Genome-Wide Interaction Study Identifies RCBTB1 as a Modifier for Smoking Effect on Carotid Intima-Media Thickness

Abstract

Carotid intima-media thickness (cIMT), a marker for atherosclerosis, is affected by smoking and has substantial interindividual variation. We sought to identify the genetic moderators influencing the effect of smoking on cIMT. With a multistage design using 722 379 single nucleotide polymorphisms (SNP), a genome-wide interaction study was performed in a discovery sample of 669 Hispanics, followed by replication in 589 subjects (264 Hispanics, 172 non-Hispanic blacks, 153 non-Hispanic whites). Assuming an additive genetic model, regression analysis was performed to test for smoking-SNP interaction on cIMT while controlling for age, sex, and the top 3 principal components of ancestry. The strongest interaction in Hispanics was found with a synonymous splicing SNP (rs3751383) in exon 9 of RCBTB1 (P=2.5e(-6) in discovery sample; P=0.01 in the Hispanic replication sample; P<8.8e(-9) in the combined Hispanic sample). Stratification analysis in the combined Hispanic sample showed that smoking had no effect on cIMT among rs3751383 G homozygote (P=0.15), a moderate effect among rs3751383 heterozygote (P=0.01), and a strong effect among rs3751383 A homozygote (P=2.1e(-7)). A consistent trend was observed in the non-Hispanic white and black data sets, leading to an interaction effect of P<2.9e(-9) in the meta-analysis of all 1258 subjects. Our study represents the first genome-wide smoking-SNP interaction study of cIMT and identifies RCBTB1 as a modifier of the smoking effect on cIMT. Testing for gene-environment interactions can help uncover genetic factors that contribute to the interindividual variation in response to the same environmental exposure.