title: Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans.
abstract: OBJECTIVE
  To examine whether polymorphisms in genes coding for drug-metabolizing enzymes (DMEs) have an impact on rheumatoid arthritis (RA) risk due to cigarette smoking in African Americans.
  
  
  METHODS
  Smoking status was evaluated in African American patients with RA compared with non-RA controls, with smoking exposure categorized as heavy smoker (≥10 pack-years) versus never smoker/<10 pack-years. Individuals were genotyped for a homozygous deletion polymorphism in the M1 gene loci of glutathione S-transferase (GSTM1-null) in addition to tagging single-nucleotide polymorphisms (SNPs) in N-acetyltransferase 1 (NAT1), NAT2, and epoxide hydrolase 1 (EPXH1). Associations of these genotypes with RA risk were examined using logistic regression, and gene-smoking interactions were assessed.
  
  
  RESULTS
  There were no significant associations of any DME genotype with RA. After adjustment for multiple comparisons, there were significant additive interactions between heavy smoking and the NAT2 SNPs rs9987109 (P(additive)  = 0.000003) and rs1208 (P(additive)  = 0.00001); the attributable proportion due to interaction ranged from 0.61 to 0.67. None of the multiplicative gene-smoking interactions examined remained significant with regard to overall disease risk, after adjustment for multiple testing. There was no evidence of significant gene-smoking interactions in analyses of GSTM1-null, NAT1, or EPXH1. DME gene-smoking interactions were similar when cases were limited to those patients who were positive for anti-citrullinated protein antibodies.
  
  
  CONCLUSIONS
  Among African Americans, RA risk imposed by heavy smoking appears to be mediated in part by genetic variation in NAT2. While further studies are needed to elucidate the mechanisms underpinning these interactions, these SNPs appear to identify African American smokers at a much higher risk for RA, in whom the relative risk is at least 2-fold higher when compared to nonsmokers lacking these risk alleles.
authors: Department of Medicine, University of Nebraska Medical Center and Omaha VA Medical Center, Omaha, NE 68198-6270, USA. tmikuls@unmc.edu
authors: Ted R
authors: TR
authors: Mikuls
authors: Tricia
authors: T
authors: Levan
authors: Karen A
authors: KA
authors: Gould
authors: Fang
authors: F
authors: Yu
authors: Geoffrey M
authors: GM
authors: Thiele
authors: Kimberly K
authors: KK
authors: Bynote
authors: Doyt
authors: D
authors: Conn
authors: Beth L
authors: BL
authors: Jonas
authors: Leigh F
authors: LF
authors: Callahan
authors: Edwin
authors: E
authors: Smith
authors: Richard
authors: R
authors: Brasington
authors: Larry W
authors: LW
authors: Moreland
authors: Richard
authors: R
authors: Reynolds
authors: Angelo
authors: A
authors: Gaffo
authors: S Louis
authors: SL
authors: Bridges
mesh_terms: D001741:Black or African American / Q000208:ethnology / Q000235:genetics*; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D016022:Case-Control Studies; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D014481:United States / Q000453:epidemiology
chemical_list: D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D004851:Epoxide Hydrolases; C522330:EPHX1 protein, human