High-Density Genotyping of Risk Loci in African Americans with RA

Maria I. Danila¹, Richard Reynolds², Qi Yan³, Nianjun Liu³, Peter K. Gregersen⁴, CLEAR Investigators², Donna K. Arnett² and S. Louis Bridges Jr.^2,5, ¹Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, ²University of Alabama at Birmingham, Birmingham, AL, ³Biostatistics, University of Alabama at Birmingham, Birmingham, AL, ⁴Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, ⁵Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: African-Americans, genetic architecture and rheumatoid arthritis (RA)

Session Information

Session Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Genetic studies have identified 101 risk loci for RA in individuals of Caucasian and Asian descent. However, to date the genetic determinants of RA in African Americans, an admixed population, are poorly understood. We sought to determine whether genetic markers of autoimmunity validated in European and Asian population influence the occurrence of RA in African Americans.

Methods: Using the ImmunoChip custom array, which contains 196,525 single nucleotide polymorphisms (SNPs) from 186 autoimmune disease associated loci, a total of 814 African Americans with RA and 933 African American healthy controls were genotyped. After quality control procedures (related samples, sex inconsistency, marker call rate >98.5% and sample call rate >90%,), 100,268 SNPs with minor allele frequency (MAF) greater than 5% were available for analysis in 601 cases and 830 controls. Set-based association analysis using the sequence kernel association test (SKAT) was also performed in the autoantibody-positive and the autoantibody-negative subsets. Fine mapping of loci identified from the Caucasian RA ImmunoChip study was performed by association testing all markers +/- 500 kB conditionally on the top Caucasian SNP for each RA locus.

Results: Among the 601 cases, 479 (80%) individuals were autoantibody-positive. In the single marker association analysis adjusted for global European admixture, the strongest statistical associations with seropositive RA were found in the MHC region in chromosome 6. However, when the analysis was restricted to the 122 cases with autoantibody-negative RA, no statistical significant association for the MHC region was found. Since many of the markers were weakly associated with RA, we also performed set-based analysis using SKAT. SNPs were assigned to 17,529 genes if they were located within 100 kb 5’ or 3’ of the coding region. We found that AP1, transporter 1 ATP-binding cassette, subfamily B, a gene on chromosome 6 in the MHC region, previously associated with primary immunodeficiency, was associated with seropositive RA (p = 3.5 x 10^-7). Conditional analyses indicated no ethnic specific SNPs refined the top association observed from the Caucasian RA Immunochip study.

Conclusion: The present study provides further evidence to support the importance of MHC region in African-Americans with RA.

Disclosure:

M. I. Danila,

NIAMS-NIH,

R. Reynolds,

NIAMS-NIH,

Q. Yan,
None;

N. Liu,
None;

P. K. Gregersen,
None;

C. Investigators,
None;

D. K. Arnett,
None;

S. L. Bridges Jr.,
None.

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