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Allele-specific enhancers mediate associations between LCAT and ABCA1 polymorphisms and HDL metabolism.

ABSTRACT: For most complex traits, the majority of SNPs identified through genome-wide association studies (GWAS) reside within noncoding regions that have no known function. However, these regions are enriched for the regulatory enhancers specific to the cells relevant to the specific trait. Indeed, many of the GWAS loci that have been functionally characterized lie within enhancers that regulate expression levels of key genes. In order to identify polymorphisms with potential allele-specific regulatory effects, we developed a bioinformatics pipeline that harnesses epigenetic signatures as well as transcription factor (TF) binding motifs to identify putative enhancers containing a SNP with potential allele-specific TF binding in linkage disequilibrium (LD) with a GWAS-identified SNP. We applied the approach to GWAS findings for blood lipids, revealing 7 putative enhancers harboring associated SNPs, 3 of which lie within the introns of LCAT and ABCA1, genes that play crucial roles in cholesterol biogenesis and lipoprotein metabolism. All 3 enhancers demonstrated allele-specific in vitro regulatory activity in liver-derived cell lines. We demonstrated that these putative enhancers are in close physical proximity to the promoters of their respective genes, in situ, likely through chromatin looping. In addition, the associated alleles altered the likelihood of transcription activator STAT3 binding. Our results demonstrate that through our approach, the LD blocks that contain GWAS signals, often hundreds of kilobases in size with multiple SNPs serving as statistical proxies to the true functional site, can provide an experimentally testable hypothesis for the underlying regulatory mechanism linking genetic variants to complex traits.

SUBMITTER: Howard AD

PROVIDER: S-EPMC6490890 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Allele-specific enhancers mediate associations between LCAT and ABCA1 polymorphisms and HDL metabolism.

Howard Alicia D AD Wang Xiaochun X Prasad Megana M Sahu Avinash Das AD Aniba Radhouane R Miller Michael M Hannenhalli Sridhar S Chang Yen-Pei Christy YC

PloS one 20190430 4

For most complex traits, the majority of SNPs identified through genome-wide association studies (GWAS) reside within noncoding regions that have no known function. However, these regions are enriched for the regulatory enhancers specific to the cells relevant to the specific trait. Indeed, many of the GWAS loci that have been functionally characterized lie within enhancers that regulate expression levels of key genes. In order to identify polymorphisms with potential allele-specific regulatory ...[more]

PMID: 31039173

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Project description:BACKGROUND:Studies on the associations of the adenosine triphosphate-binding cassette transporter A1 gene (ABCA1) rs2230806, rs2230808, and rs2066714 polymorphisms with plasma lipid levels have reported apparently conflicting findings. This meta-analysis aimed to clarify the relationships between the 3 polymorphisms and fasting lipid levels. METHODS:A comprehensive search of the literature was carried out by using the databases including Medline, Google Scholar, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and VIP. The studies that presented mean lipids and standard deviations or standard errors according to the rs2230806, rs2230808, and/or rs2066714 genotypes were examined and included. The random effects model was used. Standardized mean difference and 95% confidence interval were used to assess the differences in lipid levels between the genotypes. Heterogeneity among studies was tested by Cochran's ?-based Q-statistic, and Galbraith plots were used to detect the potential sources of heterogeneity. Publication bias was assessed by Begg's rank correlation test as well as funnel plots. RESULTS:Sixty-two studies (48,452 subjects), 12 studies (9853 subjects) and 14 studies (10,727 subjects) were identified for the rs2230806, rs2230808, and rs2066714 polymorphisms, respectively. A dominant model was used for all the polymorphisms in this meta-analysis. The A allele carriers of the rs2230806 polymorphism had higher levels of high-density lipoprotein cholesterol (HDL-C) (P?<.001), and lower levels of low-density lipoprotein cholesterol (LDL-C) (P?=.03) and triglycerides (TG) (P?<.01) than the non-carriers. The A allele carriers of the rs2230808 polymorphism had higher levels of total cholesterol (TC) (P?<.001) than the non-carriers. The G allele carriers of the rs2066714 polymorphism had higher levels of TC (P?<.01) and HDL-C (P?=?.02) than the non-carriers. CONCLUSION:The ABCA1 rs2230806, rs2230808, and rs2066714 polymorphisms are significantly associated with plasma lipid levels in the present meta-analysis.

Dataset Information

Allele-specific enhancers mediate associations between LCAT and ABCA1 polymorphisms and HDL metabolism.

Publications

Allele-specific enhancers mediate associations between LCAT and ABCA1 polymorphisms and HDL metabolism.

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