Dense genotyping of immune-related regions identifies loci for rheumatoid arthritis risk and damage in African Americans

Maria I. Danila; Vincent A. Laufer; Richard J. Reynolds; Qi Yan; Nianjun Liu; Peter K. Gregersen; Annette Lee; Marlena Kern; Carl D. Langefeld; Donna K. Arnett; S. Louis Bridges

doi:10.2119/molmed.2017.00081

Dense genotyping of immune-related regions identifies loci for rheumatoid arthritis risk and damage in African Americans

Maria I. Danila, Vincent A. Laufer, Richard J. Reynolds, Qi Yan, Nianjun Liu, Peter K. Gregersen, Annette Lee, Marlena Kern, Carl D. Langefeld, Donna K. Arnett, S. Louis Bridges

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15 Scopus citations

Abstract

More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody- positive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10^-15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10^-4 < p < 3.1 × 10^-6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.

Original language	English
Pages (from-to)	177-187
Number of pages	11
Journal	Molecular Medicine
Volume	23
DOIs	https://doi.org/10.2119/molmed.2017.00081
State	Published - 2017

Bibliographical note

Funding Information:
We thank the CLEAR investigators for recruiting participants with rheumatoid arthritis and healthy controls: Doyt Conn, MD (Grady Hospital and Emory University, Atlanta, Georgia); Beth Jonas, MD; Leigh Callahan, PhD (University of North Carolina, Chapel Hill); Edwin Smith, MD (Medical University of South Carolina, Charleston); Richard Brasington, MD (Washington University, St. Louis, Missouri); and Larry W Moreland, MD (University of Pittsburgh). We thank Drs. Robert Kimberly and Jeffrey Edberg for providing data on healthy controls from the Birmingham, Alabama, area. We would also like to thank Gleb Kichaev (David Geffen School of Medicine, University of California, Los Angeles) for helpful discussions regarding trans-ethnic fine mapping.

Publisher Copyright:
© 2017 Feinstein Institute for Medical Research.

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

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@article{93e7cc35f95b4d0cb338987bcdbedce8,

title = "Dense genotyping of immune-related regions identifies loci for rheumatoid arthritis risk and damage in African Americans",

abstract = "More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody- positive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10-15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10-4 < p < 3.1 × 10-6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.",

author = "Danila, {Maria I.} and Laufer, {Vincent A.} and Reynolds, {Richard J.} and Qi Yan and Nianjun Liu and Gregersen, {Peter K.} and Annette Lee and Marlena Kern and Langefeld, {Carl D.} and Arnett, {Donna K.} and {Louis Bridges}, S.",

note = "Funding Information: We thank the CLEAR investigators for recruiting participants with rheumatoid arthritis and healthy controls: Doyt Conn, MD (Grady Hospital and Emory University, Atlanta, Georgia); Beth Jonas, MD; Leigh Callahan, PhD (University of North Carolina, Chapel Hill); Edwin Smith, MD (Medical University of South Carolina, Charleston); Richard Brasington, MD (Washington University, St. Louis, Missouri); and Larry W Moreland, MD (University of Pittsburgh). We thank Drs. Robert Kimberly and Jeffrey Edberg for providing data on healthy controls from the Birmingham, Alabama, area. We would also like to thank Gleb Kichaev (David Geffen School of Medicine, University of California, Los Angeles) for helpful discussions regarding trans-ethnic fine mapping. Publisher Copyright: {\textcopyright} 2017 Feinstein Institute for Medical Research.",

year = "2017",

doi = "10.2119/molmed.2017.00081",

language = "English",

volume = "23",

pages = "177--187",

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T1 - Dense genotyping of immune-related regions identifies loci for rheumatoid arthritis risk and damage in African Americans

AU - Danila, Maria I.

AU - Laufer, Vincent A.

AU - Reynolds, Richard J.

AU - Yan, Qi

AU - Liu, Nianjun

AU - Gregersen, Peter K.

AU - Lee, Annette

AU - Kern, Marlena

AU - Langefeld, Carl D.

AU - Arnett, Donna K.

AU - Louis Bridges, S.

N1 - Funding Information: We thank the CLEAR investigators for recruiting participants with rheumatoid arthritis and healthy controls: Doyt Conn, MD (Grady Hospital and Emory University, Atlanta, Georgia); Beth Jonas, MD; Leigh Callahan, PhD (University of North Carolina, Chapel Hill); Edwin Smith, MD (Medical University of South Carolina, Charleston); Richard Brasington, MD (Washington University, St. Louis, Missouri); and Larry W Moreland, MD (University of Pittsburgh). We thank Drs. Robert Kimberly and Jeffrey Edberg for providing data on healthy controls from the Birmingham, Alabama, area. We would also like to thank Gleb Kichaev (David Geffen School of Medicine, University of California, Los Angeles) for helpful discussions regarding trans-ethnic fine mapping. Publisher Copyright: © 2017 Feinstein Institute for Medical Research.

PY - 2017

Y1 - 2017

N2 - More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody- positive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10-15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10-4 < p < 3.1 × 10-6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.

AB - More than 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody- positive RA and 933 African American controls on the Immunochip (iChip) array. Using multivariable regression, we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (odds ratio = 1.97, p = 1.28 × 10-15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11 and TNFSF18 loci were suggestively associated (10-4 < p < 3.1 × 10-6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants, including rs9653442, rs7608424 and rs6712515, as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1 and ETS1 - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we used the dense genotyping of the iChip array and the unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1 and IL2RA.

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JO - Molecular Medicine

JF - Molecular Medicine

ER -

Dense genotyping of immune-related regions identifies loci for rheumatoid arthritis risk and damage in African Americans

Abstract

Bibliographical note

ASJC Scopus subject areas

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