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

ABSTRACT: 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 × 10-15) 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 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 AFF3, ETS1, and IL2RA.

SUBMITTER: Danila MI

PROVIDER: S-EPMC5583066 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Danila Maria I MI Laufer Vincent Albert VA Reynolds Richard J RJ Yan Qi Q Liu Nianjun N Gregersen Peter K PK Lee Annette A Kern Marlena M Langefeld Carl D CD Arnett Donna K DK Bridges S Louis SL

Molecular medicine (Cambridge, Mass.) 20170629

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) rs196499 ...[more]

PMID: 28681901

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Project description:IntroductionTo determine whether IL4R single-nucleotide polymorphisms (SNPs) rs1805010 (I50V) and rs1801275 (Q551R), which have been associated with disease severity in rheumatoid arthritis (RA) patients of European ancestry, relate to the presence of rheumatoid nodules and radiographic erosions in African Americans.MethodsTwo IL4R SNPs, rs1805010 and rs1801275, were genotyped in 749 patients from the Consortium for Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR) registries. End points were rheumatoid nodules defined as present either by physical examination or by chest radiography and radiographic erosions (radiographs of hands/wrists and feet were scored using the modified Sharp/van der Heijde system). Statistical analyses were performed by using logistic regression modeling adjusted for confounding factors.ResultsOf the 749 patients with RA, 156 (20.8%) had rheumatoid nodules, with a mean age of 47.0 years, 84.6% female gender, and median disease duration of 1.9 years. Of the 461 patients with available radiographic data, 185 (40.1%) had erosions (score>0); their mean age was 46.7 years; 83.3% were women; and median disease duration was 1.5 years. Patients positive for HLA-DRB1 shared epitope (SE) and autoantibodies (rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP)) had a higher risk of developing rheumatoid nodules in the presence of the AA and AG alleles of rs1801275 (odds ratio (OR)adj=8.08 (95% confidence interval (CI): 1.60-40.89), P=0.01 and ORadj=2.97 (95% CI, 1.08 to 8.17), P=0.04, respectively). Likewise, patients positive for the HLA-DRB1 SE and RF alone had a higher risk of developing rheumatoid nodules in presence of the AA and AG alleles of rs1801275 (ORadj=8.45 (95% CI, 1.57 to 45.44), P=0.01, and ORadj=3.57 (95% CI, 1.18 to 10.76), P=0.02, respectively) and in the presence of AA allele of rs1805010 (ORadj=4.52 (95% CI, 1.20 to 17.03), P=0.03). No significant association was found between IL4R and radiographic erosions or disease susceptibility, although our statistical power was limited by relatively small numbers of cases and controls.ConclusionsWe found that IL4R SNPs, rs1801275 and rs1805010, are associated with rheumatoid nodules in autoantibody-positive African-American RA patients with at least one HLA-DRB1 allele encoding the SE. These findings highlight the need for analysis of genetic factors associated with clinical RA phenotypes in different racial/ethnic populations.

Dataset Information

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

Publications

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

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