laboratory and reported genetic loci as risk factors for DKD.Research design and methodsFour hundred and ninety unrelated Emirati nationals with type 2 diabetes mellitus (T2DM) were recruited with and without DKD, and clinical and laboratory data were obtained. Following adjustments for possible confounders, a logistic regression model was developed to test the associations of 63 single nucleotide polymorphisms (SNPs) in 43 genetic loci with DKD (145 patients with DKD and 265 without DKD). Linear regression models, adjusted for age and gender, were then used to study the genetic associations of five renal function traits, including 83 SNPs with albumin-to-creatinine ratio, 92 SNPs with vitamin D (25-OH cholecalciferol), 288 SNPs with estimated glomerular filtration rate (eGFR), 363 SNPs with serum creatinine and 73 SNPs with blood urea.ResultsPatients with DKD, as compared with those without the disease, were mostly men (52%vs38% for controls), older (67vs59 years) and had significant rates of hypertension and dyslipidaemia. Furthermore, patients with DKD had T2DM for a longer duration of time (16vs10 years), which in an additive manner was the single factor that significantly contributed to the development of DKD (p=0.02, OR=3.12, 95% CI 1.21 to 8.02). Among the replicated associations of the genetic loci with different renal function traits, the most notable includedSHROOM3with levels of serum creatinine, eGFR and DKD (Padjusted=0.04, OR=1.46);CASR,GCandCYP2R1with vitamin D levels; as well asWDR72with serum creatinine and eGFR levels.ConclusionsAssociations were found between several genetic loci and risk markers for DKD, which may influence kidney function traits and DKD in a population of Arab ancestry.
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Kuzova, Elena, Tzveta Georgieva, and Vesselka Duleva. "FADS1 genetic variant rs174547 as a molecular-genetic biomarker for CVD risk: A study from Bulgaria." Hrana i ishrana 62, no. 1 (2021): 15–27. http://dx.doi.org/10.5937/hraish2101015k.
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The input of molecular genetic biomarkers allows individual assessment of metabolic pathways and the behaviour of the major enzymes responsible for nutrient conversion. This in turn enriches the nutrigenetic information fund, and the panels of well-studied gene variants and their interaction with nutrients can be used to create precise personalized diets. Our objective was to determine the significance of the rs174547 genetic variant in the fatty acid desaturase 1 (FADS1) gene in the metabolism of saturated and unsaturated fatty acids ingested with food and to identify the potential of FADS1 rs174547 as a molecular genetic marker to be included in a panel of nutrigenetic studies in order to prepare a personalized diet plan. A total of 123 volunteers (43 men and 80 women) from Bulgaria, aged 28 to 65 years, were tested for rs174547 in the FADS1 gene. A DNA sample was taken from each volunteer by a non-invasive method (buccal swabs), and the genetic variant of each individual was determined by molecular genetic approaches. Their general health was assessed by taking anthropometric and body impedance measurements data and completing a lifestyle survey. The lipid profile included testing for triglycerides, total cholesterol, HDL and LDL cholesterol, and blood sugar. Information on the total food intake was collected through questionnaire methods. The results of the statistical tests show that there is a statistically significant difference between the two genotypes only in HDL cholesterol levels (P = 0.044, at P < 0.05) - carriers of the C/T genotype have lower mean concentration values of HDL-cholesterol (1.27 mmol/l) than for T/T variant carriers (1.48 mmol/l). Among men, there were statistically significant differences in mean levels of total cholesterol (P = 0.012) and HDL cholesterol (P = 0.008) between the two genotypes. Among women, there was a statistically significant difference between the two genotypes only in terms of mean triglyceride levels (P = 0.007). The differences in the other studied indicators do not satisfy the criterion for significance (P < 0.05). The results suggest an effect of the intake of SFA (saturated fatty acids) and MUFA (monounsaturated fatty acids) on the relationship between rs174547 polymorphism and plasma lipids (total and LDL-cholesterol) only in men. Studies of the Bulgarian population prove extremely low intake of omega-3 fatty acids due to low consumption of fish. These findings and the lack of data for Bulgaria on genetic variants of FADS1 are a prerequisite for conducting in-depth studies of both risk groups, such as patients with cardiovascular disease, dyslipidaemia or nutritional deficiency of LC-PUFAs, and in healthy people.
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Soffientini, Ugo, and Annette Graham. "Intracellular cholesterol transport proteins: roles in health and disease." Clinical Science 130, no. 21 (September 22, 2016): 1843–59. http://dx.doi.org/10.1042/cs20160339.
