An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis

Chikashi Terao, Akari Suzuki, Katsunori Ikari, Yuta Kochi, Koichiro Ohmura, Masaki Katayama, Shuichiro Nakabo, Natsuki Yamamoto, Taku Suzuki, Takuji Iwamoto, Kimiko Yurugi, Yasuo Miura, Taira Maekawa, Kiyoshi Takasugi, Michiaki Kubo, Hiroh Saji, Atsuo Taniguchi, Shigeki Momohara, Kazuhiko Yamamoto, Hisashi YamanakaTsuneyo Mimori, Fumihiko Matsuda

Research output: Contribution to journalArticle

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Abstract

Objective Anti-citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA-DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA-DRB1 and ACPA levels in patients with RA. Methods We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA-DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA. Results HLA-DRB1∗09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. HLA-DRB1∗08:03 and DRB1∗14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P=1.9 × 10-51). The association was mainly conferred by alanine residue (P=4.5 × 10-51). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA-DRB1 alleles (HLA-DRB1∗08:03, DRB1∗09:01, DRB1∗14:06, DRB1∗15:01, and DRB1 15:02). Conclusion Amino acid position 74 in HLA-DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap.

Original languageEnglish
Pages (from-to)2038-2045
Number of pages8
JournalArthritis and Rheumatology
Volume67
Issue number8
DOIs
Publication statusPublished - 01-08-2015

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HLA-DRB1 Chains
Rheumatoid Arthritis
Amino Acids
Antibodies
Proteins
Alleles

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology

Cite this

Terao, Chikashi ; Suzuki, Akari ; Ikari, Katsunori ; Kochi, Yuta ; Ohmura, Koichiro ; Katayama, Masaki ; Nakabo, Shuichiro ; Yamamoto, Natsuki ; Suzuki, Taku ; Iwamoto, Takuji ; Yurugi, Kimiko ; Miura, Yasuo ; Maekawa, Taira ; Takasugi, Kiyoshi ; Kubo, Michiaki ; Saji, Hiroh ; Taniguchi, Atsuo ; Momohara, Shigeki ; Yamamoto, Kazuhiko ; Yamanaka, Hisashi ; Mimori, Tsuneyo ; Matsuda, Fumihiko. / An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis. In: Arthritis and Rheumatology. 2015 ; Vol. 67, No. 8. pp. 2038-2045.
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title = "An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis",
abstract = "Objective Anti-citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA-DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA-DRB1 and ACPA levels in patients with RA. Methods We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA-DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA. Results HLA-DRB1∗09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. HLA-DRB1∗08:03 and DRB1∗14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P=1.9 × 10-51). The association was mainly conferred by alanine residue (P=4.5 × 10-51). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA-DRB1 alleles (HLA-DRB1∗08:03, DRB1∗09:01, DRB1∗14:06, DRB1∗15:01, and DRB1 15:02). Conclusion Amino acid position 74 in HLA-DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap.",
author = "Chikashi Terao and Akari Suzuki and Katsunori Ikari and Yuta Kochi and Koichiro Ohmura and Masaki Katayama and Shuichiro Nakabo and Natsuki Yamamoto and Taku Suzuki and Takuji Iwamoto and Kimiko Yurugi and Yasuo Miura and Taira Maekawa and Kiyoshi Takasugi and Michiaki Kubo and Hiroh Saji and Atsuo Taniguchi and Shigeki Momohara and Kazuhiko Yamamoto and Hisashi Yamanaka and Tsuneyo Mimori and Fumihiko Matsuda",
year = "2015",
month = "8",
day = "1",
doi = "10.1002/art.39133",
language = "English",
volume = "67",
pages = "2038--2045",
journal = "Arthritis and Rheumatology",
issn = "2326-5191",
publisher = "John Wiley and Sons Ltd",
number = "8",

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Terao, C, Suzuki, A, Ikari, K, Kochi, Y, Ohmura, K, Katayama, M, Nakabo, S, Yamamoto, N, Suzuki, T, Iwamoto, T, Yurugi, K, Miura, Y, Maekawa, T, Takasugi, K, Kubo, M, Saji, H, Taniguchi, A, Momohara, S, Yamamoto, K, Yamanaka, H, Mimori, T & Matsuda, F 2015, 'An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis', Arthritis and Rheumatology, vol. 67, no. 8, pp. 2038-2045. https://doi.org/10.1002/art.39133

