THU0016 A comprehensive contribution of genes of the hypoxia inducible factor-1 alpha signaling pathway to knee osteoarthritis susceptibility
Authors: J Fernandez-Torres, GA Martínez-Nava, A Lόpez-Reyes, Y Zamudio-Cuevas, D Clavijo-Cornejo, K Martínez-Flores, MC Gutiérrez-Ruíz, LE Gόmez-Quiroz, C Pineda
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The hallmark of osteoarthritis (OA) is the breakdown of articular cartilage. Articular cartilage is an avascular tissue, and this generates a hypoxic microenvironment. Hypoxia inducible factor-1α (HIF-1α) is the main transcriptional regulator of cellular and developmental response to hypoxia. <h3>Objectives</h3> The present study was designed to investigate whether genetic polymorphisms of the HIF-1α signaling pathway are involved in the development of knee OA. <h3>Methods</h3> A total of 243 unrelated Mexican-mestizo individuals comprising 93 knee OA patients and 150 healthy controls were recruited into the study. 42 genetic polymorphisms from 22 genes involved in the HIF-1α signaling pathway (<i>PIK3R1</i>, <i>AKT2</i>, <i>GSK3B</i>, <i>IL6</i>, <i>AGER</i>, <i>HIF1A</i>, <i>EGLN1, VHL</i>, <i>HIF1AN</i>, <i>VEGFA</i>, <i>EPO</i>, <i>NOS2</i>, <i>NOS3</i>, <i>IGF1</i>, <i>EGF</i>, <i>EDN1</i>, <i>MMP1</i>, <i>MMP3</i>, <i>MMP13</i>, <i>CA</i>, <i>COL2A1</i>, <i>COL3A1</i>) were genotyped in cases and controls using TaqMan-based allelic discrimination assays. <h3>Results</h3> After adjusting for age, sex and admixture, significant associations with knee OA were found for 7 SNPs in the case-control study. The following genotypes and alleles were associated with protection against OA: the CT genotype of the <i>HIF1AN</i> rs11190613 polymorphism (OR=0.44, 95% CI=0.19–1.0, <i>P</i>=0.05); the AA genotype of the <i>VEGFA</i> rs1570360 polymorphism (OR=0.14, 95% CI=0.02–0.69, <i>P</i>=0.016); the GT genotype and T allele of the <i>VEGFA</i> rs729761 polymorphism (OR=0.47, 95% CI=0.22–1.0, <i>P</i>=0.05; and OR=0.51, 95% CI=0.27–0.97, <i>P</i>=0.041, respectively); the GA genotype of the <i>COL2A1</i> rs1793953 polymorphism (OR=0.40, 95% CI=0.20–0.79, <i>P</i>=0.008); and the GG genotype and G allele of the <i>CKM</i> rs4884 polymorphism (OR=0.34, 95% CI=0.14–0.84, <i>P</i>=0.019; and OR=0.51, 95% CI=0.32–0.82, respectively). Otherwise, the CT genotype of the <i>COL3A1</i> rs2138533 polymorphism (OR=2.89, 95% CI=1.28–6.5, <i>P</i>=0.01); and the GA genotype of the <i>IGF1</i> rs35767 polymorphism (OR=2.22, 95% CI=1.11–4.43, <i>P</i>=0.024) were associated with an increased risk of OA. However, by using of epistatic interactions between HIF-1α pathway polymorphisms, we found that the gene-gene interaction had a synergistic effect over the estimated OR-values (see table). <h3>Conclusions</h3> In this study we could observe that the gene-gene interaction of the HIF-1α signaling pathway highly increases the risk of developing OA, with the exception of <i>COL2A1</i> and <i>HIF1AN</i> interaction which had a protective role against OA. Further studies are needed to validate this results. <h3>References</h3> Fernández-Torres J, et al. Polymorphic variation of hypoxia inducible factor-1 A (HIF1A) gene might contribute to the development of knee osteoarthritis: a pilot study. BMC Musculoskelet Disord 2015; 16:218. Rodríguez-Fontanela C, et al. Assessment of osteoarthritis candidate genes in a meta-analysis of nine genome-wide association studies. Arthritis Rheumatol 2014; 66:940–949. <h3>Disclosure of Interest</h3> None declared