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Effective cholesterol homoeostasis is essential in maintaining cellular function, and this is achieved by a network of lipid-responsive nuclear transcription factors, and enzymes, receptors and transporters subject to post-transcriptional and post-translational regulation, whereas loss of these elegant, tightly regulated homoeostatic responses is integral to disease pathologies. Recent data suggest that sterol-binding sensors, exchangers and transporters contribute to regulation of cellular cholesterol homoeostasis and that genetic overexpression or deletion, or mutations, in a number of these proteins are linked with diseases, including atherosclerosis, dyslipidaemia, diabetes, congenital lipoid adrenal hyperplasia, cancer, autosomal dominant hearing loss and male infertility. This review focuses on current evidence exploring the function of members of the ‘START’ (steroidogenic acute regulatory protein-related lipid transfer) and ‘ORP’ (oxysterol-binding protein-related proteins) families of sterol-binding proteins in sterol homoeostasis in eukaryotic cells, and the evidence that they represent valid therapeutic targets to alleviate human disease.
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O'Nunain, Katie, Eleanor Sanderson, Michael Holmes, George Davey Smith, and Tom Richardson. "A genome-wide association study of childhood adiposity and blood lipids." Wellcome Open Research 6 (November 10, 2021): 303. http://dx.doi.org/10.12688/wellcomeopenres.16928.1.
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Background: The rising prevalence of childhood obesity and dyslipidaemia is a major public health concern due to its association with morbidity and mortality in later life. Methods: In this study, we have conducted genome-wide association studies (GWAS) for eight measures of adiposity and lipids in a cohort of young individuals (mean age 9.9) from the Avon Longitudinal Study of Parents and Children (ALSPAC). These measures were body mass index (BMI), systolic and diastolic blood pressure, high- density and low-density lipoprotein cholesterol, triglycerides, apolipoprotein A-I and apolipoprotein B. We next undertook functional enrichment, pathway analyses and linkage disequilibrium (LD) score regression to evaluate genetic correlations with later-life cardiometabolic diseases. Results: Using GWAS we identified 14 unique loci associated with at least one risk factor in this cohort of age 10 individuals (P<5x10-8), with lipoprotein lipid-associated loci being enriched for liver tissue-derived gene expression and lipid synthesis pathways. LD score regression provided evidence of various genetic correlations, such as childhood systolic blood pressure being genetically correlated with later-life coronary artery disease (rG=0.26, 95% CI=0.07 to 0.46, P=0.009) and hypertension (rG=0.37, 95% CI=0.19 to 0.55, P=6.57x10-5), as well as childhood BMI with type 2 diabetes (rG=0.35, 95% CI=0.18 to 0.51, P=3.28x10-5). Conclusions: Our findings suggest that there are genetic variants inherited at birth which begin to exert their effects on cardiometabolic risk factors as early as age 10 in the life course. However, further research is required to assess whether the genetic correlations we have identified are due to direct or indirect effects of childhood adiposity and lipid traits.
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Roche, Helen M., Catherine Phillips, and Michael J. Gibney. "The metabolic syndrome: the crossroads of diet and genetics." Proceedings of the Nutrition Society 64, no. 3 (August 2005): 371–77. http://dx.doi.org/10.1079/pns2005445.
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The metabolic syndrome is a very common disease associated with an increased risk of type 2 diabetes mellitus (T2DM) and CVD. The clinical characteristics of the metabolic syndrome include insulin resistance, dyslipidaemia, abdominal obesity and hypertension. The diverse clinical characteristics illustrate the complexity of the disease process, which involves several dysregulated metabolic pathways. Thus, multiple genetic targets must be involved in the pathogenesis and progression of the metabolic syndrome. Nevertheless, the human genome has not changed markedly in the last decade but the prevalence of the metabolic syndrome has increased exponentially, which illustrates the importance of gene–environmental interactions. There is good evidence that nutrition plays an important role in the development and progression of the metabolic syndrome. Indeed, obesity is a key aetiological factor in the development of the metabolic syndrome. Understanding the biological impact of gene–nutrient interactions will provide a key insight into the pathogenesis and progression of diet-related polygenic disorders, including the metabolic syndrome. The present paper will explore the interactions between genetic background and dietary exposure or nutritional therapy, focusing on the role of dietary fatty acids within the context of nutrient regulation of gene expression and individual responsiveness to dietary therapy. Only with a full understanding of gene–gene, gene–nutrient and gene–nutrient–environment interactions can the molecular basis of the metabolic syndrome be solved to minimise the adverse health effects of obesity and reduce the risk of the metabolic syndrome, and subsequent T2DM and CVD.
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Sulaiman, Raashda A. "Inherited metabolic disorders and dyslipidaemia." Journal of Clinical Pathology 73, no. 7 (November 22, 2019): 384–90. http://dx.doi.org/10.1136/jclinpath-2019-205910.
