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 early, active RA patients.
METHODS
We evaluated 524 RA patients enrolled to the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trials. We tested validated susceptibility variants – 69 single nucleotide polymorphisms (SNPs); 15 HLA-DRB1 alleles; amino acid polymorphisms in 6 HLA molecule positions – for their associations with progression in Larsen, disease activity scores on a 28-joint count (DAS28) and Health Assessment Questionnaire (HAQ) scores over 2 years using linear mixed-effects and latent growth curve models.
RESULTS
HLA variants 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 antibodies to citrullinated protein antigens (ACPA)-positive patients, suggesting that whilst their effects are not mediated by ACPA they only predict joint damage in ACPA-positive RA. Non-HLA variants did not associate with X-ray damage (assessed individually and cumulatively as a weighted genetic risk score). Two SNPs − rs11889341 (STAT4; P=0.0001); 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 characterise the genetic architecture of radiological progression in RA.
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 early, active RA patients.
METHODS
We evaluated 524 RA patients enrolled to the Combination Anti-Rheumatic Drugs in Early RA (CARDERA) trials. We tested validated susceptibility variants – 69 single nucleotide polymorphisms (SNPs); 15 HLA-DRB1 alleles; amino acid polymorphisms in 6 HLA molecule positions – for their associations with progression in Larsen, disease activity scores on a 28-joint count (DAS28) and Health Assessment Questionnaire (HAQ) scores over 2 years using linear mixed-effects and latent growth curve models.
RESULTS
HLA variants 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 antibodies to citrullinated protein antigens (ACPA)-positive patients, suggesting that whilst their effects are not mediated by ACPA they only predict joint damage in ACPA-positive RA. Non-HLA variants did not associate with X-ray damage (assessed individually and cumulatively as a weighted genetic risk score). Two SNPs − rs11889341 (STAT4; P=0.0001); 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 characterise the genetic architecture of radiological progression in RA.
Original language | English |
---|---|
Pages (from-to) | 1131-1140 |
Number of pages | 10 |
Journal | Journal of Rheumatology |
Volume | 42 |
Issue number | 7 |
DOIs | |
Publication status | Published - 15 May 2015 |