HLA-DRB1*0401/0404 genotype and rheumatoid arthritis: Increased association in men, young age at onset, and disease severity

Objective. To confirm the reported strong association between the HLA-DRB1*0401/0404 genotype and susceptibility to rheumatoid arthritis (RA), and to investigate the influence of sex, age at disease onset, and variables of disease severity on the strength of this association. Methods. A case control design was adopted comparing the frequency of specific HLA-DRB1 genotypes between 201 Caucasian patients with RA and 139 controls. HLA typing was performed using a polymerase chain reaction based oligonucleotide approach with HLA-DR4 subtyping using an amplification refractory mutation system RFLP technique. Results. The risk of RA in those carrying a single shared epitope (SE) allele was 4 times, and in those carrying 2 SE alleles, 8 times that in the SE negative individuals. This increase was highest in individuals carrying 2 different SE alleles, with the risk in *0401/*0404 cases being 26 times higher. This genotype was associated with a 90-fold increased risk in men and this was more than doubled when age at disease onset was below 30. In all patients with RA, this genotype was associated with a substantially increased risk of being rheumatoid factor positive and having subcutaneous nodules and/or radiological erosion. Conclusion. Possession of the HLA-DRB1*0401/*0404 genotype carries a substantially high risk for RA development specifically in its more severe forms. The risks are particularly increased in young men.