Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population

Chikashi Terao, Yukinori Okada, Katsunori Ikari, Yuta Kochi, Akari Suzuki, Koichiro Ohmura, Keitaro Matsuo, Atsuo Taniguchi, Michiaki Kubo, Soumya Raychaudhuri, Kazuhiko Yamamoto, Hisashi Yamanaka, Yoichiro Kamatani, Tsuneyo Mimori, Fumihiko Matsuda

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)853-858
Number of pages6
JournalJournal of Medical Genetics
Volume54
Issue number12
DOIs
Publication statusPublished - 01-12-2017

Fingerprint

HLA-DRB1 Chains
Rheumatoid Arthritis
Alleles
Peptides
Antibodies
Population
Proteins
Heterozygote
Logistic Models
Regression Analysis
Demography
Phenotype

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Terao, Chikashi ; Okada, Yukinori ; Ikari, Katsunori ; Kochi, Yuta ; Suzuki, Akari ; Ohmura, Koichiro ; Matsuo, Keitaro ; Taniguchi, Atsuo ; Kubo, Michiaki ; Raychaudhuri, Soumya ; Yamamoto, Kazuhiko ; Yamanaka, Hisashi ; Kamatani, Yoichiro ; Mimori, Tsuneyo ; Matsuda, Fumihiko. / Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population. In: Journal of Medical Genetics. 2017 ; Vol. 54, No. 12. pp. 853-858.
@article{75390f4da48947cba7a66531d657c337,
title = "Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population",
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.",
author = "Chikashi Terao and Yukinori Okada and Katsunori Ikari and Yuta Kochi and Akari Suzuki and Koichiro Ohmura and Keitaro Matsuo and Atsuo Taniguchi and Michiaki Kubo and Soumya Raychaudhuri and Kazuhiko Yamamoto and Hisashi Yamanaka and Yoichiro Kamatani and Tsuneyo Mimori and Fumihiko Matsuda",
year = "2017",
month = "12",
day = "1",
doi = "10.1136/jmedgenet-2017-104779",
language = "English",
volume = "54",
pages = "853--858",
journal = "Journal of Medical Genetics",
issn = "0022-2593",
publisher = "BMJ Publishing Group",
number = "12",

}

Terao, C, Okada, Y, Ikari, K, Kochi, Y, Suzuki, A, Ohmura, K, Matsuo, K, Taniguchi, A, Kubo, M, Raychaudhuri, S, Yamamoto, K, Yamanaka, H, Kamatani, Y, Mimori, T & Matsuda, F 2017, 'Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population', Journal of Medical Genetics, vol. 54, no. 12, pp. 853-858. https://doi.org/10.1136/jmedgenet-2017-104779

Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population. / Terao, Chikashi; Okada, Yukinori; Ikari, Katsunori; Kochi, Yuta; Suzuki, Akari; Ohmura, Koichiro; Matsuo, Keitaro; Taniguchi, Atsuo; Kubo, Michiaki; Raychaudhuri, Soumya; Yamamoto, Kazuhiko; Yamanaka, Hisashi; Kamatani, Yoichiro; Mimori, Tsuneyo; Matsuda, Fumihiko.

In: Journal of Medical Genetics, Vol. 54, No. 12, 01.12.2017, p. 853-858.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic landscape of interactive effects of HLA-DRB1 alleles on susceptibility to ACPA(+) rheumatoid arthritis and ACPA levels in Japanese population

AU - Terao, Chikashi

AU - Okada, Yukinori

AU - Ikari, Katsunori

AU - Kochi, Yuta

AU - Suzuki, Akari

AU - Ohmura, Koichiro

AU - Matsuo, Keitaro

AU - Taniguchi, Atsuo

AU - Kubo, Michiaki

AU - Raychaudhuri, Soumya

AU - Yamamoto, Kazuhiko

AU - Yamanaka, Hisashi

AU - Kamatani, Yoichiro

AU - Mimori, Tsuneyo

AU - Matsuda, Fumihiko

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85037050508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85037050508&partnerID=8YFLogxK

U2 - 10.1136/jmedgenet-2017-104779

DO - 10.1136/jmedgenet-2017-104779

M3 - Article

VL - 54

SP - 853

EP - 858

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

IS - 12

ER -