TY - JOUR
T1 - Genome-wide interaction study identifies RCBTB1 as a modifier for smoking effect on carotid intima-media thickness
AU - Wang, Liyong
AU - Rundek, Tatjana
AU - Beecham, Ashley
AU - Hudson, Barry
AU - Blanton, Susan H.
AU - Zhao, Hongyu
AU - Sacco, Ralph L.
AU - Dong, Chuanhui
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/1
Y1 - 2014/1
N2 - OBJECTIVE - 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. APPROACH AND RESULTS - 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 in discovery sample; P=0.01 in the Hispanic replication sample; P<8.8e 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). A consistent trend was observed in the non-Hispanic white and black data sets, leading to an interaction effect of P<2.9e in the meta-analysis of all 1258 subjects. CONCLUSIONS - 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.
AB - OBJECTIVE - 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. APPROACH AND RESULTS - 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 in discovery sample; P=0.01 in the Hispanic replication sample; P<8.8e 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). A consistent trend was observed in the non-Hispanic white and black data sets, leading to an interaction effect of P<2.9e in the meta-analysis of all 1258 subjects. CONCLUSIONS - 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.
KW - Carotid arteries
KW - Carotid intima-media thickness
KW - Hispanic Americans
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U2 - 10.1161/ATVBAHA.113.302706
DO - 10.1161/ATVBAHA.113.302706
M3 - Article
AN - SCOPUS:84891750377
VL - 34
SP - 219
EP - 225
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
SN - 1079-5642
IS - 1
ER -