Oka, A;
Asano, Y;
Hasegawa, M;
Fujimoto, M;
Ishikawa, O;
Kuwana, M;
Kawaguchi, Y;
... Ihn, H; + view all
(2017)
RXRB is a MHC-encoded susceptibility gene associated with anti-topoisomerase I antibody-positive systemic sclerosis.
Journal of Investigative Dermatology
, 137
(9)
pp. 1878-1886.
10.1016/j.jid.2017.04.028.
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Abstract
Systemic sclerosis (SSc) is a systemic autoimmune and connective tissue disorder associated with the human leukocyte antigen (HLA) locus. However, the functional relationship between HLA gene(s) and disease development remains unknown. To elucidate major histocompatibility complex (MHC)-linked SSc genetics, we performed genotyping of MHC-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 2 MHC haplotypes associated with SSc. Exome sequencing and targeted analysis of these risk haplotypes identified rs17847931 in retinoid X receptor beta (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 SSc. Furthermore, the number of risk factors was shown to be a predominant factor, as individuals with 2 factors had elevated risk (P=6.7 × 10(-13); OR=30.2). We concluded that RXRB may be involved in anti-fibrotic activity in skin and chromatin remodeling.
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