title: Genome-wide interaction study identifies RCBTB1 as a modifier for smoking effect on carotid intima-media thickness.
abstract: 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.
  
  
  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(-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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Liyong
authors.initials: L
authors.lastname: Wang
authors.forename: Tatjana
authors.initials: T
authors.lastname: Rundek
authors.forename: Ashley
authors.initials: A
authors.lastname: Beecham
authors.forename: Barry
authors.initials: B
authors.lastname: Hudson
authors.forename: Susan H
authors.initials: SH
authors.lastname: Blanton
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Ralph L
authors.initials: RL
authors.lastname: Sacco
authors.forename: Chuanhui
authors.initials: C
authors.lastname: Dong
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D002339:Carotid Arteries / Q000000981:diagnostic imaging*; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D059168:Carotid Intima-Media Thickness; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009519:New York City / Q000453:epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects* / Q000208:ethnology; D044465:White People / Q000235:genetics
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C482643:RCBTB1 protein, human
keywords: Hispanic Americans; carotid arteries; carotid intima-media thickness