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

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 HLA-DRB1 alleles. Yet controversy persists about the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide...

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Main Authors: Raychaudhuri, Soumya, Sandor, Cynthia, Stahl, Eli A., Freudenberg, Jan, Lee, Hye-Soon, Jia, Xiaoming, Alfredsson, Lars, Padyukov, Leonid, Klareskog, Lars, Worthington, Jane, Siminovitch, Katherine A., Bae, Sang-Cheol, Plenge, Robert M., Gregersen, Peter K., de Bakker, Paul I.W.
Format: Online
Language:English
Published: 2012
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288335/
id pubmed-3288335
recordtype oai_dc
spelling pubmed-32883352012-09-01 Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis Raychaudhuri, Soumya Sandor, Cynthia Stahl, Eli A. Freudenberg, Jan Lee, Hye-Soon Jia, Xiaoming Alfredsson, Lars Padyukov, Leonid Klareskog, Lars Worthington, Jane Siminovitch, Katherine A. Bae, Sang-Cheol Plenge, Robert M. Gregersen, Peter K. de Bakker, Paul I.W. Article The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to HLA-DRB1 alleles. Yet controversy persists about 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 seropositive cases and 14,974 controls, we imputed and tested classical alleles and amino acid polymorphisms for HLA-A, B, C, DPA1, DPB1, DQA1, DQB1, and DRB1 along with 3,117 SNPs across the MHC. Conditional and haplotype analyses reveal that three amino acid positions (11, 71 and 74) in HLA-DRβ1, and single amino acid polymorphisms in HLA-B (position 9) and HLA-DPβ1 (position 9), all located in the peptide-binding grooves, almost completely explain the MHC association to disease risk. This study illustrates how imputation of functional variation from large reference panels can help fine-map association signals in the MHC. 2012-01-29 /pmc/articles/PMC3288335/ /pubmed/22286218 http://dx.doi.org/10.1038/ng.1076 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Raychaudhuri, Soumya
Sandor, Cynthia
Stahl, Eli A.
Freudenberg, Jan
Lee, Hye-Soon
Jia, Xiaoming
Alfredsson, Lars
Padyukov, Leonid
Klareskog, Lars
Worthington, Jane
Siminovitch, Katherine A.
Bae, Sang-Cheol
Plenge, Robert M.
Gregersen, Peter K.
de Bakker, Paul I.W.
spellingShingle Raychaudhuri, Soumya
Sandor, Cynthia
Stahl, Eli A.
Freudenberg, Jan
Lee, Hye-Soon
Jia, Xiaoming
Alfredsson, Lars
Padyukov, Leonid
Klareskog, Lars
Worthington, Jane
Siminovitch, Katherine A.
Bae, Sang-Cheol
Plenge, Robert M.
Gregersen, Peter K.
de Bakker, Paul I.W.
Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
author_facet Raychaudhuri, Soumya
Sandor, Cynthia
Stahl, Eli A.
Freudenberg, Jan
Lee, Hye-Soon
Jia, Xiaoming
Alfredsson, Lars
Padyukov, Leonid
Klareskog, Lars
Worthington, Jane
Siminovitch, Katherine A.
Bae, Sang-Cheol
Plenge, Robert M.
Gregersen, Peter K.
de Bakker, Paul I.W.
author_sort Raychaudhuri, Soumya
title Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
title_short Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
title_full Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
title_fullStr Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
title_full_unstemmed Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis
title_sort five amino acids in three hla proteins explain most of the association between mhc and seropositive rheumatoid arthritis
description The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to HLA-DRB1 alleles. Yet controversy persists about 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 seropositive cases and 14,974 controls, we imputed and tested classical alleles and amino acid polymorphisms for HLA-A, B, C, DPA1, DPB1, DQA1, DQB1, and DRB1 along with 3,117 SNPs across the MHC. Conditional and haplotype analyses reveal that three amino acid positions (11, 71 and 74) in HLA-DRβ1, and single amino acid polymorphisms in HLA-B (position 9) and HLA-DPβ1 (position 9), all located in the peptide-binding grooves, almost completely explain the MHC association to disease risk. This study illustrates how imputation of functional variation from large reference panels can help fine-map association signals in the MHC.
publishDate 2012
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3288335/
_version_ 1611508882636537856

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