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

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

doi:10.1038/ng.1076

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

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

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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-DRI 21 and singleĝ€"amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPI 21 (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. © 2012 Nature America, Inc. All rights reserved.

Original language	English
Pages (from-to)	291-296
Number of pages	5
Journal	Nature Genetics
Volume	44
Issue number	3
DOIs	https://doi.org/10.1038/ng.1076
Publication status	Published - Mar 2012

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Raychaudhuri, S., Sandor, C., Stahl, E. A., Freudenberg, J., Lee, H. S., Jia, X., Alfredsson, L., Padyukov, L., Klareskog, L., Worthington, J., Siminovitch, K. A., Bae, S. C., Plenge, R. M., Gregersen, P. K., & De Bakker, P. I. W. (2012). Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nature Genetics, 44(3), 291-296. https://doi.org/10.1038/ng.1076

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

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-DRI 21 and singleĝ€{"}amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPI 21 (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. {\textcopyright} 2012 Nature America, Inc. All rights reserved.",

author = "Soumya Raychaudhuri and Cynthia Sandor and Stahl, {Eli A.} and Jan Freudenberg and Lee, {Hye Soon} and Xiaoming Jia and Lars Alfredsson and Leonid Padyukov and Lars Klareskog and Jane Worthington and Siminovitch, {Katherine A.} and Bae, {Sang Cheol} and Plenge, {Robert M.} and Gregersen, {Peter K.} and {De Bakker}, {Paul I W}",

year = "2012",

month = mar,

doi = "10.1038/ng.1076",

language = "English",

volume = "44",

pages = "291--296",

journal = "Nature Genetics",

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Raychaudhuri, S, Sandor, C, Stahl, EA, Freudenberg, J, Lee, HS, Jia, X, Alfredsson, L, Padyukov, L, Klareskog, L, Worthington, J, Siminovitch, KA, Bae, SC, Plenge, RM, Gregersen, PK & De Bakker, PIW 2012, 'Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis', Nature Genetics, vol. 44, no. 3, pp. 291-296. https://doi.org/10.1038/ng.1076

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AU - Raychaudhuri, Soumya

AU - Sandor, Cynthia

AU - Stahl, Eli A.

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AU - Lee, Hye Soon

AU - Jia, Xiaoming

AU - Alfredsson, Lars

AU - Padyukov, Leonid

AU - Klareskog, Lars

AU - Worthington, Jane

AU - Siminovitch, Katherine A.

AU - Bae, Sang Cheol

AU - Plenge, Robert M.

AU - Gregersen, Peter K.

AU - De Bakker, Paul I W

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AB - 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-DRI 21 and singleĝ€"amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPI 21 (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. © 2012 Nature America, Inc. All rights reserved.

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DO - 10.1038/ng.1076

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SP - 291

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JO - Nature Genetics

JF - Nature Genetics

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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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