Ian C Scott1, Frühling Rijsdijk1, Jemma Walker1, Jelmar Quist1, Sarah L Spain1, Rachael Tan1, Sophia Steer1, Yukinori Okada1, Soumya Raychaudhuri1, Andrew P Cope1, Cathryn M Lewis1. 1. From the Department of Medical and Molecular Genetics, and Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, and Social, Genetic and Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, and Department of Rheumatology, King's College London, and Guy's Hospital, London, UK; Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.I.C. Scott, PhD, Clinical Research Fellow, Department of Medical and Molecular Genetics, and Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London, and Guy's Hospital; F. Rijsdijk, PhD, Reader, SGDP Centre, Institute of Psychiatry, King's College London; J. Walker, PhD, Statistical Geneticist; J. Quist, PhD, MSc, Student; S.L. Spain, PhD, Research Associate, Department of Medical and Molecular Genetics, King's College London, and Guy's Hospital; R. Tan, MRes, Core Medical Trainee, Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London; S. Steer, PhD, Consultant Rheumatologist, Department of Rheumatology, King's College Hospital; Y. Okada, PhD, Tenure Track Junior Associate Professor, Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, and Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences; S. Raychaudhuri, PhD, Professor, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School; A.P. Cope, PhD, Professor, Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, King's College London; C.M. Lewis, PhD, Prof
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.
RCT Entities:
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.
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