Javier Fernández-Torres1,2, Gabriela Angélica Martínez-Nava1, Yessica Zamudio-Cuevas1, Karina Martínez-Flores1, María Concepción Gutiérrez-Ruíz3, Luis Enrique Gómez-Quiroz3, Daniela Garrido-Rodríguez4, José Francisco Muñoz-Valle5, Edith Oregón-Romero5, Carlos Lozada6, Denise Clavijo Cornejo7, Carlos Pineda7, Alberto López-Reyes8. 1. Synovial Fluid Laboratory, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Mexico City, Mexico. 2. Biological and Health Sciences PhD Program, Universidad Autónoma Metropolitana Iztapalapa, Mexico City, Mexico. 3. Health Sciences Department, Universidad Autónoma Metropolitana Iztapalapa, Mexico City, Mexico. 4. Center for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico. 5. Departamento de Biología Molecular y Genómica, Instituto de Investigación en Ciencias Biomédicas (IICB), Universidad de Guadalajara, Guadalajara, Mexico. 6. Rheumatology Service, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Mexico City, Mexico. 7. Musculoskeletal and Rheumatic Diseases Division, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Mexico City, Mexico. 8. Synovial Fluid Laboratory, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", Mexico City, Mexico. allorey@yahoo.com.
Abstract
INTRODUCTION/ OBJECTIVES: Articular cartilage is the target tissue of osteoarthritis (OA), and because it lacks capillary networks, the microenvironment is hypoxic. Hypoxia inducible factor-1 alpha (HIF-1α) regulates the homeostasis of this tissue. The aim of this study was to investigate whether genetic polymorphisms of the HIF-1α signaling pathway are involved in the development of knee OA. METHOD: We performed a case-control association study and genotyped 134 knee OA patients and 267 healthy controls. All participants were genotyped in order to evaluate 42 SNPs from 22 genes involved in the HIF-1α signaling pathway using the OpenArray technology. Gene-gene interactions (epistasis) were analyzed using the multifactor dimensionality reduction (MDR) method. RESULTS: The MDR analysis showed epistasis between AKT2 (rs8100018) and IGF1 (rs2288377), AKT2 (rs8100018) and IGF1 (rs35767), IGF1 (rs35767) and COL2A1 (rs1793953), and between GSK3B (rs6438552) and IGF1 (rs35767) polymorphisms, with information gain values of 21.24%, 8.37%, 9.93%, and 5.73%, respectively. Additionally, our model allowed us to identify high- and low-risk genotypes among COL2A1 rs1793953, GSK3B rs6438552, AKT2 rs8100018, and IGF1 rs35767 polymorphisms. CONCLUSIONS: Knowing the interactions of these polymorphisms involved in HIF-1α signaling pathway could provide a new diagnostic support tool to identify individuals at high risk of developing knee OA.
INTRODUCTION/ OBJECTIVES:Articular cartilage is the target tissue of osteoarthritis (OA), and because it lacks capillary networks, the microenvironment is hypoxic. Hypoxia inducible factor-1 alpha (HIF-1α) regulates the homeostasis of this tissue. The aim of this study was to investigate whether genetic polymorphisms of the HIF-1α signaling pathway are involved in the development of knee OA. METHOD: We performed a case-control association study and genotyped 134 knee OA patients and 267 healthy controls. All participants were genotyped in order to evaluate 42 SNPs from 22 genes involved in the HIF-1α signaling pathway using the OpenArray technology. Gene-gene interactions (epistasis) were analyzed using the multifactor dimensionality reduction (MDR) method. RESULTS: The MDR analysis showed epistasis between AKT2 (rs8100018) and IGF1 (rs2288377), AKT2 (rs8100018) and IGF1 (rs35767), IGF1 (rs35767) and COL2A1 (rs1793953), and between GSK3B (rs6438552) and IGF1 (rs35767) polymorphisms, with information gain values of 21.24%, 8.37%, 9.93%, and 5.73%, respectively. Additionally, our model allowed us to identify high- and low-risk genotypes among COL2A1rs1793953, GSK3Brs6438552, AKT2rs8100018, and IGF1rs35767 polymorphisms. CONCLUSIONS: Knowing the interactions of these polymorphisms involved in HIF-1α signaling pathway could provide a new diagnostic support tool to identify individuals at high risk of developing knee OA.
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