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Monogenic dyslipidaemia is a diverse group of multisystem disorders. Patients may present to various specialities from early childhood to late in adult life, and it usually takes longer before the diagnosis is established. Increased awareness of these disorders among clinicians is imperative for early diagnosis. This best practice review provides an overview of primary dyslipidaemias, highlighting their clinical presentation, relevant biochemical and molecular tests. It also addresses the emerging role of genetics in the early diagnosis and prevention of these disorders.
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Semple, R. K. "EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons." European Journal of Endocrinology 174, no. 5 (May 2016): R209—R223. http://dx.doi.org/10.1530/eje-15-1131.
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Insulin orchestrates physiological responses to ingested nutrients; however, although it elicits widely ramifying metabolic and trophic responses from diverse tissues, ‘insulin resistance (IR)’, a pandemic metabolic derangement commonly associated with obesity, is usually defined solely by blunting of insulin's hypoglycaemic effect. Recent study of monogenic forms of IR has established that biochemical subphenotypes of IR exist, clustering into those caused by primary disorders of adipose tissue and those caused by primary defects in proximal insulin signalling. IR is often first recognised by virtue of its associated disorders including type 2 diabetes, dyslipidaemia (DL), fatty liver and polycystic ovary syndrome (PCOS). Although these clinically observed associations are confirmed by cross-sectional and longitudinal population-based studies, causal relationships among these phenomena have been more difficult to establish. Single gene IR is important to recognise in order to optimise clinical management and also permits testing of causal relationships among components of the IR syndrome using the principle of Mendelian randomisation. Thus, where a precisely defined genetic defect is identified that directly produces one component of the syndrome, then phenomena that are causally linked to that component should be seen. Where this is not the case, then a simple causal link is refuted. This article summarises known forms of monogenic severe IR and considers the lessons to be learned about the pathogenic mechanisms both upstream from common IR and those downstream linking it to disorders such as DL, fatty liver, PCOS and cancer.
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Yuan, Xun, Andreas Mitsis, and Christoph A. Nienaber. "Current Understanding of Aortic Dissection." Life 12, no. 10 (October 14, 2022): 1606. http://dx.doi.org/10.3390/life12101606.
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The aorta is the largest artery in the body, delivering oxygenated blood from the left ventricle to all organs. Dissection of the aorta is a lethal condition caused by a tear in the intimal layer of the aorta, followed by blood loss within the aortic wall and separation of the layers to full dissection. The aorta can be affected by a wide range of causes including acute conditions such as trauma and mechanical damage; and genetic conditions such as arterial hypertension, dyslipidaemia, and connective tissue disorders; all increasing the risk of dissection. Both rapid diagnostic recognition and advanced multidisciplinary treatment are critical in managing aortic dissection patients. The treatment depends on the severity and location of the dissection. Open surgical repair is the gold standard of treatment for dissections located to the proximal part of the aorta and the arch, while endovascular interventions are recommended for most distal or type B aortic dissections. In this review article, we examine the epidemiology, pathophysiology, contemporary diagnoses, and management of aortic dissection.
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Devynck, Marie-Aude, J. Kuneš, Kim Hanh Le Quan Sang, and J. Zicha. "Membrane Microviscosity and Plasma Triacylglycerols in the Rat." Clinical Science 94, no. 1 (January 1, 1998): 79–85. http://dx.doi.org/10.1042/cs0940079.
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1. Multiple cell membrane alterations have been described in humans and animals with various genetic forms of hypertension and/or dyslipidaemia. The aim of our study was to characterize membrane microviscosity, using two different fluorescent probes exploring either the outer membrane leaflet [trimethylamino-diphenylhexatriene (TMA-DPH)] or the lipid membrane core [diphenylhexatriene (DPH)], in platelets and erythrocytes of genetically hypertensive rats of the Prague hereditary hypertriglyceridaemic (HTG) strain. The relationships of membrane microviscosity to hypertension, hypertriglyceridaemia and cell calcium handling were also investigated. 2. Membrane microviscosity was similar in HTG and normotensive control Wistar rats when measured in platelets or erythrocyte ghosts incubated in Na+-containing medium. On the contrary, TMA-DPH fluorescence anisotropy was significantly reduced in HTG platelets incubated in Na+-free medium because external Na+ removal elicited a larger rise of TMA-DPH anisotropy in Wistar platelets. 3. Plasma triacylglycerols were associated positively with platelet TMA-DPH anisotropy and negatively with DPH anisotropy in both strains. The slopes of these relationships were reduced in HTG compared with Wistar rats. Platelet TMA-DPH anisotropy correlated positively and DPH anisotropy negatively with the cytosolic calcium concentration in unstimulated platelets, the slopes being almost identical in both strains. 4. Pulse pressure correlated negatively with TMA-DPH anisotropy and positively with DPH anisotropy found in erythrocyte ghosts. 5. The present results suggest that plasma triacylglycerols and cytosolic calcium are capable of modulating the membrane microviscosity in this new animal model of genetic hypertension associated with hypertriglyceridaemia.
