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BackgroundHIF-1α is the main transcriptional regulator of cellular and developmental response to hypoxia, and also participates in the integration of the T cell receptor and cytokine receptor-mediated signals of CD4+ helper cells. Another transcription factor also involved in the immune responses is the AT-hook transcription factor (AKNA).ObjectivesTo evaluate the allele and genotype frequencies of polymorphic sites of HIF1A and ANKA genes in primary Sjögren's syndrome (pSS).MethodsWe included 110 patients with pSS and 141 ethnically matched healthy controls. Three HIF1A gene polymorphisms (Pro582Ser, Ala588Thr, and C191T) and two AKNA genes polymorphism (-1372C>A, and Pro624Leu) were genotyped using TaqMan probes in a Real-Time PCR instrument. Associations between pSS and genotypes, alleles and inheritance models of the SNPs of interest were evaluated by logistic regression adjusted by age and gender.ResultsMost of the patients were females (95.4%), median age 55 years and median disease duration of 7.8 years. The C/T genotype and the T allele of the HIF1A Pro582Ser polymorphism protected against pSS (OR=0.22; 95% CI=0.09–0.52; P<0.01; and OR=0.26; 95% CI=0.12–0.58; P<0.01; respectively). Whereas under a recessive model adjusted by age and gender, the AKNA -1372C>A polymorphism A/A genotype was associated with an increased risk of pSS (OR=2.60; 95% CI=1.11–6.12; P=0.03). Parotid enlargement was associated with the HIF1A gene polymorphism (rs11549465), conferring protection for the C/T genotype vs. C/C (OR=0.22; 95% CI 0.05–0.90, P=0.03). The allele T of the same polymorphism was also associated with parotid enlargement (OR=0.24, 95% CI=0.65–0.95; P=0.04). We did not find any association with any other clinical or serological feature.ConclusionsWe identified HIF1A Pro582Ser T allele and C/T genotype as well as AKNA -1372C>A polymorphism A/A genotype as genetic factors associated with pSS. Further studies in other populations are needed to validate our findings and to shed some light on their functional implications.References Palazon A, Goldrath A, Nizet V, Johnson R. HIF transcription factors, inflammation and immunity. Immunity 2014; 41:518–28.Sims-Mourtada JC, Bruce S, McKeller MR, et al. The human AKNA gene expresses multiple transcripts and protein isoforms as a result of alternative promoter usage, splicing, and polyadenylation. DNA Cell Biol 2005;24:325–38. Disclosure of InterestNone declared

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...

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