Do Genetic Susceptibility Variants Associate with Disease Severity in Early Active Rheumatoid Arthritis?

Abstract

Objective: Genetic variants affect both the development and severity of rheumatoid arthritis (RA). Recent studies have expanded the number of RA susceptibility variants. We tested the hypothesis that these associated with disease severity in a clinical trial cohort of patients with early, active RA.

Methods: We evaluated 524 patients with RA enrolled in the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trials. We tested validated susceptibility variants - 69 single-nucleotide polymorphisms (SNP), 15 HLA-DRB1 alleles, and amino acid polymorphisms in 6 HLA molecule positions - for their associations with progression in Larsen scoring, 28-joint Disease Activity Scores, and Health Assessment Questionnaire (HAQ) scores over 2 years using linear mixed-effects and latent growth curve models.

Results: HLA variants were associated with joint destruction. The *04:01 SNP (rs660895, p = 0.0003), *04:01 allele (p = 0.0002), and HLA-DRβ1 amino acids histidine at position 13 (p = 0.0005) and valine at position 11 (p = 0.0012) significantly associated with radiological progression. This association was only significant in anticitrullinated protein antibody (ACPA)-positive patients, suggesting that while their effects were not mediated by ACPA, they only predicted joint damage in ACPA-positive RA. Non-HLA variants did not associate with radiograph damage (assessed individually and cumulatively as a weighted genetic risk score). Two SNP - rs11889341 (STAT4, p = 0.0001) and rs653178 (SH2B3-PTPN11, p = 0.0004) - associated with HAQ scores over 6-24 months.

Conclusion: HLA susceptibility variants play an important role in determining radiological progression in early, active ACPA-positive RA. Genome-wide and HLA-wide analyses across large populations are required to better characterize the genetic architecture of radiological progression in RA.

Keywords: GENETICS; HLA ANTIGENS; OUTCOME MEASURES; RADIOGRAPHY; RHEUMATOID ARTHRITIS.

Figure 1.

Mean Larsen, DAS28, and HAQ scores over 2 years. Standard error bars for each score shown. DAS28: Disease Activity Score at 28 joints; HAQ: Health Assessment Questionnaire.

Figure 2.

Multiphase latent growth curve factor model for DAS28 and HAQ scores. i: intercept. Sl₁: slope 1 (identifies change in DAS28/HAQ from month 0–6). Sl₂: slope 2 (identifies change in DAS28/HAQ from month 6–24). E_sp: residual error terms (constrained to be equal). M_i, M_sl1, and M_sl2: intercept, slope 1, and slope 2 means, respectively. µ_io, µs_l1o, and µ_sl2o: overall mean estimate of the intercept, slope 1, and slope 2 factors, respectively. β_iSNP, β_Sl1SNP, and β_Sl2SNP: SNP dependent intercept, slope 1, and slope 2 means, respectively. β_iSex, β_Sl1Sex, and β_Sl2Sex: sex-dependent intercept, slope 1, and slope 2 means, respectively. β_iAge, β_Sl1Age, and β_Sl2Age: age-dependent intercept, slope 1, and slope 2 means, respectively. r_i-sl1, r_i-sl2 are the correlations between the intercept and slopes. r_sl1-sl2 the correlation between slope 1 and slope 2. SD_i, SD_sl1, and SD_sl2 are the SD of the latent factors. The overall variance-covariance structure and the overall means of the HAQ/DAS28 scores, which are optimized, are modeled by the variance-covariance structure and the means of the latent factors weighted by the factor loadings. DAS28: Disease Activity Score at 28 joints; HAQ: Health Assessment Questionnaire; SNP: single-nucleotide polymorphisms.

Figure 3.

Significant genetic associations with Larsen score progression. Mean Larsen scores with standard error bars shown at each timepoint stratified by genotype (“best-guess” genotypes used for imputed data in this figure, but not in the statistical analysis). His13: histidine at position 13; Val11: valine at position 11.

Figure 4.

Significant genetic associations with HAQ scores over 6–24 months. Mean HAQ scores with standard error bars shown at each timepoint stratified by genotype. HAQ: Health Assessment Questionnaire.