TY - JOUR A1 - Ling, Stephanie F. AU - Viatte, Sebastien AU - Lunt, Mark AU - Van Sijl, Alper M AU - Silva Fernández, Lucía AU - Symmons, Deborah P. M. AU - Young, Adam AU - Macgregor, Alexander J AU - Barton, Anne T1 - HLA-DRB1 Amino Acid Positions 11/13, 71, and 74 Are Associated With Inflammation Level, Disease Activity, and the Health Assessment Questionnaire Score in Patients With Inflammatory Polyarthritis. Y1 - 2016 UR - http://hdl.handle.net/20.500.11940/9562 AB - Rheumatoid arthritis (RA) susceptibility HLA-DRB1 haplotypes based on amino acid positions 11/13, 71, and 74 predict radiographic damage. The mechanism of action is unknown, but it may be mediated by inflammation. We undertook this study to systematically investigate the effect of these amino acids on nonradiographic measures of disease activity/outcomes. We tested the association of RA susceptibility HLA-DRB1 amino acids with the C-reactive protein (CRP) level, the tender joint count (TJC), the swollen joint count (SJC), the Disease Activity Score in 28 joints (DAS28), and the Health Assessment Questionnaire (HAQ) score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS) cohorts. Longitudinal modeling of disease activity/outcomes was performed using generalized linear latent and mixed models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome. A total of 2,158 patients were available for analysis in the NOAR cohort. Valine at position 11 showed the strongest association with the CRP level (P = 2.21 × 10(-6) ), the SJC (P = 7.51 × 10(-6) ), and the DAS28 (P = 0.002); it was marginally associated with the HAQ score (P = 0.044) but not with the TJC. The same amino acid and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for the CRP level and nonradiographic measures of disease activity/outcome, apart from the TJC. The results were replicated in the ERAS cohort. The effect of valine at position 11 on the SJC was mainly mediated by anti-citrullinated protein antibody status, the effect of which was mainly mediated by inflammation; however, the effect of valine at position 11 was also independent of the CRP level (P = 1.6 × 10(-4) ). Genetic markers of RA susceptibility located within HLA-DRB1 determine the levels of clinical and systemic inflammation independently, and also determine all objective measures of disease activity and outcome. KW - Rheumatology KW - Peptides, Cyclic KW - Health Surveys KW - Amino Acids KW - C-Reactive Protein KW - Arginine KW - Phenotype KW - Severity of Illness Index KW - Arthritis KW - Genotype KW - Valine KW - Arthritis, Rheumatoid KW - Antirheumatic Agents KW - Haplotypes KW - Alleles KW - HLA-DRB1 Chains KW - Inflammation KW - Artritis reumatoide, no especificada KW - encuestas de salud KW - fenotipo KW - valina KW - alelos KW - arginina KW - antirreumáticos KW - inflamación KW - índice de gravedad de la enfermedad KW - reumatología KW - cadenas HLA-DRB1 KW - aminoácidos KW - genotipo KW - haplotipos KW - péptidos cíclicos KW - artritis reumatoide KW - proteína C reactiva KW - artritis KW - Surveys and Questionnaires KW - Amino Acids KW - Arthritis, Rheumatoid KW - Antirheumatic Agents KW - artritis reumatoide KW - C-Reactive Protein KW - HLA-DRB1 Chains KW - inflamación KW - Peptides, Cyclic KW - Health Surveys KW - Genotype KW - Haplotypes KW - Inflammation KW - Phenotype KW - Arthritis KW - artritis KW - reumatología KW - Alleles KW - haplotipos KW - valina KW - arginina KW - Severity of Illness Index KW - encuestas de salud KW - artritis reumatoide KW - amino ácidos KW - cuestionarios de salud KW - genética KW - antirreumáticos KW - Proteína C-Reactiva LA - eng ER -