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Multi-analytic approach elucidates significant role of hormonal and hepatocanalicular transporter genetic variants in gallstone disease in North Indian population.

ABSTRACT: OBJECTIVE: Cholesterol gallstone disease (CGD) is a multifactorial and multistep disease. Apart from female gender and increasing age being the documented non-modifiable risk factor for gallstones the pathobiological mechanisms underlying the phenotypic expression of CGD appear to be rather complex, and one or more variations in genes could play critical roles in the diverse pathways further progressing to cholesterol crystal formation. In the present study we performed genotyping score, Multifactor dimensionality reduction (MDR) and Classification and Regression Tree analysis (CART) to identify combinations of alleles among the hormonal, hepatocanalicular transporter and adipogenesis differentiation pathway genes in modifying the risk for CGD. DESIGN: The present case-control study recruited total of 450 subjects, including 230 CGD patients and 220 controls. We analyzed common ESR1, ESR2, PGR, ADRB3, ADRA2A, ABCG8, SLCO1B1, PPAR?2, and SREBP2 gene polymorphisms to find out combinations of genetic variants contributing to CGD risk, using multi-analytical approaches (G-score, MDR, and CART). RESULTS: Single locus analysis by logistic regression showed association of ESR1 IVS1-397C>T (rs2234693), IVS1-351A>G (rs9340799) PGR ins/del (rs1042838) ADRB3-190 T>C (rs4994) ABCG8 D19H (rs11887534), SLCO1B1 Exon4 C>A (rs11045819) and SREBP2 1784G>C (rs2228314) with CGD risk. However, the MDR and CART analysis revealed ESR1 IVS1-397C>T (rs2234693) ADRB3-190 T>C (rs4994) and ABCG8 D19H (rs11887534) polymorphisms as the best polymorphic signature for discriminating between cases and controls. The overall odds ratio for the applied multi-analytical approaches ranged from 4.33 to 10.05 showing an incremental risk for cholesterol crystal formation. In conclusion, our muti-analytical approach suggests that, ESR1, ADRB3, in addition to ABCG8 genetic variants confer significant risk for cholesterol gallstone disease.

SUBMITTER: Srivastava A

PROVIDER: S-EPMC3620121 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Multi-analytic approach elucidates significant role of hormonal and hepatocanalicular transporter genetic variants in gallstone disease in North Indian population.

Srivastava Anshika A Mishra Avshesh A Singh Rajan R Rai Rajani R Srivastava Neena N Mittal Balraj B

PloS one 20130408 4

<h4>Objective</h4>Cholesterol gallstone disease (CGD) is a multifactorial and multistep disease. Apart from female gender and increasing age being the documented non-modifiable risk factor for gallstones the pathobiological mechanisms underlying the phenotypic expression of CGD appear to be rather complex, and one or more variations in genes could play critical roles in the diverse pathways further progressing to cholesterol crystal formation. In the present study we performed genotyping score, ...[more]

PMID: 23577061

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Project description:Background: A heavy burden of cardiometabolic conditions on low- and middle-income countries like India that are rapidly undergoing urbanization remains unaddressed. Indians are known to have high levels of triglycerides and low levels of HDL-C along with moderately higher levels of LDL-C. The genome-wide findings from Western populations need to be validated in an Indian context for a better understanding of the underlying etiology of dyslipidemia in India. Objective: We aim to validate 12 genetic variants associated with lipid levels among rural and urban Indian populations and derive unweighted and weighted genetic risk scores (uGRS and wGRS) for lipid levels among the Indian population. Methods: Assuming an additive model of inheritance, linear regression models adjusted for all the possible covariates were run to examine the association between 12 genetic variants and total cholesterol, triglycerides, HDL-C, LDL-C, and VLDL-C among 2,117 rural and urban Indian participants. The combined effect of validated loci was estimated by allelic risk scores, unweighted and weighted by their effect sizes. Results: The wGRS for triglycerides and VLDL-C was derived based on five associated variants (rs174546 at FADS1, rs17482753 at LPL, rs2293889 at TRPS1, rs4148005 at ABCA8, and rs4420638 at APOC1), which was associated with 36.31 mg/dL of elevated triglyceride and VLDL-C levels (β = 0.95, SE = 0.16, p < 0.001). Similarly, every unit of combined risk score (rs2293889 at TRPS1 and rs4147536 at ADH1B) was associated with 40.62 mg/dL of higher total cholesterol (β = 1.01, SE = 0.23, p < 0.001) and 33.97 mg/dL of higher LDL-C (β = 1.03, SE = 0.19, p < 0.001) based on its wGRS (rs2293889 at TRPS1, rs4147536 at ADH1B, rs4420638 at APOC1, and rs660240 at CELSR2). The wGRS derived from five associated variants (rs174546 at FADS1, rs17482753 at LPL, rs4148005 at ABCA8, rs4420638 at APOC1, and rs7832643 at PLEC) was associated with 10.64 mg/dL of lower HDL-C (β = -0.87, SE = 0.14, p < 0.001). Conclusion: We confirm the role of eight genome-wide association study (GWAS) loci related to different lipid levels in the Indian population and demonstrate the combined effect of variants for lipid traits among Indians by deriving the polygenic risk scores. Similar studies among different populations are required to validate the GWAS loci and effect modification of these loci by lifestyle and environmental factors related to urbanization.

Project description:BACKGROUND:Gestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women. METHODS:Five thousand one hundred pregnant women of gestational age 24-28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women. RESULTS:In support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p?=?0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p?<?0.025). SNPs rs7607980 near COBLL1 (p?=?0.0001), rs13389219 near GRB14 (p?=?0.026) and rs10423928 in the GIPR gene (p?=?0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM. CONCLUSIONS:GDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women.

Dataset Information

Multi-analytic approach elucidates significant role of hormonal and hepatocanalicular transporter genetic variants in gallstone disease in North Indian population.

Publications

Multi-analytic approach elucidates significant role of hormonal and hepatocanalicular transporter genetic variants in gallstone disease in North Indian population.

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