HLA HAPLOTYPE SHARING IN RHEUMATOID-ARTHRITIS SIBSHIPS - RISK ESTIMATES SUBDIVIDED BY PROBAND GENOTYPE

There is a well-known association between rheumatoid arthritis (RA) an d HLA-DR4. Recent research has indicated that both DR4 haplotypes are important in disease predisposition (favoring a recessive mode of inhe ritance). Others have suggested that certain combinations of genotypes , in particular Dw4/Dw14 heterozygotes, may be more important than oth ers. We examined the mode of inheritance of RA using data from the Art hritis and Rheumatism Council's national repository of family material [Worthington et al. (1994) Br J Rheumatol 33:970-976]. There were 85 affected sibships consisting of 77 sib pairs, 6 trios, 1 quintuplet, a nd 1 sextuplet. The affected sibs shared two, one, and zero parental H LA haplotypes in a ratio of 0.42:0.43:0.15, which was significantly di fferent from random expectations (P = 0.00009). Risk estimates for RA to sibs were calculated based on an overall sibling recurrence risk of 3.9%. Risks for those sharing two, one, and zero parental HLA haploty pes were 6.5% [95% confidence interval (CI) = 5.1-7.9%], 3.3% (95% CI = 2.6-4.0%), and 2.5% (95% CI = 1.5-3.5%), respectively. We also exami ned the risk of RA based on the DR beta 1 genotype status of sib and p roband. After excluding genotypic combinations with small numbers, the highest genotype-specific risks were seen for sibs sharing two haplot ypes with either a DR beta 10401/DR beta 1*0404 (12.5%, 95% CI = 6.9- 15.2%) or a DR beta 10401/ DR beta 1*0408 (11.1%, 95% CI = 4.5-15.1%) proband. An independent assessment based on the AGFAP methodology con firmed the increase in risk for these genotypes, in particular for DR beta 10401/DR beta 1*0408. The excess being due to *0401/*0408 rather than to 0401/*0404 may explain why the Dw4/Dw14 effect is not always observed. Genet. Epidemiol. 15:403-18, 1998. (C) 1998 Wiley-Liss, Inc .