Assessing genotype × environment interaction in linkage mapping using affected sib pairs

Rheumatoid arthritis (RA) is a complex disease that involves both environmental and genetic factors. Elucidation of the basic etiologic factors involved in RA is essential for preventing and treating this disease. However, the etiology of RA, like that of other complex diseases, is largely unknown. In the present study, we conducted autosomal multipoint linkage scans using affected sib pairs by incorporating the smoking status into analysis. We divided the affected sib pairs into three subgroups based on smoking status (ever, current, or never). Interactions between the susceptibility genes and smoking could then be assessed through linkage mapping. Results suggested that the genetic effect of chromosome 6p21.2-3 in concordant current smoker pairs was about two-fold greater than that of the concordant non-current smoker pairs or discordant pairs. With incorporation of smoking status, additional regions with evidence of linkage were identified, including chromosomes 4q and 20q; while evidence of linkage remained in the regions of chromosomes 6p, 8p, and 9p. The interaction effects varied in different regions. Results from our analyses suggested that incorporating smoking status into linkage analyses could increase the statistical power of the multipoint linkage approach applied here and help elucidate the etiology of RA.