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

TitleRole of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.
Publication TypeJournal Article
Year of Publication2020
AuthorsWang, Z, Chen, H, Bartz, TM, Bielak, LF, Chasman, DI, Feitosa, MF, Franceschini, N, Guo, X, Lim, E, Noordam, R, Richard, MA, Wang, H, Cade, B, L Cupples, A, de Vries, PS, Giulanini, F, Lee, J, Lemaitre, RN, Martin, LW, Reiner, AP, Rich, SS, Schreiner, PJ, Sidney, S, Sitlani, CM, Smith, JA, van Dijk, KWillems, Yao, J, Zhao, W, Fornage, M, Kardia, SLR, Kooperberg, C, Liu, C-T, Mook-Kanamori, DO, Province, MA, Psaty, BM, Redline, S, Ridker, PM, Rotter, JI, Boerwinkle, E, Morrison, AC
Corporate AuthorsCHARGE Gene-Lifestyle Interactions Working Group
JournalCirc Genom Precis Med
Date Published2020 08
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Alcohol Drinking, Apolipoproteins E, Cholesterol, HDL, Female, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Humans, Lipids, Male, Middle Aged, Polymorphism, Single Nucleotide, Proprotein Convertase 9, Triglycerides, Whites, Young Adult

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 consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 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 test and a joint test of genetic main and gene-environment 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 2 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 (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism 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 triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

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.

Alternate JournalCirc Genom Precis Med
PubMed ID32510982
PubMed Central IDPMC7442680
Grant ListR01 HL120393 / HL / NHLBI NIH HHS / United States
K01 HL135405 / HL / NHLBI NIH HHS / United States
R21 HL140385 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
U01 HL120393 / HL / NHLBI NIH HHS / United States
R01 DK117445 / DK / NIDDK NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
R01 HL118305 / HL / NHLBI NIH HHS / United States
R03 HL154284 / HL / NHLBI NIH HHS / United States
R01 MD012765 / MD / NIMHD NIH HHS / United States