Dataset Information

Association of common polymorphisms in the VEGFA and SIRT1 genes with type 2 diabetes-related traits in Mexicans.

ABSTRACT: Introduction:Genetic variants have been replicated for association with type 2 diabetes mellitus (T2D) and many of them with diabetes-related traits. Because T2D is highly prevalent in Mexico, this study aimed to test the association of CDKN2A/B, PPARGC1A, VEGFA, SIRT1 and UCP2 gene polymorphisms (rs10811661, rs8192678, rs2010963, rs7896005 and rs659366 respectively) with metabolic traits in 415 unrelated Mexican mestizos with T2D under three models of inheritance. Material and methods:A total of 415 unrelated Mexican mestizos were genotyped by TaqMan assays. Triglycerides, cholesterol, glucose, high-density lipoprotein cholesterol (HDL-C), insulin and anthropometric measurements were determined and the HOMA-IR was calculated. Association studies were tested by the Kruskal-Wallis test, linear regression, statistical power analysis, Bonferroni correction, paired SNP analysis, and physical interaction by GeneMANIA. Results:All polymorphisms were in Hardy-Weinberg equilibrium, and the association by genotype with T2D-related traits displayed nominal significance for rs8192678 with glucose (p = 0.023) and triglycerides (p = 0.013); rs2010963 with diastolic blood pressure (DBP) (p = 0.012) and cholesterol (p = 0.013); rs7896005 with DBP (p = 0.012) and insulin (p = 0.011); and rs659366 with cholesterol (p = 0.034), glucose (p = 0.031) and triglycerides (p = 0.028); and the association of rs2010963 with HDL-C (p = 0.0007) was significant. Linear regression performed with three models of inheritance, adjusted by age + sex + BMI and corrected with Bonferroni, showed a significant association of rs2010963 with HDL-C in an additive model (p = 0.007); and rs7896005 was significantly associated with DBP in the recessive model (p = 0.006). Conclusions:Rigorous analysis evidenced the association of VEGFA rs2010963 and SIRT1 rs7896005 with HDL-C and DBP respectively; these traits are known predictors of cardiovascular complications, which increase the risk of cardiovascular diseases in this population.

SUBMITTER: Totomoch-Serra A

PROVIDER: S-EPMC6209716 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Association of common polymorphisms in the VEGFA and SIRT1 genes with type 2 diabetes-related traits in Mexicans.

Totomoch-Serra Armando A Muñoz Maria de Lourdes ML Burgueño Juan J Revilla-Monsalve Maria Cristina MC Diaz-Badillo Alvaro A

Archives of medical science : AMS 20180328 6

<h4>Introduction</h4>Genetic variants have been replicated for association with type 2 diabetes mellitus (T2D) and many of them with diabetes-related traits. Because T2D is highly prevalent in Mexico, this study aimed to test the association of CDKN2A/B, PPARGC1A, VEGFA, SIRT1 and UCP2 gene polymorphisms (rs10811661, rs8192678, rs2010963, rs7896005 and rs659366 respectively) with metabolic traits in 415 unrelated Mexican mestizos with T2D under three models of ...[more]

PMID: 30393491

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Project description:To evaluate the associations between six single-nucleotide polymorphisms (SNPs) in intron 1 of FTO and body mass index (BMI), a case-control association study of 2314 unrelated Mexican-Mestizo adult subjects was performed. The association between each SNP and BMI was tested using logistic and linear regression adjusted for age, gender, and ancestry and assuming additive, recessive, and dominant effects of the minor allele. Association analysis after BMI stratification showed that all five FTO SNPs (rs1121980, rs17817449, rs3751812, rs9930506, and rs17817449), were significantly associated with obesity class II/III under an additive model (P<0.05). Interestingly, we also documented a genetic model-dependent influence of gender on the effect of FTO variants on increased BMI. Two SNPs were specifically associated in males under a dominant model, while the remainder were associated with females under additive and recessive models (P<0.05). The SNP rs9930506 showed the highest increased in obesity risk in females (odds ratio = 4.4). Linear regression using BMI as a continuous trait also revealed differential FTO SNP contributions. Homozygous individuals for the risk alleles of rs17817449, rs3751812, and rs9930506 were on average 2.18 kg/m(2) heavier than homozygous for the wild-type alleles; rs1121980 and rs8044769 showed significant but less-strong effects on BMI (1.54 kg/m(2) and 0.9 kg/m(2), respectively). Remarkably, rs9930506 also exhibited positive interactions with age and BMI in a gender-dependent manner. Women carrying the minor allele of this variant have a significant increase in BMI by year (0.42 kg/m(2), P = 1.17 x 10(-10)). Linear regression haplotype analysis under an additive model, confirmed that the TGTGC haplotype harboring all five minor alleles, increased the BMI of carriers by 2.36 kg/m(2) (P = 1.15 x 10(-5)). Our data suggest that FTO SNPs make differential contributions to obesity risk and support the hypothesis that gender differences in the mechanisms involving these variants may contribute to disease development.

Project description:Mitochondrial dysfunction has been observed in skeletal muscle of people with diabetes and insulin-resistant individuals. Furthermore, inherited mutations in mitochondrial DNA can cause a rare form of diabetes. However, it is unclear whether mitochondrial dysfunction is a primary cause of the common form of diabetes. To date, common genetic variants robustly associated with type 2 diabetes (T2D) are not known to affect mitochondrial function. One possibility is that multiple mitochondrial genes contain modest genetic effects that collectively influence T2D risk. To test this hypothesis we developed a method named Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA; http://www.broadinstitute.org/mpg/magenta). MAGENTA, in analogy to Gene Set Enrichment Analysis, tests whether sets of functionally related genes are enriched for associations with a polygenic disease or trait. MAGENTA was specifically designed to exploit the statistical power of large genome-wide association (GWA) study meta-analyses whose individual genotypes are not available. This is achieved by combining variant association p-values into gene scores and then correcting for confounders, such as gene size, variant number, and linkage disequilibrium properties. Using simulations, we determined the range of parameters for which MAGENTA can detect associations likely missed by single-marker analysis. We verified MAGENTA's performance on empirical data by identifying known relevant pathways in lipid and lipoprotein GWA meta-analyses. We then tested our mitochondrial hypothesis by applying MAGENTA to three gene sets: nuclear regulators of mitochondrial genes, oxidative phosphorylation genes, and approximately 1,000 nuclear-encoded mitochondrial genes. The analysis was performed using the most recent T2D GWA meta-analysis of 47,117 people and meta-analyses of seven diabetes-related glycemic traits (up to 46,186 non-diabetic individuals). This well-powered analysis found no significant enrichment of associations to T2D or any of the glycemic traits in any of the gene sets tested. These results suggest that common variants affecting nuclear-encoded mitochondrial genes have at most a small genetic contribution to T2D susceptibility.

Dataset Information

Association of common polymorphisms in the VEGFA and SIRT1 genes with type 2 diabetes-related traits in Mexicans.

Publications

Association of common polymorphisms in the <i>VEGFA</i> and <i>SIRT1</i> genes with type 2 diabetes-related traits in Mexicans.

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