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A replication study of GWAS-derived lipid genes in Asian Indians: the chromosomal region 11q23.3 harbors loci contributing to triglycerides.

ABSTRACT: Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role of six of these loci (CELSR2-PSRC1-SORT1 rs599839; CDKN2A-2B rs1333049; BUD13-ZNF259 rs964184; ZNF259 rs12286037; CETP rs3764261; APOE-C1-C4-C2 rs4420638) in our Asian Indian cohort from the Sikh Diabetes Study (SDS) comprising 3,781 individuals (2,902 from Punjab and 879 from the US). Two of the six SNPs examined showed convincing replication in these populations of Asian Indian origin. Our study confirmed a strong association of CETP rs3764261 with high-density lipoprotein cholesterol (HDL-C) (p?=?2.03×10(-26)). Our results also showed significant associations of two GWAS SNPs (rs964184 and rs12286037) from BUD13-ZNF259 near the APOA5-A4-C3-A1 genes with triglyceride (TG) levels in this Asian Indian cohort (rs964184: p?=?1.74×10(-17); rs12286037: p?=?1.58×10(-2)). We further explored 45 SNPs in a ?195 kb region within the chromosomal region 11q23.3 (encompassing the BUD13-ZNF259, APOA5-A4-C3-A1, and SIK3 genes) in 8,530 Asian Indians from the London Life Sciences Population (LOLIPOP) (UK) and SDS cohorts. Five more SNPs revealed significant associations with TG in both cohorts individually as well as in a joint meta-analysis. However, the strongest signal for TG remained with BUD13-ZNF259 (rs964184: p?=?1.06×10(-39)). Future targeted deep sequencing and functional studies should enhance our understanding of the clinical relevance of these genes in dyslipidemia and hypertriglyceridemia (HTG) and, consequently, diabetes and CAD.

SUBMITTER: Braun TR

PROVIDER: S-EPMC3356398 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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A replication study of GWAS-derived lipid genes in Asian Indians: the chromosomal region 11q23.3 harbors loci contributing to triglycerides.

Braun Timothy R TR Been Latonya F LF Singhal Akhil A Worsham Jacob J Ralhan Sarju S Wander Gurpreet S GS Chambers John C JC Kooner Jaspal S JS Aston Christopher E CE Sanghera Dharambir K DK

PloS one 20120518 5

Recent genome-wide association scans (GWAS) and meta-analysis studies on European populations have identified many genes previously implicated in lipid regulation. Validation of these loci on different global populations is important in determining their clinical relevance, particularly for development of novel drug targets for treating and preventing diabetic dyslipidemia and coronary artery disease (CAD). In an attempt to replicate GWAS findings on a non-European sample, we examined the role o ...[more]

PMID: 22623978

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Project description:Genome-wide association studies and meta-analysis indicate that several genes/loci are consistently associated with rheumatoid arthritis (RA) in European and Asian populations. To evaluate the transferability status of these findings to an ethnically diverse north Indian population, we performed a replication analysis. We investigated the association of 47 single-nucleotide polymorphisms (SNPs) at 43 of these genes/loci with RA in a north Indian cohort comprising 983 RA cases and 1007 age and gender matched controls. Genotyping was done using Infinium human 660w-quad. Association analysis by chi-square test implemented in plink was carried out in two steps. Firstly, association of the index or surrogate SNP (r2>0.8, calculated from reference GIH Hap-Map population) was tested. In the second step, evidence for allelic/locus heterogeneity at aforementioned genes/loci was assessed for by testing additional flanking SNPs in linkage equilibrium with index/surrogate marker.Of the 44 European specific index SNPs, neither index nor surrogate SNPs were present for nine SNPs in the genotyping array. Of the remaining 35, associations were replicated at seven genes namely PTPN22 (rs1217407, p?=?3×10(-3)); IL2-21 (rs13119723, p?=?0.008); HLA-DRB1 (rs660895, p?=?2.56×10(-5); rs6457617, p?=?1.6×10(-09); rs13192471, p?=?6.7×10(-16)); TNFA1P3 (rs9321637, p?=?0.03); CCL21 (rs13293020, p?=?0.01); IL2RA (rs2104286, p?=?1.9×10(-4)) and ZEB1 (rs2793108, p?=?0.006). Of the three Asian specific loci tested, rs2977227 in PADI4 showed modest association (p<0.02). Further, of the 140 SNPs (in LE with index/surrogate variant) tested, association was observed at 11 additional genes: PTPRC, AFF3, CD28, CTLA4, PXK, ANKRD55, TAGAP, CCR6, BLK, CD40 and IL2RB. This study indicates limited replication of European and Asian index SNPs and apparent allelic heterogeneity in RA etiology among north Indians warranting independent GWAS in this population. However, replicated associations of HLA-DRB1, PTPN22 (which confer ?50% of the heritable risk to RA) and IL2RA suggest that cross-ethnicity fine mapping of such loci is apposite for identification of causal variants.

Project description:BackgroundGiven the characteristic atherogenic dyslipidemia of south Indian population and crucial role of APOA1, APOC3, APOA4 and APOA5 genes clustered in 11q23.3 chromosomal region in regulating lipoprotein metabolism and cholesterol homeostasis, a large number of recently identified variants are to be explored for their role in regulating the serum lipid parameters among south Indians.MethodsUsing fluidigm SNP genotyping platform, a prioritized set of 96 SNPs of the 11q23.3 chromosomal region were genotyped on 516 individuals from Hyderabad, India, and its vicinity and aged >45 years.ResultsThe linear regression analysis of the individual lipid traits viz., TC, LDLC, HDLC, VLDL and TG with each of the 78 SNPs that confirm to HWE and with minor allele frequency > 1%, suggests 23 of those to be significantly associated (p ≤ 0.05) with at least one of these quantitative traits. Most importantly, the variant rs632153 is involved in elevating TC, LDLC, TG and VLDLs and probably playing a crucial role in the manifestation of dyslipidemia. Additionally, another three SNPs rs633389, rs2187126 and rs1263163 are found risk conferring to dyslipidemia by elevating LDLC and TC levels in the present population. Further, the ROC (receiver operating curve) analysis for the risk scores and dyslipidemia status yielded a significant area under curve (AUC) = 0.675, suggesting high discriminative power of the risk variants towards the condition. The interaction analysis suggests rs10488699-rs2187126 pair of the BUD13 gene to confer significant risk (Interaction odds ratio = 14.38, P = 7.17 × 105) towards dyslipidemia by elevating the TC levels (β = 37.13, p = 6.614 × 105). On the other hand, the interaction between variants of APOA1 gene and BUD13 and/or ZPR1 regulatory genes at this region are associated with elevated TG and VLDL.ConclusionThe variants at 11q23.3 chromosomal region seem to determine the quantitative lipid traits and in turn dyslipidemia in the population of Hyderabad. Particularly, the variants rs632153, rs633389, rs2187126 and rs1263163 might be risk conferring to dyslipidemia by elevating LDLC and TC levels, while the variants of APOC3 and APOA1 genes might be the genetic determinants of elevated triglycerides in the present population.

Project description:BackgroundHypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk.MethodsWe performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD.ResultsOne rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042).ConclusionsOur results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Dataset Information

A replication study of GWAS-derived lipid genes in Asian Indians: the chromosomal region 11q23.3 harbors loci contributing to triglycerides.

Publications

A replication study of GWAS-derived lipid genes in Asian Indians: the chromosomal region 11q23.3 harbors loci contributing to triglycerides.

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