Analysis of 61 SNPs from the CAD specific genomic loci reveals unique set of SNPs as significant markers in the Southern Indian population of Hyderabad.

BACKGROUND: The present study is a part of the major project on coronary artery disease (CAD) carried out at Indian Statistical Institute, Hyderabad to investigate the pattern of association of SNPs selected from the CAD specific genomic loci. The study is expected to portray the genetic susceptibility profile of CAD specifically in the Southern Indian population of Hyderabad. METHODS: The study was conducted in a cohort of 830 subjects comprising 350 CAD cases and 480 controls from Hyderabad. A prioritized set of 61 SNPs selected from the NHGRI GWAS catalogue were genotyped using FluidigmNanofluidic SNP Genotyping System and appropriate statistical analyses were used in interpreting the results. RESULTS: After data pruning, out of 45 SNPs qualified for the association analysis, four SNPs were found to be highly significantly associated with increased risk for CAD even after Bonferroni correction for multiple testing (p < 0.001). These results were also replicated in the random subsets of the pooled cohort (70, 50 and 30%) suggesting internal consistency. The ROC analysis of the risk scores of the significant SNPs suggested highly significant area under curve (AUC = 0.749; p < 0.0001) implying predictive utility of these risk variants. CONCLUSIONS: The rs10455872 of LP(A) gene in particular showed profound risk for CAD (OR 35.9; CI 16.7-77.2) in this regional Indian population. The other significant SNP associations observed with respect to the pooled CAD cohort and in different anatomical and phenotypic severity categories reflected on the role of genetic heterogeneity in the clinical heterogeneity of CAD. The SNP rs7582720 of WDR12 gene, albeit not individually associated with CAD, was found to be conferring significant risk through epistatic interaction with two SNPs (rs6589566, rs1263163 in ZPR1, APOA5-APOA4 genes) of the 11q23.3 region.

Association of CDKAL1, CDKN2A/B & HHEX gene polymorphisms with type 2 diabetes mellitus in the population of Hyderabad, India.

BACKGROUND & OBJECTIVES: The genome-wide association studies (GWAS) have shown an association of type 2 diabetes mellitus (T2DM) with several novel genes. We report here the findings on the pattern of genetic association of three genes (CDKAL1, CDKN2A/B and HHEX) with T2DM in the population of Hyderabad, south India. METHODS: A sample of 1379 individuals (758 T2DM cases and 621 controls) from Hyderabad, India, were genotyped for five single nucleotide polymorphisms (SNPs) of CDKAL1 (rs7754840, rs7756992) CDKN2A/B (rs10811661) and HHEX (rs1111875, rs7923837) genes on Sequenom Mass Array platform. RESULTS: The risk allele frequencies of the CDKAL1 and CDKN2A/B SNPs were relatively higher in cases than in the controls and the logistic regression analysis yielded significant odds ratios suggesting that the variant alleles conferred risk for developing T2DM in this population. the HHEX gene did not show either allelic or genotypic association with T2DM. The multivariate logistic regression analysis with reference to both alleles and genotypes of CDKAL1 SNPs showed significant association, suggesting an important role for this gene in the T2DM pathophysiology. INTERPRETATION & CONCLUSIONS: A significant association was seen of all the three SNPs of CDKAL1 and CDKN2A/B genes with T2DM but none of the two SNPs of HHEX. Further studies are required to cross-validate our findings in a relatively larger sample. It is also necessary to explore other SNPs of HHEX gene to unequivocally establish the pattern of association of this gene with T2DM in this population.

The genetic susceptibility profile of type 2 diabetes and reflection of its possible role related to reproductive dysfunctions in the southern Indian population of Hyderabad.

BACKGROUND: The genetic association studies of type 2 diabetes mellitus (T2DM) hitherto undertaken among the Indian populations are grossly inadequate representation of the ethnic and geographic heterogeneity of the country. In view of this and due to the inconsistent nature of the results of genetic association studies, it would be prudent to undertake large scale studies in different regions of India considering wide spectrum of variants from the relevant pathophysiological pathways. Given the reproductive dysfunctions associated with T2DM, it would be also interesting to explore if some of the reproductive pathway genes are associated with T2DM. The present study is an attempt to examine these aspects in the southern Indian population of Hyderabad. METHODS: A prioritized panel of 92 SNPs from a large number of metabolic and reproductive pathway genes was genotyped on 500 cases and 500 controls, matched for ethnicity, age and BMI, using AGENA MassARRAYiPLEX™ platform. RESULTS: The allelic association results suggested 14 SNPs to be significantly associated with T2DM at P ≤ 0.05 and seven of those-rs2241766-G (ADIPOQ), rs6494730-T (FEM1B), rs1799817-A and rs2059806-T (INSR), rs11745088-C (FST), rs9939609-A and rs9940128-A (FTO)-remained highly significant even after correction for multiple testing. A great majority of the significant SNPs were risk in nature. The ROC analysis of the risk scores of the significant SNPs yielded an area under curve of 0.787, suggesting substantial power of our study to confer these genetic variants as predictors of risk for T2DM. CONCLUSIONS: The associated SNPs of this study are known to be specifically related to insulin signaling, fatty acid metabolism and reproductive pathway genes and possibly suggesting the role of overlapping phenotypic features of insulin resistance, obesity and reproductive dysfunctions inherent in the development of diabetes. Large scale studies involving gender specific approach may be required in order to identify the precise nature of population and gender specific risk profiles for different populations, which might be somewhat distinct.