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de Melo, Anderson Sanches, Sabrine Vilan Dias, Ricardo de Carvalho Cavalli, Viviane Cunha Cardoso, Heloisa Bettiol, Marco Antonio Barbieri, Rui Alberto Ferriani, and Carolina Sales Vieira. "Pathogenesis of polycystic ovary syndrome: multifactorial assessment from the foetal stage to menopause." REPRODUCTION 150, no. 1 (July 2015): R11—R24. http://dx.doi.org/10.1530/rep-14-0499.
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Polycystic ovary syndrome (PCOS) is a multifactorial disorder that arises from interactions between genetic, environmental and intra-uterine factors. Small-for-gestational-age (SGA) babies and the daughters of mothers with PCOS represent possible postnatal clinical targets for developmental programming by steroid excess. The presence of excess glucocorticoids and/or androgens during foetal organogenesis and growth might promote changes in gene expression, and these changes might be related to an increase in the risk of PCOS-like reproductive and metabolic disorders in postnatal life, such as rapid growth and weight gain during the first 2 years of life (only in SGA babies), hyperinsulinaemia, adipocyte dysfunction and childhood visceral obesity, premature pubarche and adrenarche (only in SGA babies) and PCOS. In the fourth decade of life, women who have PCOS may be at higher risk for type 2 diabetes mellitus, dyslipidaemia and systemic arterial hypertension, which suggests that these women are also at higher risk for cardiovascular disease during menopause. However, PCOS can also occur in women who were born at appropriate weight for GA or in newborns of women without PCOS, which suggests that genetic variation and environmental factors play important roles in the development and maintenance of PCOS in a population. Genome-wide association studies based on adequate population samples have shown a higher frequency of genetic polymorphisms of the LHCGR, THADA and DENND1A genes in women with PCOS. Genetic studies of PCOS have also included analyses of structural changes in the chromosome based on an assessment of telomere length in single, cross-sectional evaluations, and these studies have produced controversial results. The present narrative review assesses the multifactorial origins of PCOS (including environmental, genetic and intra-uterine factors) and the development of conditions associated with this disorder. It is concluded that although PCOS might originate in the intra-uterine environment through developmental programming by steroid excess, the interaction between genetic and environmental factors is crucial for its appearance. Follow-up studies should be conducted to assess the same populations over their entire lifespans while taking into account different aspects of the pathogenesis of PCOS.
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Ferland-McCollough, David, Susan E. Ozanne, Kenneth Siddle, Anne E. Willis, and Martin Bushell. "The involvement of microRNAs in Type 2 diabetes." Biochemical Society Transactions 38, no. 6 (November 24, 2010): 1565–70. http://dx.doi.org/10.1042/bst0381565.
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T2D (Type 2 diabetes mellitus) is a major health issue that has reached epidemic status worldwide. T2D is a progressive metabolic disorder characterized by reduced insulin sensitivity, insulin resistance and pancreatic β-cell dysfunction. Improper treatment of TD2 can lead to severe complications such as heart disease, stroke, kidney failure, blindness and nerve damage. The aetiology and molecular mechanisms of T2D are not fully understood, but compelling evidence points to a link between T2D, obesity, dyslipidaemia and insulin resistance. Although T2D seems to be strongly linked to environmental factors such as nutrition and lifestyle, studies have shown that genetic factors, such as polymorphisms associated with metabolic genes, imprinting, fetal programming and miRNA (microRNA) expression, could also contribute to the development of this disease. miRNAs are small 22–25-nt-long untranslated RNAs that negatively regulate the translation of mRNAs. miRNAs are involved in a large number of biological functions such as development, metabolism, immunity and diseases such as cancer, cardiovascular diseases and diabetes. The present review examines the various miRNAs that have been identified as being potentially involved in T2D, focusing on the insulin-sensitive organs: white adipose tissue, liver, skeletal muscle and the insulin-producing pancreatic β-cells.
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Larrea-Sebal, Asier, Chiara Trenti, Shifa Jebari-Benslaiman, Stefano Bertolini, Sebastiano Calandra, Emanuele A. Negri, Efrem Bonelli, et al. "Functional Characterization of p.(Arg160Gln) PCSK9 Variant Accidentally Found in a Hypercholesterolemic Subject." International Journal of Molecular Sciences 24, no. 4 (February 7, 2023): 3330. http://dx.doi.org/10.3390/ijms24043330.
