ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2021
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP PRSYM
    • 2016-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 1704

Mapping The Shared and Distinct HLA Alleles For Seropositive and Seronegative Rheumatoid Arthritis

Buhm Han1, Stephen Eyre2, Dorothee Diogo1, John Bowes3, Yukinori Okada1, Leonid Padyukov4, Robert M. Plenge5, Lars Klareskog6, Jane Worthington7, Peter K. Gregersen8, Paul de Bakker9 and Soumya Raychaudhuri1, 1Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 2Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester, United Kingdom, 3Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, United Kingdom, 4Rheumatology Unit, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden, 5Division of Rheumatology, Immunology and Allergy and Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 6Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, 7Arthritis Research UK Epidemiology Unit, Arthritis Research UK Epidemiology Unit, The University of Manchester, Manchester, United Kingdom, 8Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, 9Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: genetics, rheumatoid arthritis (RA) and serologic tests

  • Tweet
  • Email
  • Print
Session Information

Session Title: Genetics and Genomics of Rheumatic Disease I

Session Type: Abstract Submissions (ACR)

Background/Purpose: Investigators have long speculated that the two subtypes of rheumatoid arthritis (RA), anti-citrullinated protein autoantibody positive (ACPA+) and negative (ACPA-), have distinct underlying genetic factors. The MHC region is the strongest genetic risk factor to ACPA+ RA, but plays a much more modest role in ACPA- RA. To understand the similarities and differences between these two disease subtypes, we fine-mapped and compared MHC associations. 

Methods: Using densely genotyped SNP data consisting of 7,222 ACPA+ RA cases, 3,339 ACPA- RA cases, and 15,870 controls from six different cohorts (Eyre et al., Nat Gen, 2012), we imputed and tested HLA alleles in the two RA subtypes separately. 

Results: We mapped associations to ACPA+ RA using forward search conditional analysis and confirmed previously published associations at amino acid sites at positions 13 (P < 10-705), 71, and 74 in HLA-DRB1, position 9 in HLA-B, and position 9 in HLA-DPB1. In addition, we identified a novel association at position 77 in HLA-A (P=1.7×10‑8) located in the peptide binding groove implicating antigen presentation as the major mechanism by which MHC variation confers risk. Then in parallel we mapped associations to ACPA- RA. We recognized that ACPA- RA associations to the MHC might be confounded due to the inclusion of misclassified samples that are actually ACPA+ RA (false negative testing) or ankylosing spondylitis. We developed a novel statistical approach that estimates the proportion of misclassified samples and regresses out their effects. Using this approach we observed that each cohort consistently contained 3-9% of cases that likely had ankylosing spondylitis, and a variable number of cases that likely had ACPA+ RA. Controlling for misclassification effects, we identified the amino acid residues at position 13 in HLA-DRB1 as strongly associated with risk (Omnibus test P=1.2×10‑16). Serine conferred the highest risk (OR=1.28, P=5.7×10-13); in stark contrast serine conferred protection to ACPA+ disease (OR=0.4). We also observed a shared association to the presence of an aspartate in position 9 in HLA-B (P=1.3×10-15, OR=1.38) with a more modest effect size than for ACPA+ disease (OR=2.1).

Conclusion: Our analysis is the first to define specific amino acid sites for ACPA- RA, and demonstrates a distinct genetic basis for ACPA+ and ACPA- RA in the MHC region. Our analysis also underscores the importance of phenotypic classification for accurate fine-mapping.


Disclosure:

B. Han,
None;

S. Eyre,
None;

D. Diogo,
None;

J. Bowes,
None;

Y. Okada,
None;

L. Padyukov,
None;

R. M. Plenge,

Corrona,

5,

Ignyta,

4;

L. Klareskog,

No own commercial interests,

2;

J. Worthington,
None;

P. K. Gregersen,

Janssen Pharmaceutica Product, L.P.,

2;

P. de Bakker,
None;

S. Raychaudhuri,
None.

  • Tweet
  • Email
  • Print

« Back to 2013 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/mapping-the-shared-and-distinct-hla-alleles-for-seropositive-and-seronegative-rheumatoid-arthritis/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts during your browser session by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2022 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies