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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity
American Journal of Human Genetics, Volume 94, No. 4, Year 2014
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Description
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-DRB1â̂ -03 (encoding serine at 11) and HLA-B â̂ -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 < 2.9 × 10-107). We also identified an association with ACPA + RA at HLA-A position 77 (p = 2.7 × 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. © 2014 The American Society of Human Genetics.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3980428/bin/mmc1.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC3980428/bin/mmc2.xlsx
https://efashare.b-cdn.net/share/pmc/articles/PMC3980428/bin/mmc3.pdf
Authors & Co-Authors
Han, Buhm
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
United States, Cambridge
Partners Healthcare Personalized Medicine
Eyre, Stephen
United Kingdom, Manchester
Centre for Epidemiology Versus Arthritis
United Kingdom, Manchester
Health Innovation Manchester
Zhernakova, Alexandra
Netherlands, Leiden
Leids Universitair Medisch Centrum
Netherlands, Groningen
Rijksuniversiteit Groningen
Bowes, John D.
United Kingdom, Manchester
Centre for Epidemiology Versus Arthritis
United Kingdom, Manchester
Health Innovation Manchester
Padyukov, Leonid
Sweden, Stockholm
Karolinska Universitetssjukhuset
Okada, Yukinori
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
United States, Cambridge
Partners Healthcare Personalized Medicine
González-Gay, Miguel Ángel
Spain, Santander
Hospital Universitario Marqués de Valdecilla
Rantapåå-Dahlqvist, Solbritt
Sweden, Umea
Umeå Universitet
Martin, Javier
Spain, Madrid
Consejo Superior de Investigaciones Científicas
Huizinga, Tom W.J.
Netherlands, Leiden
Leids Universitair Medisch Centrum
Plenge, Robert M.
United States, Rahway
Merck & Co., Inc.
Gregersen, Peter K.
United States, Manhasset
Feinstein Institute for Medical Research
Klareskog, Lars G.
Sweden, Stockholm
Karolinska Universitetssjukhuset
De Bakker, Paul IW W.
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
Netherlands, Utrecht
University Medical Center Utrecht
Raychaudhuri, Soumya
United States, Boston
Harvard Medical School
United States, Cambridge
Massachusetts Institute of Technology
United States, Cambridge
Partners Healthcare Personalized Medicine
United Kingdom, Manchester
Centre for Epidemiology Versus Arthritis
Statistics
Citations: 135
Authors: 15
Affiliations: 14
Identifiers
Doi:
10.1016/j.ajhg.2014.02.013
ISSN:
00029297
Research Areas
Genetics And Genomics
Study Design
Cohort Study
Case-Control Study