Association of HLA-DRB1 genotype with younger age onset and elder age onset rheumatoid arthritis in Japanese populations

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint destructions and human leukocyte antigen (HLA)-DRB1 is an important genetic risk factor for RA and influences the phenotype of RA. The clinical features of elder age onset RA (EORA) were known to be different from those of younger age onset RA (YORA). Previous studies reported the different association pattern of DRB1 alleles with YORA or EORA. The associations of DRB1 genotype with these RA subsets remained almost unknown. We investigated the genotype association of DRB1 with YORA or EORA in Japanese populations. HLA genotyping was performed in Japanese RA patients and the association of allele or genotype carrier frequencies were analyzed. The genotype frequency of DRB1(∗)04:05/DRB1(∗)04:06 (P = .0204, OR 7.69, 95%CI 1.39–42.72), DRB1(∗)04:05/DRB1(∗)12:01 (P = .0050, OR 5.53, 95%CI 1.71–17.88), and DRB1(∗)04:05/DRB1(∗)15:01 (P = .0124, OR 3.34, 95%CI 1.39–8.02) in YORA was higher than EORA. However, the frequencies of DRB1(∗)01:01/DRB1(∗)04:05 in YORA was tended to be lower than EORA (P = .0784, OR 0.14, 95%CI 0.01–2.42). The gene dosage effect of the shared epitope alleles was detected in EORA, but not in YORA. Trans-complementing DQ heterodimer molecules, formed by DQA1 and DQB1 of the haplotypes with and without shared epitope alleles, might explain the higher genotype frequencies of “shared epitope /not shared epitope”. Linear regression analyses showed the primary role of DQB1(∗)04:01 allele for the age at onset of RA. This is the first report for the associations of DRB1 genotype with YORA or EORA in the Japanese population and the differential distribution of the genotypes was noted between these RA subsets. The involvement of DQ molecules for the age at onset of RA was suggested.