Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 23; no. 1; pp. 177 - 187
• Main Authors: Danila, Maria I, Laufer, Vincent Albert, Reynolds, Richard J, Yan, Qi, Liu, Nianjun, Gregersen, Peter K, Lee, Annette, Kern, Marlena, Langefeld, Carl D, Arnett, Donna K, Bridges, Jr, S Louis
• Format: Journal Article
• Language: English
• Published: England BioMed Central 01.01.2017; Feinstein Institute for Medical Research; BMC
• Subjects: Adult; African Americans; African Americans - genetics; Aged; Arthritis, Rheumatoid - diagnostic imaging; Arthritis, Rheumatoid - genetics; Asian people; Consortia; Disease; Female; Genomes; Genotype; Health risk assessment; Humans; Interleukin-2 Receptor alpha Subunit - genetics; Male; Middle Aged; Minority & ethnic groups; Nuclear Proteins - genetics; Polymorphism, Single Nucleotide; Proto-Oncogene Protein c-ets-1 - genetics; Quality control; Rheumatic diseases; Rheumatoid arthritis; Risk; Severity of Illness Index; immunochip; genetics; African Americans; trans-ethnic; rheumatoid arthritis; aff3; fine-mapping
• ISSN: 1076-1551; 1528-3658
• DOI: 10.2119/molmed.2017.00081

Over 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 (OR = 1.97, p = 1.28 × 10 ) near was the most strongly associated risk SNP for RA susceptibility; SNPs in , , and loci were suggestively associated (10 < p < 3.1 × 10 ). Trans-ethnic fine mapping of 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 gene expression level. Variants in , , , , and - 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 and beyond those found in other ethnicities. In summary, we use the dense genotyping of the iChip array and unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of , , and .