Glutathione S-transferase (GST) genes as well as heme oxygenase 1 gene (HMOX1) encode enzymes that detoxify carcinogens and protect against oxidative stress. This study was undertaken to examine the impact of gene-smoking interactions on susceptibility to rheumatoid arthritis (RA).
Caucasian patients with RA and matched control subjects (n = 549 each) were selected from the Nurses' Health Study. Genotyping of the patients' blood by TaqMan and BioTrove assays identified homozygous deletions at the M1 and T1 loci of GST (GSTM1-null and GSTT1-null, respectively) as well as alleles for GSTP1 (rs1695) and HMOX1 (rs2071746). In addition, the effect of gene-smoking interactions on the risk of all RA and RA serologic phenotypes was studied in separate logistic models that were adjusted for covariates. Multiplicative interactions were assessed by including a product term in a logistic model, and additive interactions were assessed using the attributable proportion (AP) due to interaction. For replication of the results, analyses revealing significant interactions were repeated in an independent case-control cohort from the Epidemiological Investigation of Rheumatoid Arthritis study.
For the risk of all RA, multiplicative (P = 0.05) and additive (AP = 0.53, P = 0.0005) interactions between the GSTT1-null polymorphism and smoking and multiplicative interactions (P = 0.05) between HMOX1 and smoking were observed. For the risk of seropositive RA, multiplicative (P = 0.01) and additive (AP = 0.62, P < 0.0001) interactions between GSTT1-null and smoking and additive interactions (AP = 0.41, P = 0.03) between HMOX1 and smoking were observed. After correction for multiple comparisons, the additive interactions between GSTT1-null and smoking remained significant. The M1-null and P1 variants of GST did not show significant interactions, and no associations with seronegative RA were observed. In replication analyses, significant multiplicative interactions (P = 0.04) and additive interactions (AP = 0.32, P = 0.02) were observed between GSTT1-null and smoking in the risk of anti-citrullinated protein antibody-positive RA.
Significant gene-environment interactions between the GSTT1-null polymorphism and heavy smoking were observed when assessing the risk of RA. Future studies are needed to assess the impact of these interactions on RA prediction.