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Familial hypercholesterolaemia (FH) is an autosomal dominant dyslipidaemia, characterised by elevated LDL cholesterol (LDL-C) levels in the blood. Three main genes are involved in FH diagnosis: LDL receptor (LDLr), Apolipoprotein B (APOB) and Protein convertase subtilisin/kexin type 9 (PCSK9) with genetic mutations that led to reduced plasma LDL-C clearance. To date, several PCSK9 gain-of-function (GOF) variants causing FH have been described based on their increased ability to degrade LDLr. On the other hand, mutations that reduce the activity of PCSK9 on LDLr degradation have been described as loss-of-function (LOF) variants. It is therefore important to functionally characterise PCSK9 variants in order to support the genetic diagnosis of FH. The aim of this work is to functionally characterise the p.(Arg160Gln) PCSK9 variant found in a subject suspected to have FH. Different techniques have been combined to determine efficiency of the autocatalytic cleavage, protein expression, effect of the variant on LDLr activity and affinity of the PCSK9 variant for the LDLr. Expression and processing of the p.(Arg160Gln) variant had a result similar to that of WT PCSK9. The effect of p.(Arg160Gln) PCSK9 on LDLr activity is lower than WT PCSK9, with higher values of LDL internalisation (13%) and p.(Arg160Gln) PCSK9 affinity for the LDLr is lower than WT, EC50 8.6 ± 0.8 and 25.9 ± 0.7, respectively. The p.(Arg160Gln) PCSK9 variant is a LOF PCSK9 whose loss of activity is caused by a displacement of the PCSK9 P’ helix, which reduces the stability of the LDLr-PCSK9 complex.
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Josiane Gertrude Bindi Ngasse Bwegne, Clarisse Noel Ayina Ayina, Abraham Hermann Bagbila wend Pagnangdé, Noël Babayana Etaga, Quelie Selakong Nzekuie, Macaire Samdpawindé Ouedraogo, Samuel Honoré Mandengue, and Jacqueline Ze Minkande. "Newbouldia’s Laevis biological effects against metabolic syndrome components: A review." World Journal of Advanced Research and Reviews 16, no. 2 (November 30, 2022): 121–38. http://dx.doi.org/10.30574/wjarr.2022.16.2.1104.
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This study focused on a review of existing data on Newbouldia laevis and its potential effects on metabolic syndrome. Progressive changes in lifestyle that promote sedentary lifestyle, nutritional imbalances associated with excessive levels of refined sugars and fat that promote excess calories, and genetic factors have contributed significantly to the increase in cardiovascular disease, diabetes and the emergence of the concept of metabolic syndrome. Metabolic syndrome refers to an aggregation of factors that intervene, most often together, it is defined as a set of biological and clinical disorders whose metabolic aberrations are mainly: Insulin resistance and dysglycemia, obesity (general and abdominal), atherogenic dyslipidaemia, high blood pressure pro-inflammatory and prothrombotic states. The management of metabolic syndrome is very complex, because the components are associated differently in each patient due to the genetic susceptibility of each to develop one component over another, and the many environmental factors influencing the development of the pathology. The African continent is full of a great diversity of plant species, most of which are used by people as medicines to solve their health problems, because they are readily available. The African hyssop or Newbouldia laevis is a plant in the family Bignoniaceae. The qualitative phytochemical screening revealed the presence of alkaloids, tannins, saponins, terpenes, flavonoids, and cardiac glycosides anthraquinones in Newbouldia laevis leaf extract. Several therapeutic properties have been attributed to the plant Newbouldia laevis including anti-hyperglycemic, cardio-protective and hypotensive activity, body weight reduction, anti-inflammatory, antithrombotic, hepato-protective, antiparasitic, antibiotic. Herbal medicine is an alternative way to treat metabolic syndrome, and its importance is growing.
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Marcinkowska, Adrianna, Slawomir Cisiecki, and Marcin Rozalski. "Platelet and Thrombophilia-Related Risk Factors of Retinal Vein Occlusion." Journal of Clinical Medicine 10, no. 14 (July 12, 2021): 3080. http://dx.doi.org/10.3390/jcm10143080.
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Retinal vein occlusion (RVO) is a heterogenous disorder in which the formation of a thrombus results in the retinal venous system narrowing and obstructing venous return from the retinal circulation. The pathogenesis of RVO remains uncertain, but it is believed to be multifactorial and to depend on both local and systemic factors, which can be divided into vascular, platelet, and hypercoagulable factors. The vascular factors include dyslipidaemia, high blood pressure, and diabetes mellitus. Regarding the platelet factors, platelet function, mean platelet volume (MPV), platelet distribution width (PDW), and platelet large cell ratio (PLCR) play key roles in the diagnosis of retinal vein occlusion and should be monitored. Nevertheless, the role of a hypercoagulable state in retinal vein occlusion remains unclear and requires further studies. Therefore, the following article will present the risk factors of RVO associated with coagulation disorders, as well as the acquired and genetic risk factors of thrombophilia. According to Virchow’s triad, all factors mentioned above lead to thrombus formation, which causes pathophysiological changes inside venous vessels in the fundus of the eye, which in turn results in the vessel occlusion. Therefore, a diagnosis of retinal vein occlusion should be based on both eye examination and general examination, including laboratory tests.
