Association of hypoxia‐inducible factor 1A (HIF1A) gene polymorphisms with systemic sclerosis in a French European Caucasian population

Abstract

Objective: Systemic sclerosis (SSc) is a connective tissue disease characterized by generalized microangiopathy leading to chronic hypoxia. The aim of this study was to determine whether polymorphisms of the hypoxia‐inducible factor 1A gene (HIF1A) affects susceptibility to SSc in a large French European Caucasian population.

Methods: A case–control study was performed in 659 SSc patients and 511 healthy matched controls. Three tag single nucleotide polymorphisms (SNPs) of the HIF1A gene (rs12434438 A/G, rs1957757 C/T, and rs11549465 C/T) were genotyped allowing whole gene coverage according to HapMap data.

Results: The frequency of genotypes carrying at least one G allele (A/G and/or GG) of the rs12434438 SNP was significantly higher in SSc patients than in controls [p_corr = 0.018, odds ratio (OR) 1.44, 95% confidence interval (CI) 1.08–1.91]. Regarding SSc subgroup analyses, the heterozygous genotype A/G was associated with SSc (p_corr = 0.012, OR 1.47, 95% CI 1.13–1.9), with the limited cutaneous form of SSc (p_corr = 0.04, OR 1.43, 95% CI 1.08–1.91), and with positive anti‐centromere antibodies (ACA; p_corr = 0.016, OR 1.61, 95% CI 1.16–2.23). No association was detected for the remaining two HIF1A SNPs tested. Haplotype analyses did not detect any association with SSc.

Conclusions: We observed an association between the HIF1A gene and SSc in a European Caucasian population, supporting a role for HIF1 in the pathophysiology of SSc.