Abstract
Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene–environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10−9. There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.
Highlights
Serum lipids are important determinants of cardiovascular disease and related morbidity [1]
The heritability of circulating lipid levels is estimated to be 40%–60% and recent genome-wide association (GWA) studies implicated a total of 95 loci associated with serum high-density lipoprotein cholesterol (HDL-C), lowdensity lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels [2]
Serum lipids are known to be affected by multiple epidemiological risk factors like body composition, lifestyle, and sex
Summary
Serum lipids are important determinants of cardiovascular disease and related morbidity [1]. Identified common variants explain 10%–12% of the total variation in lipid levels, corresponding to ,25% of the trait heritability [2]. Epidemiological risk factors, such as alcohol consumption, smoking, physical activity, diet and body composition are known to affect lipid levels [3,4,5]. These risk factors show moderate to high heritabilities, and over 120 loci with genome-wide significant association have been identified (http://www.genome.gov/ 26525384). To better understand the biological processes modifying lipid levels, several twin studies [6,7,8] and candidate gene studies [9,10,11,12,13,14] have tested for interactions between genes and epidemiological risk factors
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