Abstract
Background: Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants.Results: We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in ITGA7) was associated with fasting triglyceride levels (P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 (P = 1.77E-07) and SLCO2A1 (P = 7.18E-07) and triglycerides, as well as between POT1 (P = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved P-values of 0.04 (ITGA7), 0.08 (SLCO2A1), and 0.02 (POT1). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides (P = 0.07 and P = 0.02), highlighting functional relevance of our findings.Conclusion: In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.
Highlights
MATERIALS AND METHODSThe understanding of the biology behind lipid-metabolism has increased exponentially in the past two decades, enabled by the vast interrogation of the human genome
We found rs11171663 in ITGA7 to be significantly associated with fasting TG levels (P = 7.66E08), explaining approximately 3.2% of the total trait variance
Lack of replication in ethnically distinct cohorts supports the population-specific effect of rare variants on lipid traits, because single-nucleotide variants (SNVs) with P < 0.05 in the top three genes in GOLDN were not found in Heredity and Phenotype Intervention (HAPI) Heart at all, and only few were shared with HyperGEN/Genetic Epidemiology Network of Arteriopathy (GENOA)
Summary
MATERIALS AND METHODSThe understanding of the biology behind lipid-metabolism has increased exponentially in the past two decades, enabled by the vast interrogation of the human genome. Two major limitations exist in the current exploration for causal loci associated with lipid metabolism: (1) Identification of SNVs in non-coding regions or SNVs in large regions that span several candidate genes; and (2) missing detection of candidate genes altogether, if population-specific (Assimes and Quertermous, 2014). Examining exonic variants across diverse ancestry groups likely augments the identification of novel loci. Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. Most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants
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