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: INFα, INFγ, INFβ, IL1α, IL1β, IL1R, IL2, IL6, ILSR, ILSR, BCL2, CD40L, NOS3, NRAMP, α1 anti-trypsins and α1, 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 INFγ 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, IFNγ, and IL2 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease.