If Genes Spell RA, Smoking Doesn't Punctuate the Problem

SAN FRANCISCO, Aug. 4 -- Women with a strong genetic predisposition to rheumatoid arthritis aren't exacerbating the problem by smoking, surprised investigators here discovered.

Smoking doubled the disease risk for women lacking genetic susceptibility, but in those with strong genetic risk factors -- whose odds of getting the disease were already high -- smoking did not significantly boost the odds further, said Lindsay Criswell, M.D., M.P.H., of the University of California San Francisco.

The results were "unexpected," because Dr. Criswell and colleagues had hypothesized that a genetic predisposition would interact with tobacco exposure to raise the risk for RA higher than either factor could alone, the scientists said online today in the Annals of Rheumatic Diseases.

The analysis included more than 600 older white women (average age 60), enrolled in the Iowa Women's Health Study. Information on disease state and smoking status were obtained via surveys given at baseline in 1986 and again in 1992 and 1997.

In addition, all participants were genotyped for the two most important genetic risk factors known: certain polymorphisms in the HLA-DRB1 gene and in the glutathione S-transferase M1 (GTSM1) gene. Both genes are believed to have a role in metabolizing potentially toxic substances, including the components of tobacco smoke.

About one-quarter of the participants (24.7%) were current smokers and more than 41% had smoked at some point during their lives. During the study period, 115 participants were diagnosed with incident rheumatoid arthritis.

As expected, smoking and the presence of the genetic variations were all independent risk factors for rheumatoid arthritis:

• Smoking: odds ratio=6.0; 95% confidence interval=1.8 to 20.0; P=0.0036
• HLA-DRB1 polymorphism: OR=4.6; 95% CI=1.9 to 11.2; P=0.0006
• GSTM1 polymorphism: OR=3.4; 95% CI=1.4 to 8.2; P=0.0074

Surprisingly, however, smokers with HLA-DRB1 genetic risk did not have increased odds of getting the disease compared with their non-smoking counterparts (OR=0.91; 95% CI=0.48 to 1.72). In individuals without this genetic risk factor, smokers' risk was nearly doubled compared with non-smokers (OR=1.81; 95% CI=0.88 to 3.71).

Similarly, smokers with GTSM1 genetic risk were not significantly more likely to develop rheumatoid arthritis than their non-smoking counterparts (OR=1.32; 95% CI=0.71 to 2.45). However, smokers without GTSM1 genetic risk were at significant increased risk (OR=2.10; 95% CI=1.13 to 3.89).

Genetic predisposition may be "such a strong risk factor for rheumatoid arthritis (main effect) that cigarette smoking adds no additional risk or only a small amount," the researches speculated.

"These provocative results clearly require confirmation in other studies," they added.

The authors pointed out the significance of these observations. "The interaction of genetic susceptibility with environmental risk factors has been insufficiently studied, yet failure to account for this complexity is likely to impede progress in the identification of genetic and environmental determinants of rheumatoid arthritis and other complex diseases," they concluded.

They also pointed out that the study was limited in part by the composition of the study group. All study participants were postmenopausal Caucasian women with a mean age at enrollment of approximately 60, and the sample size was limited.