Epigenome-wide methylation haplotype association analysis identified HLA-DRB1, HLA-DRB5 and HLA-DQB1 as risk factors for rheumatoid arthritis

作者：Xu, Jing; Chen, Haiyan; Sun, Chen; Wei, Siyu; Tao, Junxian; Jia, Zhe; Chen, Xingyu; Lv, Wenhua; Lv, Hongchao; Tang, Guoping^*; Jiang, Yongshuai^*; Zhang, Mingming^*

来源：International Journal of Immunogenetics, 2023, 50(6): 291-298.

DOI：10.1111/iji.12637

• disease susceptibility
• DNA methylation
• HLA-DQB1 antigen
• HLA-DRB1 chains
• HLA-DRB5 chains
• rheumatoid arthritis

The aim of this study was to compare nonrandom associations between physically adjacent single methylation polymorphism loci among rheumatoid arthritis (RA) and normal subjects for investigating RA-risk methylation haplotypes (meplotype). With 354 ACPA-positive RA patients and 335 normal controls selected from a case-control study based on Swedish population, weconducted the firstRAepigenome-widemeplotype association study using our software EWAS2.0, mainly including (i) converted the ss value to methylation genotype (menotype) data, (ii) identified methylation disequilibrium (MD) block, (iii) calculated frequent of each meplotypes in MD block and performed case-control association test and (iv) screened for RA-risk meplotypes by odd ratio (OR) and p-values. Ultimately, 545 meplotypes on 334MDblocks were identified significantly associated with RA (p-value <.05). These meplotypes were mapped to 329 candidate genes related to RA. Subsequently, combinedwith gene optimization, eight RA-risk meplotypes were identified on three risk genes: HLA-DRB1, HLA-DRB5 and HLA-DQB1. Our results reported the relationship between DNA methylation pattern on HLA-DQB1 and the cg22984282 ' and ' cg13423887 ' on HLA-DQB1 gene (meplotypeUU, p-value = 2.90E - 6, OR = 1.68, 95% CI = [1.35, 2.10]) may increase the risk of RA. Our results demonstrates the potential of methylation haplotype analysis to identify RA-related genes from a new perspective and its applicability to the study of other disease.

• 单位
  1; 哈尔滨医科大学; 浙江大学