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.
- rheumatoid arthritis
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Contributors Wrote the paper: CT. Conceived and designed the study: CT. Analysed the data: CT, YO, YK. Substantial contribution to acquired samples and creation of data in genome-wide association study: CT, YO, KI, YK, AS, KO, KM, AT, MK, SR, KY, HY, YK, TM, FM. All authors revised and approved the manuscript to be published.
Funding This study was supported by JSPS KAKENHI (grant nos JP16H06251 and JP16K15513), KANAE foundation for the promotion of medical science, The Uehara Memorial Foundation, The John Mung Advanced Program, Kyoto University.
Competing interests None declared.
Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.
Ethics approval This study was approved by the ethical review board in each institution.
Provenance and peer review Not commissioned; externally peer reviewed.