Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis

By Soumya Raychaudhuri, C. Sandor, Eli A. Stahl, J. Freudenberg, Hye-Soon Lee, Xiaoming Jia, L. Alfredsson, L. Padyukov, L. Klareskog, Jane Worthington and 5 more. Nature Genetics, 2012

954 citations recorded by the source corpus.

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.

Subfields: Immunology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/7614318168379b361ccd26e81b7e2ef3900f076b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Beth Stevens
2. D. Su
3. Robert M. Plenge
4. M. Carroll

In Rheumatology

1. Mark J. Daly

Citations in the corpus

• HIBAG – HLA Genotype Imputation with Attribute Bagging (2013, positive): “14 We therefore compared the performance of HIBAG with BEAGLE v3.”
• HLA variation and disease (2018, background): “Identifying the precise coding or non-coding variants involved — by using improved analytical methods 125 or MHC deep sequencing 126 — may provide further insight into peptide-binding groove amino acid substitutions that could alter HLA–antigen interactions and into the differential regulation of…”
• Major Histocompatibility Complex Genomics and Human Disease (2013, neutral): “(99) examined 5,018 rheumatoid arthritis patients and 14,974 controls using a large reference panel to impute classical HLA alleles.”
• Autoantibodies, autoimmune risk alleles and clinical associations in rheumatoid arthritis cases and non-RA controls in the electronic medical records (2013, neutral): “In addition, the associations in the HLA region are complex and require dense genotyping (27), an approach that was not available for this study.”
• Genetics of rheumatoid arthritis contributes to biology and drug discovery (2013, positive): “In the population-specific genetic risk model, the 100 RA risk loci outside of the major histocompatibility complex(MHC)region 12 explained5.”
• Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies (2018, background): “The strongest genetic risk factor associated with ACPA-positive RA is found in genes encoding HLADR, especially HLA-DR1 and HLA-DR4, also known as “shared epitopes” (SEs).(16) It is thought that SE influences RA outcome via the production of ACPA and thus represents a primary risk factor for ACPA pr”
• Oral microbiomes: more and more importance in oral cavity and whole body (2018, background): “contribute to disease pathogenesis (McInnes and Schett, 2011; Raychaudhuri et al., 2012; Okada et al., 2014; McInnes and Schett, 2007; Viatte et al., 2013).”
• Schizophrenia risk from complex variation of complement component 4 (2016, background): “In some autoimmune diseases, genetic associations at the MHC locus arise from alleles of HLA genes 11,12 ; however, schizophrenia’s association to the MHC is not yet explained.”
• Multi-Population Classical HLA Type Imputation (2013, background): “Classical HLA allele imputation has, in other settings, been used to identify particular amino acids within classical peptides contributing to disease risk [6].”
• High density genetic mapping identifies new susceptibility loci for rheumatoid arthritis (2012, methodology): “Previously, we fine mapped MHC associations observed in GWAS data of partially overlapping samples by applying imputation of HLA classical alleles and amino acids 5 .”
• Imputing Amino Acid Polymorphisms in Human Leukocyte Antigens (2013, background): “We and others have previously demonstrated the potential of HLA imputation for a wide range of phenotypes including host control of HIV-1 replication [17,26], rheumatoid arthritis [27], ulcerative colitis [28], primary biliary cirrhosis [29], psoriasis [30], ankylosing spondylitis [31], multiple scl”