Genetic influences on susceptibility to rheumatoid arthritis in African-Americans

Vincent A. Laufer, Hemant K. Tiwari, Richard J. Reynolds, Maria I. Danila, Jelai Wang, Jeffrey C. Edberg, Robert P. Kimberly, Leah C. Kottyan, John B. Harley, Ted R. Mikuls, Peter K. Gregersen, Devin M. Absher, Carl D. Langefeld, Donna K. Arnett, S. Louis Bridges

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Large meta-analyses of rheumatoid arthritis (RA) susceptibility in European (EUR) and East Asian (EAS) populations have identified >100 RA risk loci, but genome-wide studies of RA in African-Americans (AAs) are absent. To address this disparity, we performed an analysis of 916 AA RA patients and 1392 controls and aggregated our data with genotyping data from >100 000 EUR and Asian RA patients and controls.We identified two novel risk loci that appear to be specific to AAs: GPC5 and RBFOX1 (PAA < 5 × 10-9). Most RA risk loci are shared across different ethnicities, but among discordant loci, we observed strong enrichment of variants having large effect sizes.We found strong evidence of effect concordance for only 3 of the 21 largest effect index variants in EURs.We used the trans-ethnic fine-mapping algorithm PAINTOR3 to prioritize risk variants in >90 RA risk loci. Addition of AA data to those of EUR and EAS descent enabled identification of seven novel high-confidence candidate pathogenic variants (defined by posterior probability > 0.8). In summary, our trans-ethnic analyses are the first to include AAs, identified several new RA risk loci and point to candidate pathogenic variants that may underlie this common autoimmune disease. These findings may lead to better ways to diagnose or stratify treatment approaches in RA.

Original languageEnglish
Pages (from-to)858-874
Number of pages17
JournalHuman Molecular Genetics
Volume28
Issue number5
DOIs
StatePublished - Mar 1 2019

Bibliographical note

Funding Information:
We gratefully acknowledge the CLEAR Investigators Doyt L. Conn, MD, Beth L. Jonas, MD, Leigh F. Callahan, PhD, Edwin A. Smith, MD, Richard D. Brasington, Jr., MD and Larry W. Moreland, MD. The assistance of Stephanie Ledbetter, MS is greatly appreciated. We thank Dr Yukinori Okada for providing data and for helpful discussions. We appreciate the guidance and advice of Dr Robert Plenge and his willingness to provide samples. National Institutes of Health (R01 AR057202 and 2P60 AR048095 to S.L.B., K01 AR060848 to R.J.R., K23 AR062100 to M.I.D., R37 AI024717 and 1U01 HG008666 to J.B.H., UL1 TR001417 and P01 AR49084 to R.P.K.); US Department of Veterans Affairs (to J.B.H.).

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press. All rights reserved.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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