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Fine Mapping Serone...
Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity
- Article/chapterEnglish2014
Publisher, publication year, extent ...
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Elsevier BV,2014
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:umu-88384
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-88384URI
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https://doi.org/10.1016/j.ajhg.2014.02.013DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:128587243URI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA RA and observed independent associations for serine and leucine at position 11 in HLA-DR beta 1 (p = 1.4 x 10 (13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 x 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1*03 (encoding serine at 11) and HLA-B*08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DR beta 1 Ser11+Leu11: p = 5.8 x 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 x 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DR beta 1 position 11 were distinct (p < 2.9 x 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 x 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.
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Diogo, Dorothee
(author)
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Eyre, Steve
(author)
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Kallberg, Henrik
(author)
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Zhernakova, Alexandra
(author)
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Bowes, John
(author)
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Padyukov, LeonidKarolinska Institutet
(author)
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Okada, Yukinori
(author)
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Gonzalez-Gay, Miguel A.
(author)
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Rantapää-Dahlqvist, SolbrittUmeå universitet,Reumatologi(Swepub:umu)sora0001
(author)
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Martin, Javier
(author)
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Huizinga, Tom W. J.
(author)
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Plenge, Robert M.
(author)
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Worthington, Jane
(author)
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Gregersen, Peter K.
(author)
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Klareskog, LarsKarolinska Institutet
(author)
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de Bakker, Paul I. W.
(author)
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Raychaudhuri, Soumya
(author)
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Karolinska InstitutetReumatologi
(creator_code:org_t)
Related titles
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In:American Journal of Human Genetics: Elsevier BV94:4, s. 522-5320002-92971537-6605
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Han, Buhm
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Diogo, Dorothee
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Eyre, Steve
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Kallberg, Henrik
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Zhernakova, Alex ...
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Bowes, John
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Padyukov, Leonid
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Okada, Yukinori
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Gonzalez-Gay, Mi ...
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Rantapää-Dahlqvi ...
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Martin, Javier
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Huizinga, Tom W. ...
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Plenge, Robert M ...
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Worthington, Jan ...
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Gregersen, Peter ...
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Klareskog, Lars
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de Bakker, Paul ...
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Raychaudhuri, So ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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Umeå University
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Karolinska Institutet