HLA-DRB1 genotype influences risk for and severity of rheumatoid arthritis

Objective. To examine how HLA-DRB1 genotypes influence rheumatoid arthritis (RA) risk; and clinical severity. Methods. We performed polymerase chain reaction based DRB1 and tumor necros is factor (TNF) genotyping of 309 Caucasian RA and 283 Caucasian control su bjects. For risk analyses, we grouped the DRB1 alleles encoding each specif ic shared epitope: *0401 alone, *0404 with *0102, *0405 with *0408 and *010 1, and *1001 alone. For estimates of RA outcome, we retrospectively obtaine d data regarding ARA classification criteria, age of disease onset and dise ase duration, number of slow acting antirheumatic drugs (SAARD) used, and r heumatoid factor (RF). Results. Homozygous shared-epitope DRB1 genotypes, compound heterozygous ge notypes, and simple heterozygous genotypes all conferred elevated relative risk (RR) for RA (RR 4.3, 11.7, and 3.5, respectively). However, compound h eterozygous genotypes conferred more risk than either simple heterozygous g enotype (RR 3.3, p = 0.004) or homozygous genotype (RR 2.8, p = 0.036). The re was a trend toward more compound heterozygous genotypes in the male RA g roup than in the female RA group (p < 0.1), and male sex was associated wit h higher frequency of rheumatoid nodules (56 vs 35% for female RA). RA outc ome was estimated by number of SAARD used; mean SAARD used was higher in ma le than in female RA (p < 0.01) and higher in genotypes containing one or 2 shared epitope DRB1 alleles than in those negative for shared epitope DRB1 alleles (p < 0.05). Analyses also suggested that shared epitope DRB1 genot ype significantly influenced the occurrence of seropositive RA. Seropositiv e RA fraction was related to either number of shared epitope alleles (0, 1, or 2) represented in the DRB1 genotype, or, alternatively, to the combinat ion of sex with shared epitope DRB1 genotype. The presence of one or 2 shar ed epitope DRB1 alleles influenced the occurrence of high titer seropositiv e RA as defined by sheep cell agglutination rest (p < 0.01). TNFab microsat ellite markers and TNF promoter polymorphisms did not influence SAARD numbe r, seropositive RA, or high titer seropositive RA. Conclusion. Not all shared epitope DRB1 genotypes conferred the same relati ve risk, and the male RA group tended to have more compound heterozygous ge notypes and more severe RA as indicated by rheumatoid nodules and SAARD usa ge. DRB1 genotypes with one or 2 shared epitope DRB1 alleles influenced the RA outcome as estimated by numbers of SAARD used and RF.