Academic literature on the topic 'Gly9arg'

Abstract Background: Arg702Trp, Gly908Arg, and Leu1007fsinsC variants of the NOD2 gene (nucleotide-binding oligomerization domain containing 2; alias, CARD15) influence the risk of Crohn disease. Methods: We conducted a systematic review to examine whether Arg702Trp, Gly908Arg, and Leu1007fsinsC are equally important risk factors for Crohn disease. In addition, we used studies for which combined information from all genotypes was available to compare risks in simple heterozygotes, compound heterozygotes, and homozygotes. PubMed, EMBASE, and Web of Science were searched. Seventy-five articles (18 727 cases and 17 102 controls) met the inclusion criteria and contributed data to the metaanalyses. Results: The odds ratios per allele for Crohn disease were 2.2 (95% CI, 2.0–2.5) for Arg702Trp, 2.6 (2.2–2.9) for Gly908Arg, and 3.8 (3.4–4.3) for Leu1007fsinsC (z-test results: Arg702Trp vs Gly908Arg, P = 0.03; Arg702Trp vs Leu1007fsinsC, P < 0.001; Gly908Arg vs Leu1007fsinsC, P < 0.001). When all 3 genotypes were combined, odds ratios for Crohn disease were 2.4 (95% CI, 2.0–2.8) for simple heterozygotes, 9.0 (6.0–13.5) for compound heterozygotes, and 6.7 (4.1–10.9) for homozygotes, compared with noncarriers (z-test results: simple heterozygotes vs compound heterozygotes, P < 0.001; simple heterozygotes vs homozygotes, P < 0.001; compound heterozygotes vs homozygotes, P = 0.18). Conclusions: The per-allele risk of Crohn disease was markedly higher for Leu1007fsinsC than for Arg702Trp and Gly908Arg. Combining all genotypes revealed the risks of Crohn disease for compound heterozygotes and homozygotes to be similar and markedly higher than for simple heterozygotes.

Insulin resistance is a key component in the pathogenesis of polycystic ovary syndrome (PCOS) and type 2 diabetes. Polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, IRS-1 (Gly972Arg) and IRS-2 (Gly1057Asp), influence susceptibility to type 2 diabetes. This study was undertaken to assess the influence of these polymorphisms on insulin resistance, glucose tolerance, and androgen levels in nondiabetic PCOS women. We studied 227 PCOS subjects including 126 and 48 nondiabetic white and African-American subjects, respectively. The IRS-1 Gly972Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. The IRS-2 Gly1057Asp allele frequencies were 0.85 (Gly) and 0.15 (Asp) in African-Americans and 0.59 (Gly) and 0.41 (Asp) in whites. There was no association of IRS-1 genotype with any clinical or hormonal measure in nondiabetic white or African-American PCOS subjects. However, nondiabetic subjects with the IRS-2 Gly/Gly genotype had significantly higher 2-h oral glucose tolerance test glucose levels compared with those with Gly/Asp and Asp/Asp genotypes in whites or Gly/Asp genotype in African-Americans (there were no Asp/Asp subjects in our modest size African-American sample). These results suggest that the IRS-2 Gly1057Asp polymorphism influences blood glucose levels in nondiabetic white and African-American women with PCOS. Thus, individuals with the common IRS-2 Gly/Gly genotype may be at increased risk of developing type 2 diabetes.

Aim and objective The aim of the study was to investigate the relationships between insulin receptor substrate (IRS) 1 (Gly972Arg) and IRS2 (Gly1057Asp) genes with obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in Asian Indians. Method A total of 410 overweight/obese subjects (130 with OSA with NAFLD, 100 with OSA without NAFLD, 95 without OSA and with NAFLD and 85 without OSA and without NAFLD) were recruited. Degree of NAFLD was based on liver ultrasound and of OSA on overnight polysomnography. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by gene sequencing. Result Mean values of blood pressure, body fat markers, blood glucose, lipids, liver function, and markers of insulin resistance were significantly increased in OSA and NAFLD subjects (p<0.05). In addition, according to age (years) categories, blood pressure, blood glucose, lipids, obesity markers, and markers of insulin resistance were significantly higher in 45–60 years group as compared to 20–45 years group (p<0.05). In IRS1 gene, the genotype frequency (%) of Arg/Arg was significantly higher in NAFLD and OSA subjects. In addition, Gly/Arg genotype of IRS1 gene was associated with significantly higher body mass index, fat mass, %body fat, triglycerides, cholesterol, alkaline phosphate, aspartate transaminase, fasting insulin and HOMA-IR levels in OSA and NAFLD subjects. No significant difference in genotype frequencies of IRS2 was observed between four groups. Further we found that subjects carrying IRS1 Gly/Arg (OR 4.49, 95% C.I. 1.06–12.52, p = 0.002) genotype possess a much higher risk of OSA and NAFLD compared to IRS2 Gly/Asp (OR 1.01, 95% C.I. 0.8–2.56, p = 0.05). In sub group analysis of IRS1 Gly/Arg have significant differences between the mild, moderate and severe group (P<0.05). In addition, patients with the ‘Gly’ allele were inclined to develop more severe OSA. Conclusion We concluded that Asian Indian subject carrying the allele Gly972Arg polymorphism of IRS1 is predisposed to develop OSA and NAFLD.

