Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Han, 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 |
Journal | Am J Hum Genet |
Volume | 94 |
Issue | 4 |
Pages | 522-32 |
Date Published | 2014 Apr 03 |
ISSN | 1537-6605 |
Keywords | Alleles, Arthritis, Rheumatoid, Case-Control Studies, Genetic Heterogeneity, HLA Antigens, Humans |
Abstract | 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 |
URL | http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(14)00071-8 |
DOI | 10.1016/j.ajhg.2014.02.013 |
Pubmed | |
Alternate Journal | Am. J. Hum. Genet. |
PubMed ID | 24656864 |
PubMed Central ID | PMC3980428 |
Grant List | 1R01AR062886-01 / 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 |
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.
Recent Broad Publications
News at the broad
News / 01.15.18