Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

Originally published 8 Jun 2020 | Circulation: Genomic and Precision Medicine

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Background - Alcohol intake influences plasma lipid levels and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

Methods - In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) were measured in 34,153 individuals with European ancestry from five discovery studies and 32,277 individuals from six replication studies. Rare and low-frequency functional protein coding variants (minor allele frequency ≤ 5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction (G×E) test and a joint test of genetic main and G×E interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least two drinks per week, were considered.

Results - We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9LPALPLLIPGANGPTL4APOBAPOC3 and CD300LG) remained significant after conditioning on the common index single nucleotide polymorphism (SNP) identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on TG in a novel locus was significantly discovered (p-value = 6.65×10-6 for the interaction test) and replicated at nominal significance level (p-value = 0.013) in SMC5.

Conclusions - In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

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