title: Mitochondrial DNA haplogroups influence the risk of incident knee osteoarthritis in OAI and CHECK cohorts. A meta-analysis and functional study.
abstract: OBJECTIVE
  To evaluate the influence of the mitochondrial DNA (mtDNA) haplogroups in the risk of incident knee osteoarthritis (OA) and to explain the functional consequences of this association to identify potential diagnostic biomarkers and therapeutic targets.
  
  
  METHODS
  Two prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 2579 subjects of the incidence subcohort, and the cohort hip and cohort knee (CHECK) included 635, both with 8-year follow-up. The analysis included the association of mtDNA haplogroups with the rate of incident knee OA in subjects from both cohorts followed by a subsequent meta-analysis. Transmitochondrial cybrids harbouring haplogroup J or H were constructed to detect differences between them in relation to physiological features including specific mitochondrial metabolic parameters, reactive oxygen species production, oxidative stress and apoptosis.
  
  
  RESULTS
  Compared with H, the haplogroup J associates with decreased risk of incident knee OA in subjects from OAI (HR=0.680; 95% CI 0.470 to 0.968; p<0.05) and CHECK (HR=0.728; 95% CI 0.469 to 0.998; p<0.05). The subsequent meta-analysis including 3214 cases showed that the haplogroup J associates with a lower risk of incident knee OA (HR=0.702; 95% CI 0.541 to 0.912; p=0.008). J cybrids show a lower free radical production, higher cell survival under oxidative stress conditions, lower grade of apoptosis as well as lower expression of the mitochondrially related pro-apoptotic gene BCL2 binding component 3 (BBC3). In addition, J cybrids also show a lower mitochondrial respiration and glycolysis leading to decreased ATP production.
  
  
  CONCLUSIONS
  The physiological effects of the haplogroup J are beneficial to have a lower rate of incident knee OA over time. Potential drugs to treat OA could focus on emulating the mitochondrial behaviour of this haplogroup.
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, A Coruña, España.
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, A Coruña, España.
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, A Coruña, España.
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, A Coruña, España.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Cortés-Pereira
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, España.
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, A Coruña, España.
authors.forename: Tamara
authors.initials: T
authors.lastname: Hermida-Gómez
authors.affiliation: Unidad de Epidemiología Clínica y Bioestadística, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), As Xubias, A Coruña, España.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pértega
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, A Coruña, España.
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, A Coruña, España.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-López
authors.affiliation: Departamento de Bioquímica, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC y Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid, Madrid, Spain.|Laboratorio de Enfermedades Mitocondriales, Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12) Madrid, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Garesse
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, A Coruña, España.
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, A Coruña, España.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Rego-Pérez
mesh_terms: D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D004272:DNA, Mitochondrial / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D015994:Incidence; D020370:Osteoarthritis, Knee / Q000453:epidemiology* / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species
keywords: Epidemiology; Gene Polymorphism; Knee Osteoarthritis