A large-scale genetic analysis reveals an autoimmune origin of idiopathic retroperitoneal fibrosis

Two amino acid variants (Thr and Asn) can be found at position 77, and 5 can be found at position 74 (Arg, Glu, Ala, Leu, and Gln; Fig 2 and Table E5 in this article's Online Repository at www.jacionline.org).5 Asn77 and Arg74, which were completely linked, were associated with RPF (P = 5.02E-14; OR, 2.46; 95% CI, 1.95-3.11; see Table E5). Because Asn77 and Arg74 were only present at the HLA-DRB1*0301 and HLA-DRB1*0302 alleles, their effect was indistinguishable from that of HLA-DRB1*03 (OR, 2.46; 95% CI, 1.95-3.11). Because rs386813511 is a noncoding variant, we evaluated its potential regulatory role (by using HaploReg v4.1) and found that most of its proxies overlapped with histone marks enriched at promoters and enhancers and DNase hypersensitivity sites in immune cell lines. Different amino acid residues encoded by HLA variants possibly make the HLA molecule prone to autoantigen presentation.8 We found that amino acids Asn and Arg at positions 77 and 74 (Asn77 and Arg74) of the HLA-DRβ molecule were the most relevant for disease risk. Because these amino acids are only present at the HLA-DRB1*0301 and HLA-DRB1*0302 alleles, their effect on disease risk coincided with that of HLA-DRB1*03.