title: A replication study and meta-analysis of mitochondrial DNA variants in the radiographic progression of knee osteoarthritis.
abstract: To conduct a replication study and meta-analysis involving the study of mtDNA variants in the radiographic progression of OA in different cohorts worldwide, including Cohort Hip and Cohort Knee (CHECK), the OA Initiative and a cohort from Spain.
  
  
  
  The influence of the haplogroups in the rate of radiographic progression at 96 months in 431 subjects from CHECK was assessed in terms of Kellgren and Lawrence (KL) grade. Progression was defined as a change from KL ⩾ 1 at baseline to any higher grade during the follow-up. Extended Cox proportional hazard models were used to analyse the influence of mtDNA variants in the rate of radiographic knee OA progression. A subsequent meta-analysis of 1603 subjects following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted to combine the data of individual studies. A sensitivity analysis was performed to validate the stability of the results.
  
  
  
  CHECK subjects carrying the haplogroup T showed the lowest rate of radiographic knee OA progression [hazard ratio (HR) 0.645 (95% CI 0.419, 0.978); P < 0.05]. When pooled, subjects within the superhaplogroup JT showed the same trend [HR 0.707 (95% CI 0.501, 0.965); P < 0.05]. BMI [HR 1.046 (95% CI 1.018, 1.073); P < 0.05] and bilateral OA [HR 2.266 (95% CI 1.733, 2.954); P < 0.05] at baseline are risk factors for radiographic knee OA progression as well. In the meta-analysis there was a reduced rate of radiographic progression in subjects with haplogroup T [HR 0.612 (95% CI 0.454, 0.824); P = 0.001] or in the superhaplogroup JT [HR 0.765 (95% CI 0.624, 0.938); P = 0.009]. Sensitivity analysis revealed that the results were robust.
  
  
  
  The mtDNA variants in the superhaplogroup JT associate with a reduced rate of radiographic OA progression. The mtDNA polymorphisms in the superhaplogroup JT emerge as potential complementary genetic biomarkers for disease progression.
authors.affiliation: Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias.|CIBER-BBN Instituto de Salud Carlos III, INIBIC-CHUAC.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Fernández-Moreno
authors.affiliation: Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias.
authors.forename: Angel
authors.initials: A
authors.lastname: Soto-Hermida
authors.affiliation: Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias.
authors.forename: María E
authors.initials: ME
authors.lastname: Vázquez-Mosquera
authors.affiliation: Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Cortés-Pereira
authors.affiliation: Unidad de Epidemiología Clínica y Bioestadística.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pértega
authors.affiliation: Plataforma de Genómica, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias, A Coruña, 15006, España, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Relaño
authors.affiliation: Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias.
authors.forename: Natividad
authors.initials: N
authors.lastname: Oreiro-Villar
authors.affiliation: Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-López
authors.affiliation: Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Blanco
authors.affiliation: Servicio de Reumatología, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias ignacio.rego.perez@sergas.es.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rego-Pérez
mesh_terms: D000368:Aged; D015992:Body Mass Index; D015331:Cohort Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D006239:Haplotypes; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011859:Radiography; D015203:Reproducibility of Results; D012307:Risk Factors; D013030:Spain
chemical_list: D004272:DNA, Mitochondrial
keywords: genetics; knee; meta-analysis; molecular biology; osteoarthritis