RXRB Is an MHC-Encoded Susceptibility Gene Associated with Anti-Topoisomerase I Antibody-Positive Systemic Sclerosis.

Area of Science:

• Genetics
• Immunology
• Rheumatology

Background:

• Systemic sclerosis (SSc) is a complex autoimmune disease linked to the human leukocyte antigen (HLA) locus.
• The precise genetic mechanisms connecting HLA genes to SSc pathogenesis remain unclear.

Purpose of the Study:

• To investigate the genetic associations within the major histocompatibility complex (MHC) region in systemic sclerosis.
• To identify specific genetic variants and haplotypes contributing to SSc susceptibility in a Japanese population.

Main Methods:

• Genotyping of MHC-borne microsatellites and HLA-DPB1 alleles in 318 SSc patients and 561 healthy controls.
• Exome sequencing and targeted analysis of identified risk haplotypes.
• Statistical analysis to determine associations and odds ratios.

Main Results:

• Two MHC haplotypes were significantly associated with systemic sclerosis.
• A specific susceptibility variant, rs17847931 in RXRB (encoding p.V95A), was identified on a risk haplotype (P = 1.3 × 10^-15, OR = 9.4).
• The presence of multiple risk factors significantly elevated SSc risk (P = 6.7 × 10^-13, OR = 30.2).

Conclusions:

• The RXRB gene variant rs17847931 is a key susceptibility factor for systemic sclerosis.
• The identified MHC haplotypes and RXRB variant provide insights into SSc genetic underpinnings.
• RXRB may play a role in antifibrotic activity and chromatin remodeling relevant to SSc.