title: Combined influence of genetic and environmental factors in age of rheumatoid arthritis onset.
abstract: To study the combined effect of both genetic and environmental factors in the age of rheumatoid arthritis onset. Patients (n = 507). Shared epitope characterization was performed using Lifecodes HLA-SSO. Genotyping of protein tyrosine phosphatase non-receptor 22 (PTPN22) rs2476601 and signal transducers and activators of transcription 4 (STAT4) rs7574865 polymorphism was performed using fast real-time PCR System. Shared epitope, antibodies directed against cyclic citrulinated peptide (anti-CCP) antibodies and a higher level of education were associated with a younger age at disease onset (P = 0.033, P = 0.004 and P < 0.0001, respectively). Neither carriers of the minor allele of PTPN22 rs2476601 nor STAT4 rs7574 polymorphisms showed a significant association with a younger age at disease onset (P = 0.355, P = 0.065, respectively). We found an additive effect of the three genetic markers in the age at onset: subjects with three markers were associated with a disease onset 9.56, 8.61, and 6.41 years before than those with none, one, or two genetic markers (P = 0.004, P = 0.006 and P = 0.043, respectively). We also described the additive effect of shared epitope, anti-CCP antibodies, educational level, PTPN22, and STAT4 polymorphisms in age at onset. Patients with two, three, four, or five variables were associated with a significant younger age of disease onset (4.72 [0.05-9.38] years (P = 0.048), 9.56 [4.72-14.40] years (P < 0.0001), 12.74 [6.84-18.64] years (P < 0.0001), and 20.87 [10.40-37.17] years (P < 0.0001)). Risk factors for the development of rheumatoid arthritis are also associated, with an additive effect, with a younger age at disease onset.
authors.affiliation: Rheumatology Service, Hospital Clinico San Carlos, C/Profesor Martín Lagos s/n, 28040 Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rodríguez-Rodríguez
authors.forename: José Ramón
authors.initials: JR
authors.lastname: Lamas
authors.forename: Jezabel
authors.initials: J
authors.lastname: Varadé
authors.forename: Pilar
authors.initials: P
authors.lastname: Tornero-Esteban
authors.forename: Lydia
authors.initials: L
authors.lastname: Abasolo
authors.forename: Emilio Gomez
authors.initials: EG
authors.lastname: de la Concha
authors.forename: Juan Angel
authors.initials: JA
authors.lastname: Jover
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.forename: Benjamín
authors.initials: B
authors.lastname: Fernández-Gutiérrez
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001172:Arthritis, Rheumatoid / Q000453:epidemiology* / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D002648:Child; D004522:Educational Status; D004777:Environment; D000939:Epitopes; D005260:Female; D020022:Genetic Predisposition to Disease; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016014:Linear Models; D008297:Male; D010456:Peptides, Cyclic / Q000276:immunology; D011110:Polymorphism, Genetic; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D050797:STAT4 Transcription Factor / Q000235:genetics*; D013030:Spain / Q000453:epidemiology
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C487763:cyclic citrullinated peptide; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22