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Bauer, Robert C., Batuhan O. Yenilmez, and Daniel J. Rader. "Tribbles-1: a novel regulator of hepatic lipid metabolism in humans." Biochemical Society Transactions 43, no. 5 (October 1, 2015): 1079–84. http://dx.doi.org/10.1042/bst20150101.
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The protein tribbles-1, encoded by the gene TRIB1, is increasingly recognized as a major regulator of multiple cellular and physiological processes in humans. Recent human genetic studies, as well as molecular biological approaches, have implicated this intriguing protein in the aetiology of multiple human diseases, including myeloid leukaemia, Crohn's disease, non-alcoholic fatty liver disease (NAFLD), dyslipidaemia and coronary artery disease (CAD). Genome-wide association studies (GWAS) have repeatedly identified variants at the genomic TRIB1 locus as being significantly associated with multiple plasma lipid traits and cardiovascular disease (CVD) in humans. The involvement of TRIB1 in hepatic lipid metabolism has been validated through viral-mediated hepatic overexpression of the gene in mice; increasing levels of TRIB1 decreased plasma lipids in a dose-dependent manner. Additional studies have implicated TRIB1 in the regulation of hepatic lipogenesis and NAFLD. The exact mechanisms of TRIB1 regulation of both plasma lipids and hepatic lipogenesis remain undetermined, although multiple signalling pathways and transcription factors have been implicated in tribbles-1 function. Recent reports have been aimed at developing TRIB1-based lipid therapeutics. In summary, tribbles-1 is an important modulator of human energy metabolism and metabolic syndromes and worthy of future studies aimed at investigating its potential as a therapeutic target.
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Roche, Helen M. "Fatty acids and the metabolic syndrome." Proceedings of the Nutrition Society 64, no. 1 (February 2005): 23–29. http://dx.doi.org/10.1079/pns2004405.
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The metabolic syndrome is a very common condition, characterised by insulin resistance, dyslipidaemia, abdominal obesity and hypertension, that is associated with a high risk of type 2 diabetes mellitus (T2DM) and CVD. Obesity is a key aetiological factor in the development of the metabolic syndrome. In light of the increasing prevalence of obesity, there is a high requirement to reduce the impact of the adverse health effects associated with the metabolic syndrome. The aetiological role of nutrient-derived metabolic stressors, in particular fatty acids, in the development of obesity and the metabolic syndrome is explored. Also, the evidence that pro-inflammatory stressors may predispose to obesity-induced insulin resistance is reviewed. The present paper explores the concept that reducing the impact of metabolic and inflammatory stressors may reduce the adverse health effects of obesity and slow the progression towards the metabolic syndrome and T2DM. Evidence from human dietary intervention studies that have investigated the potential therapeutic effects of dietary fatty acid modification is explored. The present review highlights the requirement to take account of genetic background, within the context of nutrient regulation of gene expression and individual responsiveness to dietary therapy. This approach will further the understanding of the interaction between fatty acids in the pathogenesis and progression of the metabolic syndrome.
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Moore, J. Bernadette. "Non-alcoholic fatty liver disease: the hepatic consequence of obesity and the metabolic syndrome." Proceedings of the Nutrition Society 69, no. 2 (February 17, 2010): 211–20. http://dx.doi.org/10.1017/s0029665110000030.
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Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease in both adults and children worldwide. As a disease spectrum, NAFLD may progress from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. An estimated 20–35% of the general population has steatosis, 10% of whom will develop the more progressive non-alcoholic steatohepatitis associated with markedly increased risk of cardiovascular- and liver-related mortality. Development of NAFLD is strongly linked to components of the metabolic syndrome including obesity, insulin resistance, dyslipidaemia and type 2 diabetes. The recognition that NAFLD is an independent risk factor for CVD is a major public health concern. There is a great need for a sensitive non-invasive test for the early detection and assessment of the stage of NAFLD that could also be used to monitor response to treatment. The cellular and molecular aetiology of NAFLD is multi-factorial; genetic polymorphisms influencing NAFLD have been identified and nutrition is a modifiable environmental factor influencing NAFLD progression. Weight loss through diet and exercise is the primary recommendation in the clinical management of NAFLD. The application of systems biology to the identification of NAFLD biomarkers and factors involved in NAFLD progression is an area of promising research.
