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Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
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Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
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Journal Article
Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
2012
Overview
Soumya Raychaudhuri, Paul de Bakker and colleagues report fine mapping of the rheumatoid arthritis associations within the MHC by combining genome-wide SNP data and imputation of classical HLA alleles and SNPs across the MHC. They identify five amino acid positions in HLA-DRβ1, HLA-B and HLA-DPβ1 that together can explain most of the MHC association to 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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Amino Acid Substitution - genetics
/ Animal Genetics and Genomics
/ Arthritis, Rheumatoid - genetics
/ Biological and medical sciences
/ Biomedical and Life Sciences
/ Diabetes
/ Diseases of the osteoarticular system
/ Fundamental and applied biological sciences. Psychology
/ Genetics of eukaryotes. Biological and molecular evolution
/ Genome-Wide Association Study
/ Genomes
/ HLA histocompatibility antigens
/ HLA-DP beta-Chains - genetics
/ Humans
/ letter
/ Major histocompatibility complex
/ Major Histocompatibility Complex - genetics
/ Peptides