The genetic susceptibility profile of the South Indian women with polycystic ovary syndrome and the universality of the lack of association of type 2 diabetes genes.

We explored genetic susceptibility profile of the South Indian women with a large set of SNPs and tested if the lack of association of type 2 diabetes genes with PCOS, recently observed in a number of studies, holds true for this Indian population and suggest probable universality of this phenomenon. A prioritized set of 92 SNPs that belong to important reproductive and metabolic pathway genes were genotyped on 250 PCOS cases and 299 ethnically matched controls, representing the southern Indian population of Hyderabad, using SEQUENOM MassARRAY iPLEX™ platform. These data were analyzed both for individual SNP association patterns as well as for gene-gene interactions, besides obtaining cumulative risk score and the ROC curve with the help of appropriate statistical packages such as PLINK, SNPAssoc of R-program, Haploview, GMDR and SPSS. The analysis of 72 of the 92 SNPs, after excluding 20 of those that showed either minor allele frequency < 1% and/or deviated from Hardy Weinberg Equilibrium (p < .001), suggested that only 13 were associated with PCOS at p ≤ .05, but none after correction for multiple testing. Further, neither any of the diabetic genes nor the interactions between diabetic and reproductive pathway genes were found to be significant even at p ≤ .05.The lack of association of any of the SNPs with PCOS and/or the gene-gene interactions among them may be because of the minor effects of each of them on the phenotype(OR < 2). Further, that none of the type 2 diabetes genes were associated with PCOS in the present study as well as in the earlier studies from different ethnic groups may indicate probable universality of this pattern. It is possible that there are still other genetic variants, novel as well as already known, which may confer greater risk than the ones considered in this study and further studies are warranted to ascertain this both in the present population as well as in other ethnic and/or geographic groups of the Indian subcontinent.

Association of IRS1, CAPN10, and PPARG gene polymorphisms with type 2 diabetes mellitus in the high-risk population of Hyderabad, India.

BACKGROUND: We attempted to validate earlier findings on the nature of the association of the IRS1, CAPN10, and PPARG genes with type 2 diabetes mellitus (T2DM) in the high-risk population of Hyderabad, India. METHODS: A sample of 1379 subjects (758 T2DM patients, 621 controls) was genotyped for single nucleotide polymorphisms (SNPs) of the IRS1 (rs1801278), CAPN10 (rs3792267, rs5030952), and PPARG (rs1801282) genes. RESULTS: The allele and genotype frequencies of IRS1 (rs1801278) and CAPN10 (rs3792267) SNPs differed significantly between the patient and control groups. Logistic regression analysis suggested a significant association of these two SNPs (P ≤ 0.007) with T2DM and the strength of association did not alter when adjusted for age, gender, body mass index, and the waist : hip ratio as covariates. The same two SNPs showed significant association in multivariate logistic regression analyses, even after Bonferroni correction for multiple testing, suggesting an independent nature of the role of these genes in the manifestation of T2DM in our population. CONCLUSIONS: We replicated the significant association of rs1801278 and rs3792267 SNPs of the IRS1 and CAPN10 genes with T2DM in the population of Hyderabad. Despite the known biological significance of the PPARG gene and a sufficient statistical power of the present study, we could not replicate the association of PPARG with T2DM in our high-risk population. Given the vast ethnic, geographic, and genetic heterogeneity of the Indian population, many more studies are needed covering the ethnic and geographic heterogeneity of India to enable identification of an Indian-specific profile of genes associated with T2DM.

No detectable association of IGF2BP2 and SLC30A8 genes with type 2 diabetes in the population of Hyderabad, India.

Genome-wide association studies identified novel genes associated with T2DM which have been replicated in different populations. We try to examine here if certain frequently replicated SNPs of Insulin growth factor 2 m-RNA binding protein 2 (IGF2BP2) (rs4402960, rs1470579) and Solute Carrier family 30 member 8 (SLC30A8) (rs13266634) genes, known to be implicated in insulin pathway, are associated with T2DM in the population of Hyderabad, which is considered to be a diabetic capital of India. Genotyping of the 1379 samples, 758 cases and 621 controls, for the SNPs was performed on sequenom massarray platform. The logistic regression analysis was done using SPSS software and the post-hoc power of the study was estimated using G power. The allele and genotype frequencies were similar between cases and controls, both for SNPs of IGF2BP2 and SLC30A8 genes. Logistic regression did not reveal significant allelic or genotypic association of any of the three SNPs with T2DM. Despite large sample size and adequate power, we could not replicate the association of IGF2BP2 and SLC30A8 SNPs with T2DM in our sample from Hyderabad (A.P.), India, albeit another study based on much larger sample but from heterogeneous populations from the northern parts of India showed significant association of two of the above 3 SNPs, suggesting variable nature of susceptibility of these genes in different ethnic groups. Although the IGF2BP2 and SLC30A8 genes are important in the functional pathway of Insulin secretion, it appears that these genes do not play a significant role in the susceptibility to T2DM in this population.