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 4.7961029
. 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.