Investigation of Rheumatoid Arthritis Genetic Susceptibility Markers in the Early Rheumatoid Arthritis Study Further Replicates the TRAF1 Association with Radiological Damage

Abstract

Objective.The TRAF1 genetic region conferring susceptibility to rheumatoid arthritis (RA) has been reported to associate with radiological damage. We aimed to test RA genetic susceptibility markers for association with a continuous measure of radiological damage over time using longitudinal modeling techniques.Methods.Sixty-seven RA susceptibility variants were genotyped in 474 patients in the Early Rheumatoid Arthritis Study (ERAS) using Sequenom MassArray technology. Correlation between genetic markers and Larsen score was assessed longitudinally using zero-inflated negative binomial regression to include repeat measurements in the same individual at different timepoints. Genetic markers associated with radiological damage in ERAS were tested using the same modeling techniques on previously published data from the Norfolk Arthritis Register (NOAR).Results.The single marker associated longitudinally with Larsen score in ERAS (p = 0.02) and in NOAR (p = 0.04) was rs2900180 at the TRAF1 locus. Analysis of individual timepoints in ERAS showed that rs2900180 displays its effect primarily on the extent of Larsen score early in the disease course. Combined longitudinal analysis of the 2 cohorts suggests further association of several loci with Larsen score (KIF5A, PTPN22, AFF3, TAGAP) and therefore a significant accumulation of RA severity markers among RA susceptibility markers (p = 0.016).Conclusion.The marker rs2900180 is associated with the extent of radiological damage in the ERAS cohort. This represents the second independent study correlating rs2900180 at the TRAF1 locus with radiological severity in RA. Replication in a large dataset is required to establish the role of other RA susceptibility loci in disease severity.

Association of HLA-DRB1 Haplotypes With Rheumatoid Arthritis Severity, Mortality, and Treatment Response

“…12,13 Patients with inflammatory polyarthritis who satisfied the 1987 American College of Rheumatology criteria 14 during follow-up were classified as having RA. Radiographs of the hands and feet were performed during the first 10 years of follow-up and were scored using the Larsen method 15 (described previously 16,17 ).…”

“…17,18 Entry criteria included a clinical diagnosis of RA, symptoms for less than 2 years, and no prior treatment with disease-modifying antirheumatic drugs. Radiographs of the hands and feet were performed yearly and scored using the Larsen technique for the first 9 years of follow-up.…”

Spaceflight alters expression of microRNA during T‐cell activation

“…NF-kB-1A is associated with cells that express chemokines or cytokines. TAGAP is a member of the rho GTPase activator protein superfamily, and TAGAP loci have been associated with immune diseases such as rheumatoid arthritis (20)(21)(22) and multiple sclerosis (23,24). SPRY2 protein down-regulation by miR-21 inhibits proliferation, and when SPRY2 is overexpressed, it can increase proliferation of HEK293T cells (25,26).…”

The role of genetic polymorphisms regulating vitamin D levels in rheumatoid arthritis outcome: a Mendelian randomisation approach

“…Hence, we tested SNPs previously associated with vitamin D metabolism,7 8 and SNPs in these gene regions showing some evidence of association with RA and type 1 diabetes3 10 for association with RA outcome in two prospective cohorts of early RA patients with longitudinal radiographic data available (table 1). Cohort characteristics have been described earlier elsewhere 11. Twenty SNPs mapping to four independent genetic regions were successfully genotyped using Sequenom MassArray technology in 1433 patients with 2164 X-rays from the Norfolk Arthritis Register (NOAR) and in 443 RA patients with 2924 X-rays from the Early Rheumatoid Arthritis Study (ERAS) scored using the Larsen method 11.…”

“…Cohort characteristics have been described earlier elsewhere 11. Twenty SNPs mapping to four independent genetic regions were successfully genotyped using Sequenom MassArray technology in 1433 patients with 2164 X-rays from the Norfolk Arthritis Register (NOAR) and in 443 RA patients with 2924 X-rays from the Early Rheumatoid Arthritis Study (ERAS) scored using the Larsen method 11. Longitudinal modelling of the presence of erosions was performed using generalised estimating equation (GEE) model with a logit link for binary outcomes, while the Larsen score was modelled with Generalized Linear Latent And Mixed Modelling (GLLAMM) with discrete random effects to construct a finite mixture of three-component normal distributions for the highly skewed Larsen score outcomes with extra zero scores.…”