Impact of the gene-gene interactions related to the HIF-1α signaling pathway with the knee osteoarthritis development

• Published in: Clinical rheumatology Vol. 38; no. 10; pp. 2897 - 2907
• Main Authors: Fernández-Torres, Javier, Martínez-Nava, Gabriela Angélica, Zamudio-Cuevas, Yessica, Martínez-Flores, Karina, Gutiérrez-Ruíz, María Concepción, Gómez-Quiroz, Luis Enrique, Garrido-Rodríguez, Daniela, Muñoz-Valle, José Francisco, Oregón-Romero, Edith, Lozada, Carlos, Cornejo, Denise Clavijo, Pineda, Carlos, López-Reyes, Alberto
• Format: Journal Article
• Language: English
• Published: London Springer London 01.10.2019; Springer Nature B.V
• Subjects: Adult; AKT2 protein; Arthritis; Capillaries - pathology; Cartilage (articular); Cartilage diseases; Case-Control Studies; Collagen Type II - genetics; Epistasis; Epistasis, Genetic; Female; Genotype; Glycogen Synthase Kinase 3 beta - genetics; Haplotypes; Homeostasis; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Insulin-like growth factor I; Insulin-Like Growth Factor I - genetics; Knee; Male; Medicine; Medicine & Public Health; Mexico; Middle Aged; Models, Genetic; Original Article; Osteoarthritis; Osteoarthritis, Knee - genetics; Osteoarthritis, Knee - physiopathology; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-akt - genetics; Rheumatology; Risk; Signal Transduction; Single-nucleotide polymorphism; Mexico; Multifactor dimensionality reduction; Gene-gene interaction; Single nucleotide polymorphism; Hypoxia inducible factor-1α; Osteoarthritis
• ISSN: 0770-3198; 1434-9949
• DOI: 10.1007/s10067-019-04635-w

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.