Radiographic severity of Rheumatoid Arthritis in African Americans: Results from a multicenter observational study

Bridges, S. Louis; Causey, Zenoria; Burgos, Paula I.; Huynh, Be; Hughes, Laura B.; Danila, Maria I.; Amalia, van Everdingen,; Ledbetter, Stephanie; Conn, Doyt L.; Tamhane, Ashutosh; Westfall, Andrew O.; Jonas, Beth; Callahan, Leigh F.; Smith, Edwin A.; Brasington, Richard; Moreland, Larry W.; Alarcón, Graciela S.; Heijde, Désirée M van der

doi:10.1002/acr.20040

Cited by 35 publications

(34 citation statements)

References 38 publications

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“…Is there a difference in the severity of RA in blacks that could explain this disparity? Blacks followed in an early RA longitudinal registry have early damage and erosions, similar to other early arthritis cohorts 13 . While disease activity improved over time for both blacks and whites in a large US registry, blacks maintained higher disease activity than whites and were less likely to achieve remission, and disease activity is clearly associated with progression to damage requiring arthroplasty 5,14 .…”

Section: Rheumatologysupporting

confidence: 57%

Do Recent Trends in RA Surgery Reflect Success in Disease Management?

Goodman

2018

J Rheumatol

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Section: Rheumatologysupporting

confidence: 57%

Do Recent Trends in RA Surgery Reflect Success in Disease Management?

Goodman

2018

J Rheumatol

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“…The CLEAR Registry enrolled self-declared African Americans who were diagnosed with RA. CLEAR I is a longitudinal cohort of early RA (disease duration less than 2 years from time of symptom onset), and CLEAR II is a cross-sectional cohort of RA of any duration (57). Genotyping for CPB2 SNPs rs1926447and rs3742264 was performed using a custom Infinium iSelect Genotyping Beadchip (Illumina) on DNA samples from the CLEAR I (n = 337) and CLEAR II (n = 446) registries and from…”

Section: Methodsmentioning

confidence: 99%

Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis

Song¹,

Hwang²,

Cho³

et al. 2011

J. Clin. Invest.

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The immune and coagulation systems are both implicated in the pathogenesis of rheumatoid arthritis (RA). Plasma carboxypeptidase B (CPB), which is activated by the thrombin/thrombomodulin complex, plays a procoagulant role during fibrin clot formation. However, an antiinflammatory role for CPB is suggested by the recent observation that CPB can cleave proinflammatory mediators, such as C5a, bradykinin, and osteopontin. Here, we show that CPB plays a central role in downregulating C5a-mediated inflammatory responses in autoimmune arthritis. CPB deficiency exacerbated inflammatory arthritis in a mouse model of RA, and cleavage of C5a by CPB suppressed the ability of C5a to recruit immune cells in vivo. In human patients with RA, genotyping of nonsynonymous SNPs in the CPB-encoding gene revealed that the allele encoding a CPB variant with longer half-life was associated with a lower risk of developing radiographically severe RA. Functionally, this CPB variant was more effective at abrogating the proinflammatory properties of C5a. Additionally, expression of both CPB and C5a in synovial fluid was higher in patients with RA than in those with osteoarthritis. These findings suggest that CPB plays a critical role in dampening local, C5a-mediated inflammation and represents a molecular link between inflammation and coagulation in autoimmune arthritis.

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“…In view of the heterogeneity of disease associations among ethnic groups, shorter haplotype blocks and differences in allele frequency in African Americans, we hypothesize that fine mapping will identify differences in the genetic architecture of RA in African Americans compared with other ethnicities. Strengths of this study include analysis of the largest group of African Americans with RA currently available in the world, with accompanying high-quality radiographic outcomes data (34). A major goal of research into the genetics of complex diseases is to identify pathogenic variants that produce disease associations.…”

Section: Dense Genotyping Of Immune-related Regions Identifies Loci Fmentioning

confidence: 99%

“…Radiographs of hands/wrists and feet were obtained at the CLEAR enrollment visit for participants with RA and assigned a modified total Sharp score (mTSS) (range 0-448) using the modified Sharp/van der Heijde method (34). Scoring was performed using state-of-the-art methods under the auspices of Désirée van der Heijde, a world expert in quantitative assessment of radiographs in rheumatic diseases (34).…”

Section: Study Populationmentioning

confidence: 99%

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

Danila

Laufer

Reynolds

et al. 2017

Mol Med

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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 autoantibodypositive 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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Radiographic severity of Rheumatoid Arthritis in African Americans: Results from a multicenter observational study

Cited by 35 publications

References 38 publications

Do Recent Trends in RA Surgery Reflect Success in Disease Management?

Do Recent Trends in RA Surgery Reflect Success in Disease Management?

Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis

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

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