Linkage of cytokine genes to rheumatoid arthritis. Evidence of genetic heterogeneity.

OBJECTIVE To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis (RA) in affected sibling pair families stratified for specific clinical features. METHOD Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from: INF alpha, INF gamma, INF beta, IL1 alpha, IL1 beta, IL1R, IL2, IL6, IL5R, IL8R, BCL2, CD40L, NOS3, NRAMP, alpha 1 anti-trypsin, and alpha 1 anti-chymotrypsin, using fluorescence based automated technology. Linkage was examined by defining allele sharing sibling pairs. This was assessed by maximum likelihood-inheritance by descent methods. RESULTS An increase in allele sharing was seen for IL5R in female sibling pairs (LOD 0.91, p = 0.03), for INF gamma in sibling pairs with an affected male (LOD 0.96, p = 0.03) and most significantly for IL2 in sibling pairs where one or both were persistently seronegative (LOD 1.05, p = 0.02). CONCLUSION Weak evidence of linkage of RA to IL5R, IFN gamma, and IL2 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease.