Causal Role of Alcohol Consumption in an Improved Lipid Profile: The Atherosclerosis Risk in Communities (ARIC) Study

<div><p>Introduction</p><p>Health benefits of low-to-moderate alcohol consumption may operate through an improved lipid profile. A Mendelian randomization (MR) approach was used to examine whether alcohol consumption causally affects lipid levels.</p><p>Methods</p><p>This analysis involved 10,893 European Americans (EA) from the Atherosclerosis Risk in Communities (ARIC) study. Common and rare variants in alcohol dehydrogenase and acetaldehyde dehydrogenase genes were evaluated for MR assumptions. Five variants, residing in the <i>ADH1B</i>, <i>ADH1C</i>, and <i>ADH4</i> genes, were selected as genetic instruments and were combined into an unweighted genetic score. Triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c) and its subfractions (HDL2-c and HDL3-c), low-density lipoprotein cholesterol (LDL-c), small dense LDL-c (sdLDL-c), apolipoprotein B (apoB), and lipoprotein (a) (Lp(a)) levels were analyzed.</p><p>Results</p><p>Alcohol consumption significantly increased HDL2-c and reduced TG, total cholesterol, LDL-c, sdLDL-c, and apoB levels. For each of these lipids a non-linear trend was observed. Compared to the first quartile of alcohol consumption, the third quartile had a 12.3% lower level of TG (p < 0.001), a 7.71 mg/dL lower level of total cholesterol (p = 0.007), a 10.3% higher level of HDL2-c (p = 0.007), a 6.87 mg/dL lower level of LDL-c (p = 0.012), a 7.4% lower level of sdLDL-c (p = 0.037), and a 3.5% lower level of apoB (p = 0.058, p_overall = 0.022).</p><p>Conclusions</p><p>This study supports the causal role of regular low-to-moderate alcohol consumption in increasing HDL2-c, reducing TG, total cholesterol, and LDL-c, and provides evidence for the novel finding that low-to-moderate consumption of alcohol reduces apoB and sdLDL-c levels among EA. However, given the nonlinearity of the effect of alcohol consumption, even within the range of low-to-moderate drinking, increased consumption does not always result in a larger benefit.</p></div

Instrumental Variable analysis using 2SLS.

<p>Instrumental Variable analysis using 2SLS.</p

Final instrumental SNPs.

<p>Final instrumental SNPs.</p

Characteristics of 10,893 ARIC EAs.

<p>Characteristics of 10,893 ARIC EAs.</p

Sensitivity IV analysis excluding heavy drinkers.

<p>Sensitivity IV analysis excluding heavy drinkers.</p

Association between observed alcohol consumption category and lipids.

<p>Association between observed alcohol consumption category and lipids.</p

Independent SNP variants associated with lipid traits within single gene regions.

<p>AA = African American; EA = European American; MAF = major allele frequency. Minor allele frequencies and R² values all derived from ARIC (largest cohort for both African Americans and European Americans). Direction is modeled on the first allele listed in “Alleles” column. Independent SNPs (when they exist) are indicated as: * = lowest <i>P</i> value for locus + trait + ethnicity; ** = lowest <i>P</i> value at or near IBC significance (<i>P</i><1×10⁻⁶) after conditioning on first SNP; *** = lowest <i>P</i> value at or near IBC significance (<i>P</i><1×10⁻⁶) after conditioning on first two independent SNPs; etc. Locus R2 values calculated from all independently significant SNPs at the corresponding locus.</p

SNP variants associated with lipid traits in CARe European Americans and African Americans.

<p>AA = African American; EA = European American; MAF = major allele frequency. Minor allele frequencies all derived from ARIC (largest cohort for both African Americans and European Americans). Bold indicates the most highly associated SNP (lowest <i>P</i> value) at IBC significance (<i>P</i><1×10⁻⁶) for locus + trait + ethnicity. Direction is modeled on the first allele listed in Alleles column.</p

Regional plots for novel lipid loci with array-wide significant regions in IBC meta-analysis of African ancestry.

<p><b>A.. </b><i>CD36</i> region, <b>B.. </b><i>ICAM1</i> region. Loci are shown as the lead SNP with a flanking region depicting the candidate gene and nearby genes included on the array. The purple diamond represents the lead SNP in the IBC meta-analysis and the dots represent the surrounding SNPs, with the different colors showing the LD relationship with the lead SNP based on YRI HapMap II information. −log10 p-values for association with HDL-C (for <i>CD36</i>) and TC (for <i>ICAM1</i>) are shown for each SNP (left-hand axis). Recombination rates in YRI HapMap II is shown in blue traces (right-hand axis).</p

Replication results of nine signals in 7,000 African Americans.

<p>RAF risk allele frequency, SE standard error.</p