Polymorphisms in n-acetyltransferase 2 impact rheumatoid arthritis risk due to cigarette smoking in African Americans

Abstract

Background/Purpose: Cigarette smoking is associated with an elevated risk of rheumatoid arthritis (RA) in African Americans, a risk that is most striking for those with a cumulative exposure of 10 or more pack-years. Recognizing that the risk of developing other smoking-related conditions is impacted by genetic variation in genes encoding drug metabolizing enzymes (DMEs), we sought to examine whether the risk of RA attributable to smoking in African Americans differs based on the presence of select DME gene polymorphisms. Methods: RA cases (n=727) and controls (n=268) were participants in the Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registry. Participants were categorized as either heavy smokers (>= 10 pack-years) or other (< 10 pack-years including never smokers). Tagging single nucleotide polymorphisms (SNPs) encoding N-acetyltransferase 1 (NAT1), NAT2, and epoxide hydroxylase (EPXH1) and a homozygous deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) were genotyped. RA risk was evaluated for each polymorphism using logistic regression adjusting for age and gender. Evidence of gene-smoking interactions was examined by calculating the attributable proportion (AP; additive interaction) due to interaction and by modeling the polymorphism-smoking product term (multiplicative interaction). A Bonferroni correction was used to adjust for multiple comparisons (n = 30 polymorphisms) and the level of significance was set at a p-value < 0.0017 (0.05 / 30). Haplotype analyses were constructed for NAT2 SNPs yielding at least borderline evidence of interaction (p < 0.05). A secondary analysis was conducted to evaluate the same outcomes in cases that were positive for anti-citrullinated protein antibody (ACPA). Results: There were no associations of RA risk with any of the individual polymorphisms examined and there were no significant interactions between heavy smoking and the GSTM1-null, NAT1, or EPXH1 polymorphisms after adjusting for multiple comparisons. In contrast, there were 3 NAT2 tagging SNPs with evidence of at least borderline interaction with heavy smoking in RA risk (Table 1). The NAT2 rs9987109 and rs1208 SNPs demonstrated significant additive interactions with heavy smoking. NAT2 haplotype analyses were consistent with the individual tagging SNP analyses and interactions were similar for overall disease risk compared to the risk of ACPA-positive RA. (Table presented) Conclusion: These results show that the risk of RA in African Americans due to heavy smoking is mediated by genetic variation in NAT2. These results may provide important insight into disease pathogenesis and the constituents of cigarette smoke that may drive RA risk in this understudied population.