title: Novel genetic variants modify the effect of smoking on carotid plaque burden in Hispanics.
abstract: OBJECTIVE
  Smoking greatly increases the risk of atherosclerotic plaque and the effect may vary from individual to individual. A genome-wide scan was performed for smoking×single nucleotide polymorphism (SNP) interactions on carotid plaque burden (CPB) to identify the potential genetic moderators in Hispanics.
  
  
  METHODS
  Carotid B-mode ultrasonography and genotyping by the Affymetrix 6.0 chip were performed in a discovery sample of 665 Caribbean Hispanics, followed by replication analyses in 264 Caribbean Hispanics. CPB was expressed as the sum of plaque areas over the segments in common and internal carotid arteries and bifurcation. Smoking was classified as 0, <20, and ≥20 cigarette pack-years. Assuming an additive genetic model, regression analysis was conducted to test for smoking×SNP interaction on the cube root transformed CPB while controlling for age, sex, and the top 3 principal components of ancestry.
  
  
  RESULTS
  Two SNPs showed a significant interaction with smoking on CPB with the similar effects in both discovery (P<1.0E-5) and replication (P<0.05) populations. Specifically, for SNP rs10205487 within MXD1, more smoking was significantly associated with greater CPB in A allele carriers (beta±SE: 0.24±0.08, P=0.005 in AG carriers; beta±SE: 0.48±0.12, P=0.0002 in AA carriers) but not in GG (P=0.06). For SNP rs7001413 within LY96 and JPH1, more smoking was significantly associated with greater CPB in GG carriers (beta±SE: 0.24±0.06, P=6.8E-5) but not in T carriers (P=0.06).
  
  
  CONCLUSIONS
  Our study suggests that genetic variants may modulate the effect of smoking on CPB and highlights several genes for further investigation of their role in atherosclerosis, especially in smoking population.
authors: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States; Department of Systems Medicine, School of Medicine, University of Tor Vergata Rome, Italy; IRCCS San Raffaele Pisana, Rome, Italy.
authors: David
authors: D
authors: Della-Morte
authors: John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States.
authors: Liyong
authors: L
authors: Wang
authors: John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States.
authors: Ashley
authors: A
authors: Beecham
authors: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States; John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States.
authors: Susan H
authors: SH
authors: Blanton
authors: Department of Biostatistics, Yale School of Public Health, New Haven, CT, United States.
authors: Hongyu
authors: H
authors: Zhao
authors: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States; John T. McDonald Department of Human Genetics, John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States; Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States.
authors: Ralph L
authors: RL
authors: Sacco
authors: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States; Department of Public Health Sciences, Miller School of Medicine, University of Miami, Miami, FL, United States.
authors: Tatjana
authors: T
authors: Rundek
authors: Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, United States. Electronic address: cdong@med.miami.edu.
authors: Chuanhui
authors: C
authors: Dong
mesh_terms: D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006630:Hispanic or Latino; D006801:Humans; D051218:Lymphocyte Antigen 96 / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000235:genetics* / Q000648:ultrastructure; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012907:Smoking / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D018709:Statistics, Nonparametric
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495377:LY96 protein, human; D051218:Lymphocyte Antigen 96; C079439:MXD1 protein, human; D008565:Membrane Proteins; D012097:Repressor Proteins; C412507:junctophilin
keywords: Atherosclerosis; Carotid plaque; Carotid ultrasonography; Hispanics; Smoking; Smoking-gene interaction