Osteogenesis imperfecta (OI) is an inherited disease of bone characterized by increased bone fragility. Here, we report the results of the molecular architecture of osteogenesis imperfecta research in patients from Bashkortostan Republic, Russia. In total, 16 mutations in COL1A1, 11 mutations in COL1A2, and 1 mutation in P3H1 and IFIMT5 genes were found in isolated states; 11 of them were not previously reported in literature. We found mutations in CLCN7, ALOX12B, PLEKHM1, ERCC4, ARSB, PTH1R, and TGFB1 that were not associated with OI pathogenesis in patients with increased bone fragility. Additionally, we found combined mutations (c.2869C>T, p. Gln957* in COL1A1 and c.1197+5G>A in COL1A2; c.579delT, p. Gly194fs in COL1A1 and c.1197+5G>A in COL1A2; c.2971G>C, p. Gly991Arg in COL1A2 and c.212G>C, p.Ser71Thr in FGF23; c.-14C>T in IFITM5 and c.1903C>T, p. Arg635* in LAMB3) in 4 patients with typical OI clinic phenotypes.

Pregnant women with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share a common pathophysiology associated with similar risk factors. Genetic variants used to determine the risk of developing T2DM might also be associated with the prevalence of GDM. The aim of the present study was to scrutinize the relationship between the G972R polymorphism of the insulin receptor substrate-1 (IRS-1) gene with GDM in the Saudi female population. This is a case-control study that monitored 500 Saudi women. Subjects with GDM (n=200) were compared with non-GDM (n=300) controls. We opted to evaluate rs1801278 polymorphism in the IRS1 gene, which plays a critical role in the insulin-signaling pathway. Genotyping was performed with the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. The frequency of the rs1801278 polymorphism was significantly higher in women with GDM than in women with non-GDM (for TT + CT versus CC:P=0.02). Additionally, there was a significant increase in the frequency of the Arg-encoding mutant allele from GDM to non-GDM (for T versus C:P=0.01). Our results suggest that the rs1801278 polymorphism in theIRS-1gene is involved in the occurrence of GDM in the Saudi population.

