THU0016 A comprehensive contribution of genes of the hypoxia inducible factor-1 alpha signaling pathway to knee osteoarthritis susceptibility

Abstract

BackgroundThe 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.ObjectivesThe present study was designed to investigate whether genetic polymorphisms of the HIF-1α signaling pathway are involved in the development of knee OA.MethodsA 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 (PIK3R1, AKT2, GSK3B, IL6, AGER, HIF1A, EGLN1, VHL, HIF1AN, VEGFA, EPO, NOS2, NOS3, IGF1, EGF, EDN1, MMP1, MMP3, MMP13, CA, COL2A1, COL3A1) were genotyped in cases and controls using TaqMan-based allelic discrimination assays.ResultsAfter 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 HIF1AN rs11190613 polymorphism (OR=0.44, 95% CI=0.19–1.0, P=0.05); the AA genotype of the VEGFA rs1570360 polymorphism (OR=0.14, 95% CI=0.02–0.69, P=0.016); the GT genotype and T allele of the VEGFA rs729761 polymorphism (OR=0.47, 95% CI=0.22–1.0, P=0.05; and OR=0.51, 95% CI=0.27–0.97, P=0.041, respectively); the GA genotype of the COL2A1 rs1793953 polymorphism (OR=0.40, 95% CI=0.20–0.79, P=0.008); and the GG genotype and G allele of the CKM rs4884 polymorphism (OR=0.34, 95% CI=0.14–0.84, P=0.019; and OR=0.51, 95% CI=0.32–0.82, respectively). Otherwise, the CT genotype of the COL3A1 rs2138533 polymorphism (OR=2.89, 95% CI=1.28–6.5, P=0.01); and the GA genotype of the IGF1 rs35767 polymorphism (OR=2.22, 95% CI=1.11–4.43, P=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).abORi ORc* P int VEGFA rs1570360 COL3A1 rs2138533 GGCC10.027CT2.894.51TT1.2411.1 COL3A1 rs2138533 IGF1 rs35767 TG10.037A1.493.26 CKM rs4884 COL3A1 rs2138533 AC10.036T1.274.08 COL2A1 rs1793953 HIF1AN rs11190613 AT10.05C0.710.35ORi = initial OR-value; ORc* = combined OR-value obtained by “b” column interaction with “a” column; P int = P-value of the intreraction.ConclusionsIn 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 COL2A1 and HIF1AN interaction which had a protective role against OA. Further studies are needed to validate this results.References 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 osteoarthriti...

Potential Therapeutic Mechanism of Radix Angelicae Biseratae and Dipsaci Radix Herb Pair against Osteoarthritis: Based on Network Pharmacology and Molecular Docking

“…Te main hypoxia-inducible factor (HIF) of articular chondrocytes is a transcription factor, which is also the main mediator of homeostatic response that enables cells to survive under hypoxic conditions [69]. In OA, the expression of HIF-1α decreases [70], and the loss of HIF-1α can up-regulate the expression of MMP13, degrade col2A1 and ACAN, promote chondrocyte degradation, and promote the development of OA [71]. Te advanced glycation end product receptor (RAGE) is secreted in a variety of cells, including macrophages and mast cells [72].…”