Epistasis of polymorphisms related to the articular cartilage extracellular matrix in knee osteoarthritis: Analysis-based multifactor dimensionality reduction.

Javier Fernández-Torres,Daniela Garrido-Rodríguez,Yessica Zamudio-Cuevas,Gabriela Angélica Martínez-Nava,Karina Martínez-Flores,Carlos Lozada

doi:10.1590/1678-4685-gmb-2018-0349

Javier Fernández-Torres, Daniela Garrido-Rodríguez + Show 4 more

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https://doi.org/10.1590/1678-4685-gmb-2018-0349

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Abstract

Osteoarthritis (OA) is a complex disease with a multifactorial etiology. The genetic component is one of the main associated factors, resulting from interactions between genes and environmental factors. The aim of this study was to identify gene-gene interactions (epistasis) of the articular cartilage extracellular matrix (ECM) in knee OA. Ninety-two knee OA patients and 147 healthy individuals were included. Participants were genotyped in order to evaluate nine variants of eight genes associated with ECM metabolism using the OpenArray technology. Epistasis was analyzed using the multifactor dimensionality reduction (MDR) method. The MDR analysis showed significant gene-gene interactions between MMP3 (rs679620) and COL3A1 (rs1800255), and between COL3A1 (rs1800255) and VEGFA (rs699947) polymorphisms, with information gain values of 3.21% and 2.34%, respectively. Furthermore, in our study we found interactions in high-risk genotypes of the HIF1AN, MMP3 and COL3A1 genes; the most representative were [AA+CC+GA], [AA+CT+GA] and [AA+CT+GG], respectively; and low-risk genotypes [AA+CC+GG], [GG+TT+GA] and [AA+TT+GA], respectively. Knowing the interactions of these polymorphisms involved in articular cartilage ECM metabolism could provide a new tool to identify individuals at high risk of developing knee OA.

Highlights

To date, knee osteoarthritis (OA) prevails as the main cause of physical disability in senior adults
Genetic and allelic frequencies of the single-nucleotide polymorphisms (SNP) studied in OA patients and controls After adjusting for age, gender, body mass index (BMI) and ancestry, there were no significant differences between the genotype or allele frequencies of the analyzed polymorphisms in the study groups
Genotype distributions were compatible with HardyWeinberg equilibrium (HWE) in controls, except for the HIF1AN polymorphism (Table 3)

Summary

Introduction

Knee osteoarthritis (OA) prevails as the main cause of physical disability in senior adults. Healthy articular cartilage is a hyaline, viscoelastic, avascular, aneural, and alymphatic tissue. It is composed of an ECM rich in collagens (types II, IX and XI), proteoglycans (aggrecan), and water. Despite the extreme conditions of the cartilage, hypoxia is necessary in metabolic processes, such as chondrogenesis ECM synthesis and degradation. It modulates the subchondral bone angiogenesis through the vascular endothelial growth factor A (VEGFA). These processes, and the proper maintenance of general cartilage homeostasis, are coordinated by hypoxia-inducible factor-1a (HIF-1a) (Pfander et al, 2006). If the ECM synthesis process is decreased, cartilage will become thinner and weaker, whereas it will turn hyper-

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