An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis. / Terao, Chikashi; Suzuki, Akari; Ikari, Katsunori; Kochi, Yuta; Ohmura, Koichiro; Katayama, Masaki; Nakabo, Shuichiro; Yamamoto, Natsuki; Suzuki, Taku; Iwamoto, Takuji; Yurugi, Kimiko; Miura, Yasuo; Maekawa, Taira; Takasugi, Kiyoshi; Kubo, Michiaki; Saji, Hiroh; Taniguchi, Atsuo; Momohara, Shigeki; Yamamoto, Kazuhiko; Yamanaka, Hisashi; Mimori, Tsuneyo; Matsuda, Fumihiko.

In: Arthritis and Rheumatology, Vol. 67, No. 8, 01.08.2015, p. 2038-2045.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An association between amino acid position 74 of HLA-DRB1 and anti-citrullinated protein antibody levels in Japanese patients with anti-citrullinated protein antibody-positive rheumatoid arthritis

AU - Terao, Chikashi

AU - Suzuki, Akari

AU - Ikari, Katsunori

AU - Kochi, Yuta

AU - Ohmura, Koichiro

AU - Katayama, Masaki

AU - Nakabo, Shuichiro

AU - Yamamoto, Natsuki

AU - Suzuki, Taku

AU - Iwamoto, Takuji

AU - Yurugi, Kimiko

AU - Miura, Yasuo

AU - Maekawa, Taira

AU - Takasugi, Kiyoshi

AU - Kubo, Michiaki

AU - Saji, Hiroh

AU - Taniguchi, Atsuo

AU - Momohara, Shigeki

AU - Yamamoto, Kazuhiko

AU - Yamanaka, Hisashi

AU - Mimori, Tsuneyo

AU - Matsuda, Fumihiko

PY - 2015/8/1

Y1 - 2015/8/1

N2 - Objective Anti-citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA-DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA-DRB1 and ACPA levels in patients with RA. Methods We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA-DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA. Results HLA-DRB1∗09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. HLA-DRB1∗08:03 and DRB1∗14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P=1.9 × 10-51). The association was mainly conferred by alanine residue (P=4.5 × 10-51). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA-DRB1 alleles (HLA-DRB1∗08:03, DRB1∗09:01, DRB1∗14:06, DRB1∗15:01, and DRB1 15:02). Conclusion Amino acid position 74 in HLA-DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap.

AB - Objective Anti-citrullinated protein antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA), and strong associations between HLA-DRB1 alleles and ACPA levels have been detected in RA patients. We undertook this study to elucidate the associations between particular amino acid positions in HLA-DRB1 and ACPA levels in patients with RA. Methods We analyzed ACPA data on a total of 4,371 Japanese ACPA-positive RA patients in whom HLA-DRB1 allele genotyping had been performed. Generalized linear regression analysis and omnibus testing were carried out to determine associations of HLA-DRB1 alleles, amino acid residues, or amino acid positions with levels of ACPA. Results HLA-DRB1∗09:01 and HLA-DR15 were confirmed to be associated with ACPA levels. HLA-DRB1∗08:03 and DRB1∗14:06 were associated with reduced and increased ACPA levels, respectively. We detected a strong association between ACPA levels and amino acid position 74 (P=1.9 × 10-51). The association was mainly conferred by alanine residue (P=4.5 × 10-51). After adjustment for position 74, amino acid positions 60 and 57 were found to be associated with ACPA levels. Amino acid positions 74 and 57 had previously been reported to be associated with susceptibility to ACPA-positive RA in Asians. Combinations of the amino acid residues at position 74 and position 60 or 57 could induce improvement in Akaike's information criterion comparable to that induced by the 5 significant HLA-DRB1 alleles (HLA-DRB1∗08:03, DRB1∗09:01, DRB1∗14:06, DRB1∗15:01, and DRB1 15:02). Conclusion Amino acid position 74 in HLA-DRB1 is strongly associated with ACPA levels in ACPA-positive RA, as well as with RA susceptibility. The mechanisms of ACPA production and susceptibility to ACPA-positive RA seem to partly overlap.

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