Rheumatoid arthritis is a disabling disease that affects up to 1% of the adult population. With the heritability of RA estimated at about 60%, the major genetic association has been linked to the HLA-DRB1 gene within the major histocompatibility complex (MHC) region on chromosome 6. More than 20 years ago, the """"""""shared epitope"""""""" hypothesis implicated a short stretch of amino acids (residues 70-74) in the HLA-DRB1 protein subunit, providing a solid foundation for subsequent RA studies. Yet uncertainty remains as to the causal variants within DRB1 and the existence of associations outside DRB1. In this project, we develop an imputation procedure to re-analyze existing GWAS data sets of RA in order to fine-map association signals in the MHC. Besides imputing classical HLA alleles, we also focus on the role of specific amino acid polymorphisms within the classical HLA proteins. We will analyze data sets from multiple ethnicities (European, African American, Han Chinese and Korean) in order to increase power to identify causal variants. Ultimately, insights from our project can help identify the (self-)antigens targeted in RA pathogenesis. Our analytic strategy is broadly applicable beyond RA, and could help interpret MHC associations for many other immune-related diseases based on existing GWAS data. We will share our software tools with the human genetics community.

Public Health Relevance

Rheumatoid arthritis is a disabling inflammatory polyarthritis disease that affects up to 1% of the adult population. While the importance of the major histocompatability complex was highlighted in studies since the 1970s, the specific HLA genes and their variants that play a critical role in the disease have been much harder to unambiguosly determine. In this proposal, we aim to clarify the role of HLA genes and their amino acid residue variants by analyzing existing data sets in up to 30,000 individuals of multiple ethnicities.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GGG-M (50))
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Wang, Yan Z
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Brigham and Women's Hospital
United States
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Karnes, Jason H; Bastarache, Lisa; Shaffer, Christian M et al. (2017) Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants. Sci Transl Med 9:
Wei, Wen-Hua; Viatte, Sebastien; Merriman, Tony R et al. (2017) Genotypic variability based association identifies novel non-additive loci DHCR7 and IRF4 in sero-negative rheumatoid arthritis. Sci Rep 7:5261
Han, Buhm; Pouget, Jennie G; Slowikowski, Kamil et al. (2016) A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases. Nat Genet 48:803-10
Wei, Wen-Hua; Bowes, John; Plant, Darren et al. (2016) Major histocompatibility complex harbors widespread genotypic variability of non-additive risk of rheumatoid arthritis including epistasis. Sci Rep 6:25014
Gutierrez-Arcelus, Maria; Rich, Stephen S; Raychaudhuri, Soumya (2016) Autoimmune diseases - connecting risk alleles with molecular traits of the immune system. Nat Rev Genet 17:160-74
Viatte, Sebastien; Plant, Darren; Han, Buhm et al. (2015) Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. JAMA 313:1645-56
Ermann, Joerg; Rao, Deepak A; Teslovich, Nikola C et al. (2015) Immune cell profiling to guide therapeutic decisions in rheumatic diseases. Nat Rev Rheumatol 11:541-51
Cortes, Adrian; Pulit, Sara L; Leo, Paul J et al. (2015) Major histocompatibility complex associations of ankylosing spondylitis are complex and involve further epistasis with ERAP1. Nat Commun 6:7146
Ombrello, Michael J; Remmers, Elaine F; Tachmazidou, Ioanna et al. (2015) HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A 112:15970-5
Lenz, Tobias L; Deutsch, Aaron J; Han, Buhm et al. (2015) Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat Genet 47:1085-90

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