Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
Copyright policy )Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to alleles in HLA-DRB1. However, debate persists about the identity of the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis (cases) and 14,974 unaffected controls, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1, as well as 3,117 SNPs across the MHC. Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRβ1 and single-amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPβ1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk. This study shows how imputation of functional variation from large reference panels can help fine map association signals in the MHC.
- Harvard–MIT Division of Health Sciences and Technology United States
- Harvard Medical School United States
- Feinstein Institute for Medical Research United States
- Hanyang University Hospital for Rheumatic Disease Korea (Republic of)
- Karolinska University Hospital Sweden
Models, Molecular, Polymorphism, Single Nucleotide, Article, Arthritis, Rheumatoid, Major Histocompatibility Complex, Amino Acid Substitution, Haplotypes, HLA-B Antigens, Case-Control Studies, Humans, HLA-DP beta-Chains, Genome-Wide Association Study, HLA-DRB1 Chains
Models, Molecular, Polymorphism, Single Nucleotide, Article, Arthritis, Rheumatoid, Major Histocompatibility Complex, Amino Acid Substitution, Haplotypes, HLA-B Antigens, Case-Control Studies, Humans, HLA-DP beta-Chains, Genome-Wide Association Study, HLA-DRB1 Chains
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