ASSOCIATION BETWEEN HYPOXIA-INDUCIBLE FACTOR 1A (HIF1A) GENE AND SYSTEMIC SCLEROSIS IN CAUCASIAN PATIENTS COHORT

Background: Systemic sclerosis (SSc) is a connective tissue disease characterized by early generalized microangiopathy leading to iterative ischemia/reperfusion phenomenon. Hypoxia-Inducible Factor (HIF) is a transcription factor for numerous genes (VEGF, eNOS ou Endothelin 1) in hypoxic conditions.Objectives: Our aim was to determine the possible role of HIF1A gene in systemic sclerosis in a large Caucasian patients' cohort with a case-control studyMethods: We included 1170 consecutive unrelated subjects for the study, comprising 659 Caucasian SSc patients and 511 healthy matched controls. Three SNPs of HIF1A gene (rs12434438 A/G, rs1957757 C/T and rs11549465 C/T) were genotyped. Alleles and genotypes frequencies were compared using the Fischer's exact test and Odds Ratio (OR) were calculated using, for each SNP, the most frequent genotype as reference. Quantitative RT-PCR Taq Man® methods were used under basal and hypoxic conditions to evaluate consequences of rs12434438 genotypes variation on HIF1A gene expression.Results: All the three SNPs were in Hardy-Weinberg equilibrium in controls. The genotypes carrying at least one G allele (A/G and/or GG) of the rs12434438 was significantly more frequent in global SSc patients (OR=1.39; 95%IC [1.08-1.78]), in SSc with limited cutaneous form (OR=1.35; 95%IC [1.03-1.77]) and with positive anticentromere antibodies (OR=1.50; 95%IC [1.09-2.05]) than in controls. The heterozygous genotype A/G was also associated with the of SSc (OR=1.43; 95%IC [1.13-1.9]), with SSc with limited cutaneous form (OR=1.44;95%IC [1.08-1.91] and with positive anticentromere antibodies (OR=1.61; 95%IC [1.16-2.23]). The genotypes frequencies were similar for the two other SNPs in patients and controls. Haplotypes analyses did not detect any association with SSc. Finally, preliminary results of functional tests show similar levels of HIF1A expression for the reference A/A genotype and the heterozygous G/A genotype.Conclusion: The results suggest the implication of HIF1A gene in the pathogenesis of SSc. The functional tests show that rs12434438 is not a functional SNP thus it should have to be in disequilibrium linkage with another variant which carries the susceptibility to SSc.Citation: Ann Rheum Dis, volume 67, supplement II, year 2008, page 508Session: Scleroderma, Myositis and related syndromes