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Dongiovanni, P., L. Valenti, R. Rametta, A. K. Daly, V. Nobili, E. Mozzi, J. B. S. Leathart, et al. "Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease." Gut 59, no. 2 (February 2010): 267–73. http://dx.doi.org/10.1136/gut.2009.190801.
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Background/aimsThe aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance.Patients and methods702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients.ResultsThe ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of ∼70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD.ConclusionsThe ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.
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Liu, Li, Wei Liu, Lulin Nie, Zhiwei Guo, Yi Luo, Weihong Chen, Weimin Liu, et al. "Study design and baseline characteristics of Shenzhen ageing-related disorder cohort in China." BMJ Open 10, no. 6 (June 2020): e034317. http://dx.doi.org/10.1136/bmjopen-2019-034317.
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PurposeThe Shenzhen ageing-related disorder cohort was designed to detect the associations of lifestyle, environmental and genetic factors with major ageing-related disorders, especially neurological and mental disorders.ParticipantsThe cohort was a community-dwelling prospective study of 9411 elderly adults aged 60 to 92 years from 51 community health service centres in Luohu district of Shenzhen, China. The baseline data were collected between 2017 and 2018, including demographics and socioeconomics, lifestyles, medical history, family history of major non-communicable chronic disease, environmental exposures, clinical analysis of blood and urine, clinical imaging measurements, anthropometric measures and neurological function and mental health assessments. Blood and urinary samples were collected at baseline. All participants will be followed for physiological and psychological disorders and updated lifestyle and environmental exposures every 5 years.Findings to dateThe mean age of the participants was 67.73 years at baseline, and 42.74% were males. The prevalences of individuals with unhealthy conditions were as follows: overweight/obesity (54.38%), hypertension (58.24%), diabetes mellitus (22.30%), dyslipidaemia (75.69%), chronic bronchitis (1.45%), myocardial infarction (0.55%), coronary heart disease (5.69%), stroke (1.10%), cancer (2.18%), arthritis (5.04%), Alzheimer’s disease (0.18%), Parkinson’s disease (0.23%), brain injury (5.75%), cognitive impairment (5.39%) and depression status (3.28%). The mean scores for the Lawton-Brody Activities of Daily Living Scale and the Social Support Rate Scale were 14.15 and 39.54, respectively.Future plans2000 new entrants from Luohu district will be recruited every year until 2028. The data collection is expected to be ended at the end of 2030. The data will be used to assess the causality of ageing-related disorders, especially neurological and mental disorders through integrating environmental, genetic and lifestyle factors. The data sets generated and/or analysed during the current study are not publicly available at this stage, but are available from the corresponding author on reasonable request.
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Nam, Ji Hyung, Jaeyong Shin, Sung-In Jang, Ji Hyun Kim, Kyu-Tae Han, Jun Kyu Lee, Yun Jeong Lim, and Eun-Cheol Park. "Associations between lipid profiles of adolescents and their mothers based on a nationwide health and nutrition survey in South Korea." BMJ Open 9, no. 3 (March 2019): e024731. http://dx.doi.org/10.1136/bmjopen-2018-024731.
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ObjectivesDyslipidaemia is a metabolic disease influenced by environmental and genetic factors. Especially, family history related to genetic background is a strong risk factor of lipid abnormality. The aim of this study is to evaluate the association between the lipid profiles of adolescents and their mothers.DesignA cross-sectional study.SettingThe data were derived from the Korea National Health and Nutrition Examination Survey (IV-VI) between 2009 and 2015.Participants2884 adolescents aged 12–18 years and their mothers were included.Primary outcome measuresOutcome variables were adolescents’ lipid levels. Mothers’ lipid levels were the interesting variables. The lipid profiles included total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). We identified partial correlation coefficients (r) between the lipids. Multiple linear regressions were performed to identify the amount of change in adolescents’ lipid levels for each unit increase of their mothers’ lipids. The regression models included various clinical characteristics and health behavioural factors of both adolescents and mothers.ResultsThe mean levels of adolescents’ lipids were 156.6, 83.6, 50.4 and 89.4 mg/dL, respectively for TC, TG, HDL-C and LDL-C. Positive correlations between lipid levels of adolescents and mothers were observed for TC, TG, HDL-C and LDL-C (r,95% CI: 0.271, 0.236 to 0.304; 0.204, 0.169 to 0.239; 0.289, 0.255 to 0.322; and 0.286, 0.252 to 0.319). The adolescent TC level was increased by 0.23 mg/dL for each unit increase of the mother’s TC (SE, 0.02; p<0.001). The beta coefficients were 0.16 (SE, 0.01), 0.24 (SE, 0.02) and 0.24 (SE, 0.02), respectively, in each model of TG, HDL-C and LDL-C (all p<0.001). The linear relationships were significant regardless of sex and mother’s characteristics.ConclusionsMothers’ lipid levels are associated with adolescents’ lipids; therefore, they can serve as a reference for the screening of adolescent’s dyslipidaemia.
