Materials
A total of 1096 affected sib pairs from 757 multiplex families in the North American Rheumatoid Arthritis Consortium (NARAC) study were included in the study. Only 615 or 627 sib pairs (depending on the chromosomal regions) had genotype information, and thus these were used for our analysis. The NARAC multiplex families contain 8017 individuals, most of whom are Caucasians (90.6%). We performed the analyses using the entire data set and the subset of Caucasians and found that the results from both data sets were virtually identical. We therefore reported only the results from the entire data set here. A total of 375 microsatellite markers were used in the analyses. There were 615 affected sib pairs available for chromosomes 1–11, 13–16, and 19–22, and 627 affected sib pairs available for chromosomes 12, 17, and 18. The smoking variables included "ever smoker" and "current smoker." Due to the missingness of smoking variables, the total number of affected sib pairs included in the analysis varied from 585 to 597, depending on which smoking variable was used, and which chromosomal region was studied.
Several studies have shown that the association between current heavy smokers and RA was striking, while the association between "ever smokers" and RA was modest (e.g., [6]). To understand the etiology of RA, it is therefore helpful to examine the interactions between these two smoking statuses and the trait locus of RA. The affected sib pairs were stratified according to their smoking status. The gene × smoking effect was examined separately for the two smoking variables. The three groups of affected sib pairs stratified by "ever smoked" status were (never smoked, never smoked) pairs, (never smoked, ever smoked) pairs, and (ever smoked, ever smoked) pairs; they were (non-current smoker, non-current smoker) pairs, (non-current smoker, current smoker) pairs, and (current smoker, current smoker) pairs when stratified by the "current smoking" status. For chromosomes 12, 17, and 18, the numbers of (never smoked, never smoked), (never smoked, ever smoked), and (ever smoked, ever smoked) affected sib pairs were 163, 206, and 225, respectively; there were 160, 203, and 222, respectively, for the rest of chromosomes. In addition, the numbers of affected sib pairs for (non-current smoker, non-current smoker), (non-current smoker, current smoker), and (current smoker, current smoker) were 425, 138, and 34, respectively, for chromosomes 12, 17, and 18, and 417, 137, and 34, respectively, for the rest of chromosomes. Among the 425 (417) concordant "non-current smoker" pairs, 160 (163) of them were concordant "never smoked" pairs, while 34 (34) out of 225 (222) "ever smoked" pairs were "current smoker" pairs. There were 636 (about 39.9%) former smokers who were "ever smokers", yet were not "current smokers." Five affected sibs (about 0.31%) mistakenly reported that they never smoked, yet were current smokers. The difference in numbers of the affected sib pairs defined by never/ever smoked and non-current/current smokers was made by these 641 (636+5) affected sibs.
Statistical methods
The parameters C0, C1, and C2 were the genetic effects for the three groups stratified by one of the smoking statuses, respectively. The GeneHunter program was used to calculate identity-by-decent (IBD) sharing of affected sib pairs. The GeneFinder program was applied to obtain the estimates of τ and C
i
, i = 0, 1, 2, and their 95% confidence intervals, as well as to calculate the p-values of the genetic effects to test whether C values were all equal (that is, if the gene × environment interaction was present). In addition, we compared these results with the results from analyses excluding environmental factors.