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Am J Hum Genet DOI:10.1016/j.ajhg.2014.02.013

Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity.

Publication TypeJournal Article
Year of Publication2014
AuthorsHan, B, Diogo, D, Eyre, S, Kallberg, H, Zhernakova, A, Bowes, J, Padyukov, L, Okada, Y, Gonzalez-Gay, MA, Rantapää-Dahlqvist, S, Martín, J, Huizinga, TWJ, Plenge, RM, Worthington, J, Gregersen, PK, Klareskog, L, de Bakker, PIW, Raychaudhuri, S
JournalAm J Hum Genet
Date Published2014 Apr 03
KeywordsAlleles, Arthritis, Rheumatoid, Case-Control Studies, Genetic Heterogeneity, HLA Antigens, Humans

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-DRβ1 (p = 1.4 × 10(-13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 × 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-DRβ1 Ser11+Leu11: p = 5.8 × 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 × 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DRβ1 position 11 were distinct (p


Alternate JournalAm. J. Hum. Genet.
PubMed ID24656864
PubMed Central IDPMC3980428
Grant List1R01AR062886-01 / AR / NIAMS NIH HHS / United States
K08AR055688 / AR / NIAMS NIH HHS / United States
1R01AR063759-01A1 / AR / NIAMS NIH HHS / United States
U19 AI111224 / AI / NIAID NIH HHS / United States
U01 GM092691 / GM / NIGMS NIH HHS / United States
5U01GM092691-04 / GM / NIGMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
R01 AR062886 / AR / NIAMS NIH HHS / United States
MANMKBRU-2012-1 / / Department of Health / United Kingdom
K08 AR055688 / AR / NIAMS NIH HHS / United States