TY - JOUR
T1 - RXRB Is an MHC-Encoded Susceptibility Gene Associated with Anti-Topoisomerase I Antibody-Positive Systemic Sclerosis
AU - Oka, Akira
AU - Asano, Yoshihide
AU - Hasegawa, Minoru
AU - Fujimoto, Manabu
AU - Ishikawa, Osamu
AU - Kuwana, Masataka
AU - Kawaguchi, Yasushi
AU - Yamamoto, Toshiyuki
AU - Takahashi, Hiroki
AU - Goto, Daisuke
AU - Endo, Hirahito
AU - Jinnin, Masatoshi
AU - Mano, Shuhei
AU - Hosomichi, Kazuyoshi
AU - Mabuchi, Tomotaka
AU - Ueda, Mahoko Takahashi
AU - Nakagawa, So
AU - Beck, Stephan
AU - Bahram, Seiamak
AU - Takehara, Kazuhiko
AU - Sato, Shinichi
AU - Ihn, Hironobu
N1 - Funding Information:
This study was supported by a Research on Intractable Diseases grant from the Ministry of Health, Labor, and Welfare of Japan. We are grateful for Wang Ting, Hisako Kawada, Masayuki Tanaka, and Hideki Hayashi, as well as the Support Center for Medical Research and Education, Tokai University.
Publisher Copyright:
© 2017 The Authors
PY - 2017/9
Y1 - 2017/9
N2 - Systemic sclerosis is a systemic autoimmune and connective tissue disorder associated with the human leukocyte antigen locus. However, the functional relationship between human leukocyte antigen gene(s) and disease development remains unknown. To elucidate major histocompatibility complex-linked systemic sclerosis genetics, we performed genotyping of major histocompatibility complex-borne microsatellites and HLA-DPB1 alleles using DNA obtained from 318 anti-topoisomerase I antibody-positive patients and 561 healthy controls, all of Japanese descent. Those results revealed two major histocompatibility complex haplotypes associated with systemic sclerosis. Exome sequencing and targeted analysis of these risk haplotypes identified rs17847931 in RXRB as a susceptibility variant (P = 1.3 × 10−15; odds ratio [OR] = 9.4) with amino acid substitution p.V95A on the risk haplotype harboring HLA-DPB1∗13:01. No identical variant in the other haplotype including DPB1*09:01 was observed, though that haplotype also showed a significant association (P = 8.5 × 10−22; OR = 4.3) with systemic sclerosis. Furthermore, the number of risk factors was shown to be a predominant factor, as individuals with two factors had elevated risk (P = 6.7 × 10−13; OR = 30.2). We concluded that RXRB may be involved in antifibrotic activity in skin and chromatin remodeling.
AB - Systemic sclerosis is a systemic autoimmune and connective tissue disorder associated with the human leukocyte antigen locus. However, the functional relationship between human leukocyte antigen gene(s) and disease development remains unknown. To elucidate major histocompatibility complex-linked systemic sclerosis genetics, we performed genotyping of major histocompatibility complex-borne microsatellites and HLA-DPB1 alleles using DNA obtained from 318 anti-topoisomerase I antibody-positive patients and 561 healthy controls, all of Japanese descent. Those results revealed two major histocompatibility complex haplotypes associated with systemic sclerosis. Exome sequencing and targeted analysis of these risk haplotypes identified rs17847931 in RXRB as a susceptibility variant (P = 1.3 × 10−15; odds ratio [OR] = 9.4) with amino acid substitution p.V95A on the risk haplotype harboring HLA-DPB1∗13:01. No identical variant in the other haplotype including DPB1*09:01 was observed, though that haplotype also showed a significant association (P = 8.5 × 10−22; OR = 4.3) with systemic sclerosis. Furthermore, the number of risk factors was shown to be a predominant factor, as individuals with two factors had elevated risk (P = 6.7 × 10−13; OR = 30.2). We concluded that RXRB may be involved in antifibrotic activity in skin and chromatin remodeling.
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U2 - 10.1016/j.jid.2017.04.028
DO - 10.1016/j.jid.2017.04.028
M3 - Article
C2 - 28506627
AN - SCOPUS:85028320675
SN - 0022-202X
VL - 137
SP - 1878
EP - 1886
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 9
ER -