Orientador: Mario Jose Abdalla Saad
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-06T11:08:54Z (GMT). No. of bitstreams: 1 Bellinazzi_VeraRegina_M.pdf: 1059560 bytes, checksum: bdf226ffce821be677b9c8439cc32fdd (MD5) Previous issue date: 2006
Resumo: Apesar dos mecanismos da longevidade não serem totalmente conhecidos, sabe-se que mutações em genes que reduzem a sinalização intracelular de insulina/IGF-1 são capazes de aumentar a sobrevida de animais invertebrados e mamíferos Na mosca Drosophila Melanogaster, mutações no receptor de insulina (similar ao gene do receptor de insulina humano) e no gene chico (similar ao gene do IRS-1 humano) levam ao aumento da sobrevida do animal. Em roedores, estudos sobre restrição calórica e diversas mutações tem relacionado a via de sinalização insulina/IGF-1 com longevidade. Em humanos, a sensibilidade à insulina normalmente declina com o envelhecimento, porém existem evidências que idosos longevos apresentam ação da insulina preservada e nível de IGF-1 sérico reduzido, o que sugere que a resposta à insulina tem impacto na longevidade humana. Evidências recentes que reforçam esta teoria demonstram que polimorfismos de genes da via de sinalização de insulina/IGF-1( IGF-1R e PI3K), afetam o IGF-1 sérico e a longevidade humana, sugerindo que este mecanismo esteja conservado através da evolução das espécies. Baseada nestas evidências, nosso estudo investigou a prevalência do polimorfismo mais comum do IRS-1, a substituição de glicina por arginina no códon 972 (Gly972Arg), numa amostra da população longeva brasileira, e a sua associação com diversos fenótipos e com a longevidade. Foram incluídos no estudo 94 idosos, de ambos os sexos, com idades entre 80 e 100 anos. Como grupo controle foram incluídos 194 recém-nascidos da mesma região brasileira. A freqüência genotípica encontrada nos idosos foi: Gly/GIy 80,85%, Gly/Arg 19,15%, e Arg/Arg 0%. Não foi encontrada diferença estatística entre a prevalência do polimorfismo em longevos e em neonatos brasileiros. Também não houve associação deste polimorfismo com resistência à insulina, hipertensão, diabetes, ou com alterações no IMC, circunferência da cintura, e lípides nessa população. Nossos achados indicam que não há associação do polimorfismo Gly972Arg do IRS-1 com longevidade em humanos. E possível que esta falta de relação esteja relacionada ao seu efeito neutro tanto na sensibilidade à insulina quanto no nível de IGF-1.
Abstract: Although the underlying mechanisms of longevity are not fully understood, it is known that mutations in genes that decrease the insulin/IGF-1 signal response pathway are capable of extending life span in a variety of model systems from invertebrates to mammals. In Drosophila Melanogaster, mutations of either the insulin receptor gene (similar of human insulin receptor gene) or the Chico (similar of human IRS-1 gene) led to enhanced longevity. In humans, insulin sensitivity normally declines during aging. Although there are evidences that long-lived subjects have decreased plasma IGF-1 levels and preserved insulin action, thus indicating that insulin responsiveness impacts on human longevity. Recent findings also provide novel and intriguing indications for the involvement of insulin and IGF-1 in the control of aging and longevity in humans. In particular, it has been demonstrated that polymorphic variants of IGF-1 receptor (IGF-IR) and phosphatidylinositol 3-kinase (PI3K) genes affect IGF-1 plasma levels and human longevity, indicating that the impact of these genes on species longevity is an evolutionary conserved property. On the basis of the above-mentioned literature, we investigate the prevalence of a most common IRS-1 variant, a Gly --> Arg substitution at codon 972 (GIy972Arg) in a population-based sample of Brazilian elderly, its association with phenotypes and longevity. Ninety-four Brazilian subjects (men and women), from 80-100 yr. of age, volunteered for this study. As a control population we studied 194 newborn children from our University Hospital. Genotype frequencies were Gly/Gly 80,85%, Gly/Arg 19,15%, and Arg/Arg 0%, which are in Hardy-Weinberg equilibrium In addition, no significant differences among allele and genotype distribution were found between Brazilian elderly and Brazilian newborns Also, the Arg variant was not associated with insulin resistance, hypertension, diabetes, detrimental values for body mass index, waist circumference, and lipids in the Brazilian elderly. Our findings indicate that the IRS-1 Gly972Arg variant is not related with longevity. It is possible that the lack of this association might be related to its neutral effect on insulin sensitivity and on IGF-1 levels.
Mestrado
Clinica Medica
Mestre em Clinica Medica

p27Kip1 is a Cyclin-dependent Kinase Inhibitor (CKI) belonging to CIP/Kip protein family. It is essentially known for its inhibitory action on several cyclin/CDK complexes (specifically cyclin E(A)/CDK2 and cyclin A(B)/CDK1), suggesting a role as tumor suppressor. However, when localized in cytosol, p27Kip1 has a number of CDK-independent functions, including the regulation of apoptosis, cell motility and differentiation. Some of these activities can enhance malignant transformation and/or metastasization under specific conditions. p27Kip1 is characterized by the lack of a stable tertiary structure that favors its “adaptability” to bind different targets and contributes to the heterogeneity of its functions. Because of this peculiar structure, the presence of several post translational modifications (especially phosphorylation) has a key relevance for the CKI cellular localization, metabolism and functions. In this study, we have investigated the turn-over and cyclins/CDK interactions of phosphoserine10-p27Kip1 (pSer10p27Kip1), the main CKI phosphoisoform. We also examined the localization, metabolism, phosphoisoforms pattern and interaction of a cancer-associated mutant form of the CKI (namely G9Rp27Kip1) in which glycine 9 is substituted by an arginine. Our attention focused on this p27Kip1 mutant since the residue change (i.e. glycine 9) occurs in the amino acid preceding serine 10 thus allowing the hypothesis that the mutation affects Ser10 post translational modification.