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Brouwers, Martijn C. G. J., Marleen M. J. van Greevenbroek, Jason S. Troutt, Angela Bonner Freeman, Ake Lu, Nicolaas C. Schaper, Robert J. Konrad, and Coen D. A. Stehouwer. "Plasma proprotein convertase subtilisin kexin type 9 is a heritable trait of familial combined hyperlipidaemia." Clinical Science 121, no. 9 (July 12, 2011): 397–403. http://dx.doi.org/10.1042/cs20110129.
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The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P<0.001). The latter relationship was accounted for by LDL (low-density lipoprotein)–apolipoprotein B (r=0.31, P=0.02), not by VLDL (very-low-density lipoprotein)–apolipoprotein B (r=0.09, P=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR software yielded estimates of 67–84% respectively (P<0.0001). PCSK9 increased from 122 to 150 ng/ml in 11 FCHL patients treated with atorvastatin (40 mg) once daily for 8 weeks (P=0.018). In conclusion, plasma PCSK9 is a heritable trait associated with both FCHL diagnostic hallmarks. These results, combined with the significant rise in PCSK9 levels after statin therapy, warrant further studies in order to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidaemia.
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Prokop, Edyta Kinga, Paweł Piotr Jagodziński, and Stefan Grajek. "Genetics in familial hypercholesterolaemia – from genetic research to new guidelines." Journal of Medical Science 88, no. 3 (April 3, 2019): 192–94. http://dx.doi.org/10.20883/jms.245.
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Familial Hypercholesterolaemia (FH) is genetic disorder touching up to 1 to 250 people, increasing the risk of atherosclerotic cardiovascular disease risk and early death by 3–13 times. The majority of mutations are autosomal dominant among 3 genes related to cholesterole metabolism: LDL‑receptor (LDLR), apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9). It comprises 60% of reported cases, which still is not at satisfactory level. This article summarizes new research in the field of FH and points out new therapeutic methods — PCSK9 inhibitors as advised in new European Society of Cardiology guidelines od dyslipidaemias.
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Boden, William E., Deepak L. Bhatt, Peter P. Toth, Kausik K. Ray, M. John Chapman, and Thomas F. Lüscher. "Profound reductions in first and total cardiovascular events with icosapent ethyl in the REDUCE-IT trial: why these results usher in a new era in dyslipidaemia therapeutics." European Heart Journal 41, no. 24 (December 23, 2019): 2304–12. http://dx.doi.org/10.1093/eurheartj/ehz778.
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Abstract The aims of this clinical review are to: (i) highlight the importance of elevated baseline triglycerides (TG) in the setting of well-controlled low-density lipoprotein cholesterol (LDL-C) on statins as a major contributor to residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly among patients with type 2 diabetes mellitus, metabolic syndrome, and obesity whose distinctive lipid phenotype cannot be optimally treated with LDL-C reduction therapy alone; (ii) describe the findings and clinical implications of the landmark REDUCE-IT trial in which ethyl eicosapentaenoic acid significantly improved ASCVD outcomes. While many genetic studies have shown that elevated TG are an independent causal factor for ASCVD, prior placebo-controlled trials using niacin, fibrates, omega-3 fatty acids, and dietary supplement fish oil preparations have failed to demonstrate significant CV event reduction when added to statin therapy. In contrast, the REDUCE-IT trial in 8179 participants showed convincingly that the administration of 4 g daily of icosapent ethyl (an ethyl ester of eicosapentaenoic acid) in patients at high risk for ASCVD with increased levels of baseline TG [median value, 2.44 mmol/L (216.0 mg/dL)] but well-controlled LDL-C [median value, 1.94 mmol/L (75.0 mg/dL)] reduced significantly incident events across both the trial primary endpoint and multiple prespecified secondary endpoints, including cardiovascular death, as well as both subsequent and total primary endpoint and key secondary endpoint events. Icosapent ethyl unequivocally contributed to ASCVD event reduction over and above statin therapy. The REDUCE-IT trial results should alter our approach to managing a growing population of hypertriglyceridaemic patients whose lipid phenotype requires more intensive treatment beyond LDL-C lowering alone.
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Packard, Chris, M. John Chapman, Mahendra Sibartie, Ulrich Laufs, and Luis Masana. "Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges." Heart 107, no. 17 (April 1, 2021): 1369–75. http://dx.doi.org/10.1136/heartjnl-2020-318760.
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Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of ‘lower is better’. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5–7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.