Video: Knock on Wood| Webinar: ACR/CHEST ILD Guidelines in Practice
fa-facebookfa-linkedinfa-youtube-playfa-rss

An official publication of the ACR and the ARP serving rheumatologists and rheumatology professionals

  • Conditions
    • Axial Spondyloarthritis
    • Gout and Crystalline Arthritis
    • Myositis
    • Osteoarthritis and Bone Disorders
    • Pain Syndromes
    • Pediatric Conditions
    • Psoriatic Arthritis
    • Rheumatoid Arthritis
    • Sjögren’s Disease
    • Systemic Lupus Erythematosus
    • Systemic Sclerosis
    • Vasculitis
    • Other Rheumatic Conditions
  • FocusRheum
    • ANCA-Associated Vasculitis
    • Axial Spondyloarthritis
    • Gout
    • Lupus Nephritis
    • Psoriatic Arthritis
    • Rheumatoid Arthritis
    • Systemic Lupus Erythematosus
  • Guidance
    • Clinical Criteria/Guidelines
    • Ethics
    • Legal Updates
    • Legislation & Advocacy
    • Meeting Reports
      • ACR Convergence
      • Other ACR meetings
      • EULAR/Other
    • Research Rheum
  • Drug Updates
    • Analgesics
    • Biologics/DMARDs
  • Practice Support
    • Billing/Coding
    • EMRs
    • Facility
    • Insurance
    • QA/QI
    • Technology
    • Workforce
  • Opinion
    • Patient Perspective
    • Profiles
    • Rheuminations
      • Video
    • Speak Out Rheum
  • Career
    • ACR ExamRheum
    • Awards
    • Career Development
  • ACR
    • ACR Home
    • ACR Convergence
    • ACR Guidelines
    • Journals
      • ACR Open Rheumatology
      • Arthritis & Rheumatology
      • Arthritis Care & Research
    • From the College
    • Events/CME
    • President’s Perspective
  • Search

Scientists Pinpoint Three HLA Proteins Linked to Seropositive Rheumatoid Arthritis

Carrie Printz  |  February 28, 2012

Three-dimensional ribbon models for the HLA-DR, HLA-B, and HLA-DP proteins.
click for large version

Researchers have identified five amino acids in three HLA proteins that explain most of the association between major histocompatibility complex (MHC) and seropositive rheumatoid arthritis (RA).

ad goes here:advert-1
ADVERTISEMENT
SCROLL TO CONTINUE

“About one third of the genetic risk for the disease comes from MHC—and most of that comes from three separate proteins,” says Soumya Raychaudhuri, MD, PhD, assistant professor with the divisions of rheumatology and genetics at Brigham and Women’s Hospital and Harvard Medical School in Boston. “We all understood DRB1 as a risk-conferring molecule, and now we know that HLA-B and HLA-DPB1 also play a role.”

Dr. Raychaudhuri is the lead author of the study, which was published online Jan. 29 in Nature Genetics.1 He, colleague Paul de Bakker, PhD, and others found that most of the genetic risk comes from differences in the antigen binding sites of those molecules.

ad goes here:advert-2
ADVERTISEMENT
SCROLL TO CONTINUE

“The hope is that studies such as these will help us understand which key autoantigens people are responding to,” he says. “The antigen for rheumatoid arthritis never has been easy to define.”

The strong association with MHC was first determined in the 1970s. The evidence that this association was potentially related to antigen binding was later demonstrated by the shared epitope hypotheses, first put forth in 1987 by Peter K. Gregersen, MD, Jack Silver, PhD, and Robert J. Winchester, MD.2 Despite serving as the foundation for genetic studies for RA, the shared epitope hypothesis did not fully explain the association at HLA-DRB1.

The new study builds on the shared epitope hypothesis and pins down the specific position in the molecule to which the antigen is binding, Dr. Raychaudhuri says.

“Our studies are much larger, and the genotyping and statistical analysis have advanced a lot,” he adds. “All of these things have made this study possible in a way that wouldn’t have been possible 20 years ago.”

Their results have predictive value in defining people’s relative risks for RA. However, one of the challenges of developing a genetic test for a disease is that it must be highly predictive, Dr. Raychaudhuri says.

He cites as an example that individuals who might have the greatest risk-conferring alleles at HLA-DRB1 association in both chromosomes have roughly a 15- to 20-fold risk of RA over the general population. But, since the risk of the disease in the general population is only 0.5%, such individuals would only have a 10% risk of seropositive RA.

“For the average person walking in off the street without any symptoms, this may not predict they’ll get the disease,” Dr. Raychaudhuri says. “But if there’s an ambiguous diagnosis, it could certainly add information.”

The next step for researchers is to understand the antigen that triggers the immune response and how it might interact with the different receptors that cause the disease. Finding a way to alter that interaction could be a potential avenue for therapy, he says.

 


Carrie Printz is a medical journalist based in Denver.

References

1. Raychaudhuri S, Sandor C, Stahl EA, et. al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012 Jan 29. doi: 10.1038/ng.1076. [Epub ahead of print]

2. Gregerson PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 2005;30:1205-1213.

Page: 1 2 | Multi-Page
Share: 

Filed under:ConditionsResearch RheumRheumatoid Arthritis Tagged with:ArthritisBiomarkersRA

Related Articles
    How HLA-B27 Research Landmarks, Advances Relate to Ankylosing Spondylitis Pathogenesis

    How HLA-B27 Research Landmarks, Advances Relate to Ankylosing Spondylitis Pathogenesis

    July 13, 2016

    (click for larger image) Figure 1: The MHC Class I Antigen Presentation Pathway: TCR = T cell receptor, b2m = beta 2 microglobulin, ER = endoplasmic reticulum, TAP = transporter associated with antigen processing. Brook Coppola The mechanistic link between human leukocyte antigen B27 (HLA-B27) and ankylosing spondylitis (AS) is one of the great enigmas…

    Experts Discuss the Latest Precision Medicine Research

    February 18, 2018

    Eetu Mustonen / SHUTTERSTOCK.COM SAN DIEGO—In just two decades, precision medicine has gone from futuristic concept to realistic toolbox for clinical physicians. At the 2017 ACR Clinical Research Conference on Nov. 3, the Precision Medicine in Rheumatic Diseases: Hopes and Challenges lecture featured rheumatologists and experts on genetics, genomics, pharmaco­genetics and big data who spoke…

    Conformational Flexibility in HLA-B27 Provides Clues to Development of Ankylosing Spondylitis

    July 11, 2016

    X-ray of the lower spine of a patient affected by ankylosing spondylitis. BSIP/Science Source Understanding how human leukocyte antigen (HLA) class I molecule B27 promotes spondyloarthritis has intrigued researchers for four decades. Although the association between the single gene variant HLA-B27—specifically some of its subtypes—with ankylosing spondylitis (AS) is particularly strong, how HLA-B27 directly influences…

    Doest Rheumatoid Arthritis Take a Toll?

    November 15, 2013

    Exploring the Toll background

  • About Us
  • Meet the Editors
  • Issue Archives
  • Contribute
  • Advertise
  • Contact Us
fa-facebookfa-linkedinfa-youtube-playfa-rss
  • Copyright © 2025 by John Wiley & Sons, Inc. All rights reserved, including rights for text and data mining and training of artificial technologies or similar technologies. ISSN 1931-3268 (print). ISSN 1931-3209 (online).
  • DEI Statement
  • Privacy Policy
  • Terms of Use
  • Cookie Preferences