Five Amino Acids in Three HLA Proteins Explain Most of the Association Between MHC and Seropositive Rheumatoid Arthritis

Overview

Journal Nat Genet

Specialty Genetics

Date 2012 Jan 31

PMID 22286218

Citations 467

Authors

Soumya Raychaudhuri

Cynthia Sandor

Eli A Stahl

Jan Freudenberg

Hye-Soon Lee

Xiaoming Jia

Lars Alfredsson

Leonid Padyukov

Lars Klareskog

Jane Worthington

Katherine A Siminovitch

Sang-Cheol Bae

Robert M Plenge

Peter K Gregersen

Paul I W de Bakker

Affiliations

Soon will be listed here.

Abstract

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.

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