Epistasis Between Two Gene Variants of Leptin and Vascular Endothelial Growth Factor Genes in the Development of Primary Knee Osteoarthritis.

BACKGROUND: The association of leptin (LEP) and vascular endothelial growth factor A (VEGFA) genes with the susceptibility to knee osteoarthritis (OA) has been analyzed; however, the epistasis between them has not been investigated. OBJECTIVE: The objective of the study was to analyze the association of LEP and VEGFA variants and their interaction with primary knee OA in a Mexican Mestizo population. METHODS: A case-control study was developed. Cases were ≥40 years, BMI ≤27 kg/m2, with primary knee OA and radiologic Grade ≥2. Controls were participants with no knee OA and a radiologic Grade < 2. The rs2167270 of LEP and rs2010963 of VEGFA were genotyped. Genotypic association was tested under codominant, dominant, and recessive models. Uni- and multi-variate analyses were developed through non-conditional logistic regression. The multifactor dimensionality reduction algorithm was developed to detect epistasis. RESULTS: Participants comprised 103 cases and 179 controls. Allelic and genotypic distributions did not show differences between the groups. Notwithstanding, a statistically significant interaction was observed between the LEP and VEGFA genes (p = 0.02) with a testing accuracy of 0.5199 and cross-validation consistency of 10/10. This interaction model confers an increased risk to knee OA (OR [95% CI] = 1.8 [1.1-2.9]). CONCLUSION: Interaction between LEP and VEGFA is related with genetic susceptibility to developing primary knee OA.

DNA methyltransferase genes polymorphisms are associated with primary knee osteoarthritis: a matched case-control study.

DNA methylation is an epigenetic mechanism involved in the development of primary osteoarthritis (OA). The association between DNA methyltransferases (DNMTs) genes polymorphisms and diseases in which DNA methylation plays a role in their pathogenesis has been described (e.g., cancer); however, its relationship with OA has not been investigated. The aim of this study was to analyze the association between DNMT1, DNMT3A, and DNMT3B polymorphisms with radiologic primary knee OA in Mexican mestizo population. A matched case-control study was conducted (ratio, 1:1). Cases included 244 subjects with definite radiographic knee OA (grade ≥ 2). Controls were matched by age and gender and were subjects with no definite radiographic knee OA/normal (grade < 2). The DNMTs polymorphisms were genotyped by TaqMan allelic discrimination assays. Conditional logistic regression was carried out, and the genetic association was tested under co-dominant, dominant, and recessive inheritance models. Haplotypes for DNMT1 polymorphisms were constructed and their associations were also tested. The CC genotypes of rs2228611 and rs2228612 of DNMT1 were associated with a lower risk for primary knee OA under a co-dominant and a recessive model [OR (95% CI) 0.4 (0.2-0.8)/0.5 (0.3-0.8) and 0.3 (0.1-0.8)/0.3 (0.1-0.7), respectively]. The CT haplotype of DNMT1 polymorphisms was associated with a lower risk [OR (95% CI) 0.71 (0.51-0.97)]. The CC genotype of rs2424913 of DNMT3B was associated with an increased risk under a co-dominant and a dominant model [OR (95% CI) 3.0 (1.1-8.0), and 1.6 (1.1-2.4), respectively]. Our results show that DNMTs polymorphisms are associated with primary knee OA.