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Mitonuclear epistasis involving TP63 and haplogroup Uk: risk of rapid progression of knee OA in patients from the OAI.

Authors
  • Durán-Sotuela, Alejandro1
  • Oreiro, Natividad2
  • Fernández-Moreno, Mercedes1
  • Vázquez-García, Jorge1
  • Relaño-Fernández, Sara1
  • Balboa-Barreiro, Vanesa3
  • Blanco, Francisco J4
  • Rego-Pérez, Ignacio5
  • 1 Grupo de Investigación en Reumatología (GIR). Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC). C/ As Xubias de Arriba 84, 15006, A Coruña, España.
  • 2 Grupo de Investigación en Reumatología (GIR). Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC). C/ As Xubias de Arriba 84, 15006, A Coruña, España; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain. , (Spain)
  • 3 Unidad de apoyo a la investigación. Grupo de Investigación en Enfermería y Cuidados en Salud. Grupo de Investigación en Reumatología y Salud (GIR-S). Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC). As Xubias, 15006. A Coruña, España.
  • 4 Grupo de Investigación en Reumatología (GIR). Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC). C/ As Xubias de Arriba 84, 15006, A Coruña, España; Universidade da Coruña (UDC), Centro de Investigación de ciencias Avanzadas (CICA), Grupo de Investigación en Reumatología y Salud (GIR-S). Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Campus de Oza, 15008, A Coruña, España.
  • 5 Grupo de Investigación en Reumatología (GIR). Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC). C/ As Xubias de Arriba 84, 15006, A Coruña, España. Electronic address: [email protected].
Type
Published Article
Journal
Osteoarthritis and Cartilage
Publisher
Elsevier
Publication Date
Jan 06, 2024
Identifiers
DOI: 10.1016/j.joca.2023.12.008
PMID: 38190960
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

To investigate genetic interactions between mtDNA haplogroups and nuclear single nucleotide polymorphisms (nSNPs) to analyze their impact on the development of the rapid progression of knee osteoarthritis (OA). A total of 1095 subjects from the Osteoarthritis Initiative (OAI), with a follow-up time of at least 48-months, were included. Appropriate statistical approaches were performed, including generalized estimating equations adjusting for age, gender, body mass index (BMI), contralateral knee OA, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, previous injury in target knee and the presence of the mtDNA variant m.16519C. Additional genomic data consisted in the genotyping of Caucasian mtDNA haplogroups and eight nSNPs previously associated with the risk of knee OA in robust genome-wide association studies (GWAS). The simultaneous presence of the G allele of rs12107036 at TP63 and the haplogroup Uk significantly increases the risk of a rapid progression of knee OA (OR=1,670;95%CI:1,031-2,706; adjusted p-value=0,027). The assessment of the population attributable fraction (PAF) showed that the highest proportion of rapid progressors was under the simultaneous presence of the G allele of rs12107036 and the haplogroup Uk (23,4%) (95%CI:7,89-38,9;p-value<0,05). The area under the curve (AUC) of the cross-validation model (0,730) was very similar to the obtained for the predictive model (0,735). A nomogram was constructed to help clinicians to perform clinical trials or epidemiologic studies. This study demonstrates the existence of a mitonuclear epistasis in OA, providing new mechanisms by which nuclear and mitochondrial variation influence the susceptibility to develop different OA phenotypes. Copyright © 2024. Published by Elsevier Ltd.

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