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

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 ( PCSK9 , LPA , LPL , LIPG , ANGPTL4 , APOB , APOC3 , and CD300LG ) 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 ( P =6.65×10 −6 for the interaction test) and replicated at nominal significance level ( P =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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Role of Rare and Low Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

10.1101/561225 ◽

2019 ◽

Author(s):

Zhe Wang ◽

Han Chen ◽

Traci M. Bartz ◽

Lawrence F. Bielak ◽

Daniel I. Chasman ◽

...

Keyword(s):

Alcohol Consumption ◽

Association Studies ◽

Plasma Lipid ◽

Low Frequency ◽

Environment Interaction ◽

Genome Wide Association Studies ◽

Lipid Levels ◽

Gxe Interaction ◽

Fasting Plasma

AbstractBackgroundAlcohol intake influences plasma lipid levels and such effects may be modulated by genetic variants.ObjectiveWe aimed to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.DesignIn 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 European Americans from five discovery studies and 32,275 individuals from six replication studies. Rare and low-frequency protein coding variants (minor allele frequency ≤ 5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction (GxE) test and a joint test of genetic main and GxE 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.ResultsWe discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3 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 was discovered at a Bonferroni corrected significance level (p-value <5×10−5) and replicated (p-value <0.013 for the interaction test) inSMC5.ConclusionsIn conclusion, this study applied new gene-based statistical approaches to uncover the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels.

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Abstract P130: Infant Growth as an Effect Modifier of Genetic-lipid Associations: Evidence From a Chilean Infancy Cohort

Circulation ◽

10.1161/circ.137.suppl_1.p130 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Ann Von Holle ◽

Kari E North ◽

Sheila Gahagan ◽

Estela Blanco ◽

Misa Graff ◽

...

Keyword(s):

High Velocity ◽

Growth Trajectories ◽

Environment Interaction ◽

Lipid Levels ◽

Latent Growth ◽

Low Velocity ◽

Gene Environment Interaction ◽

High Acceleration ◽

Gene Environment

Background: The postnatal period can function as a window of time for metabolic programming. As evidence from human observational studies is scarce, we examined the role of postnatal weight, length (linear growth), and weight-for-length (WFL) growth trajectories as effect modifiers of established single nucleotide polymorphism (SNP) associations on lipid levels in a cohort of adolescents from the Santiago Longitudinal Study (SLS) (n=484). Methods: Growth trajectories were characterized via two different approaches: nonlinear mixed effects model (SITAR) and a latent growth mixture model (LGMM). We assessed gene-environment interaction in an additive model within: 1) SITAR including product terms that accurately reflects the trichotomous genetic term, and 2) LGMM using stratified SNP-lipid associations by latent growth patterns. Bonferroni-corrected significant findings are reported. Results: SITAR models did not reveal any evidence of gene-environment interaction. In contrast, given three LGMM patterns of growth, gene-environment interactions emerge for both weight and WFL trajectories. One group of infants had lower velocity but higher acceleration; another group had medium velocity and lower acceleration; a third group had high velocity and lower acceleration. The association between the rs7412 (APOE) variant and HDL (mg/dL) was negative for the low velocity/high acceleration weight trajectory group (mean= -10.2; 95% CI = -16.0, -4.5; n~23) compared to the high velocity/low acceleration group (mean = 11.3; 95% CI = 2.6, 20; n~152). Similarly, the association (95% CI) between the rs78536982 (BAI3, LMBRD1) variant and triglycerides (log(mg/dL) was lower for the low velocity/high acceleration WFL group (-0.61; 0.84, -0.37; n~24) when compared to both the medium velocity/low acceleration (-0.09; -0.23, 0.05; n~271) and high velocity/low acceleration (0.001; -0.11, 0.11; n~189). In sex-stratified analyses, the high velocity/low acceleration group for males (n=254) had a negative association (95% CI) between the rs11076175 (CETP) variant and LDL (mg/dL) (-10.6; -16.7, -4.5; n~140) versus a positive association for the low velocity/high acceleration (12.6; 2.93, 22.2; n~114). Summary: These results demonstrate potential heterogeneity in the genetic association between lipid loci and adolescent lipid levels across different patterns of growth from 0 to 5 months. Future work to examine the role of infant growth as a causal factor in direct and indirect effects is of interest.

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Abstract MP62: Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

Circulation ◽

10.1161/circ.137.suppl_1.mp62 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Zhe Wang ◽

Han Chen ◽

Daniel I Chasman ◽

Ching-Ti Liu ◽

Raymond Noordam ◽

...

Keyword(s):

Alcohol Consumption ◽

Plasma Lipid ◽

Low Frequency ◽

Joint Analysis ◽

Genome Wide Association Studies ◽

Lipid Levels ◽

Gxe Interaction ◽

Functional Variants ◽

Fasting Plasma

Introduction: Alcohol intake modifies plasma lipid levels and such effects may be modulated by genetic variants. We use emerging statistical methods that extend well-established common variant approaches to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. Methods: Up to 247,870 exonic variants on the Illumina HumanExome BeadChip and fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-c and LDL-c) were measured in 46,443 European Americans from 4 studies (the Atherosclerosis Risk in Communities (ARIC) study, the Framingham Heart Study, the Netherlands Epidemiology of Obesity Study and the Women’s Genome Health Study) of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Using the gene-based rareGE method, we conducted exome-wide gene-environment (GxE) tests with genetic main effects estimated as fixed and random effects, and a joint analysis of genetic main and GxE interaction effects. Rare and low-frequency (minor allele frequency ≤ 5%) functional variants, (i.e. frameshift, nonsynonymous, stop/gain, stop/loss, and splicing) were aggregated by genes. Two dichotomous self-reported alcohol consumption variables, current drinker (at least 1 drink per week, yes/no) and regular drinker (at least 2 drinks per week, yes/no) were considered. A sample size weighted Z-test (weighted Stouffer’s method) was used to meta-analyze study-specific p -values. Exome-wide significance level was set at p < 3.7*10 -6 (0.05/13368 genes), using a Bonferroni procedure to correct for multiple testing. Results: We identified 24 gene-lipid associations at 13 known lipid loci (within 500kb) harboring rare and low-frequency variants through the joint analysis. In ARIC, numerous genes ( PCSK9, LPL, LIPG, ANGPTL4, APOB, APOC3-A5 ) remained significant after conditioning on common index single nucleotide polymorphisms (SNPs), suggesting an independent role for rare variants at loci highlighted by previous genome-wide association studies. However, no significant gene-alcohol interactions were observed with rare and low-frequency variants on TG, HDL-c or LDL-c. Conclusion: This study applied new statistical approaches to investigate the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels. Results show promise for other larger scale studies analyzing rare variant GxE interactions.

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