|Title||Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Wang, 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 Authors||CHARGE Gene-Lifestyle Interactions Working Group|
|Journal||Circ Genom Precis Med|
|Date Published||2020 08|
|Keywords||Adolescent, 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 Journal||Circ Genom Precis Med|
|PubMed Central ID||PMC7442680|
|Grant List||R01 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