The amino acid variants in HLA II molecules explain the major association with adult-onset Still's disease in the Han Chinese population

J Autoimmun. 2021 Jan:116:102562. doi: 10.1016/j.jaut.2020.102562. Epub 2020 Nov 6.

Abstract

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRβ1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.

Keywords: Adult-onset still's disease; Genome-wide association studies; Imputation; MHC; Single nucleotide polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Amino Acids / genetics*
  • Asian People / genetics
  • China
  • Gene Frequency
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods
  • Genotype
  • HLA-DQ alpha-Chains / chemistry
  • HLA-DQ alpha-Chains / genetics*
  • HLA-DRB1 Chains / chemistry
  • HLA-DRB1 Chains / genetics*
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Models, Molecular
  • Polymorphism, Single Nucleotide*
  • Protein Conformation
  • Still's Disease, Adult-Onset / ethnology
  • Still's Disease, Adult-Onset / genetics*

Substances

  • Amino Acids
  • HLA-DQ alpha-Chains
  • HLA-DQA1 antigen
  • HLA-DRB1 Chains