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Arterioscler Thromb Vasc Biol. 2014 Jan;34(1):219-25. doi: 10.1161/ATVBAHA.113.302706. Epub 2013 Nov 7.

Genome-wide interaction study identifies RCBTB1 as a modifier for smoking effect on carotid intima-media thickness.

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From the John T. McDonald Department of Human Genetics, John P. Hussman Institute for Human Genomics (L.W., A.B., S.H.B., R.L.S.), Department of Neurology (T.R., S.H.B., R.L.S., C.D.), Department of Public Health Sciences (T.R., R.L.S.), and Department of Medicine (B.H.), Miller School of Medicine, University of Miami, FL; and Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT (H.Z.).



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.


Hispanic Americans; carotid arteries; carotid intima-media thickness

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