Abstract
BACKGROUND: HLA-DRB1 is the strongest susceptibility gene to rheumatoid arthritis (RA). HLA-DRB1 alleles showed significant non-additive and interactive effects on susceptibility to RA in the European population, but these effects on RA susceptibility should vary between populations due to the difference in allelic distribution. Furthermore, non-additive or interactive effects on the phenotypes of RA are not fully known. We evaluated the non-additive and interactive effects of HLA-DRB1 alleles on RA susceptibility and anticitrullinated protein/peptide antibody (ACPA) levels in Japanese patients. METHODS: A total of 5581 ACPA(+) RA and 19 170 controls were genotyped or imputed for HLA-DRB1 alleles. Logistic regression analysis was performed for both allelic non-additive effects and interactive effects of allelic combinations. The significant levels were set by Bonferroni's correction. A total of 4371 ACPA(+) RA were analysed for ACPA levels. RESULTS: We obtained evidence of non-additive and interactive effects of HLA-DRB1 on ACPA(+) RA susceptibility (p=2.5×10(-5) and 1.5×10(-17), respectively). Multiple HLA-DRB1 alleles including HLA-DRB1*04:05, the most common susceptibility allele in the Japanese, showed significant non-additive effects (p≤0.0043). We identified multiple allelic combinations with significant interactive effects including a common combination with the European population as well as novel combinations. Additional variance of ACPA(+) RA susceptibility could be explained substantially by heterozygote dominance or interactive effects. We did not find evidence of non-additive and interactive effects on levels of ACPA. CONCLUSION: HLA allelic non-additive and interactive effects on ACPA(+) RA susceptibility were observed in the Japanese population. The allelic non-additive and interactive effects depend on allelic distribution in populations.