Takagi Kae, Kawamoto Manabu, Higuchi Tomoaki, Tochimoto Akiko, Harigai Masayoshi, Kawaguchi Yasushi
Department of Medicine, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
Department of Rheumatology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
Int J Rheum Dis. 2020 May;23(5):674-680. doi: 10.1111/1756-185X.13822. Epub 2020 Mar 6.
Hypoxia-inducible factor (HIF)1α is induced by endothelial cells under hypoxic conditions, suggesting that HIF1α may be involved in vascular impairment in patients with systemic sclerosis (SSc). The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to SSc and its complications, including pulmonary arterial hypertension (PAH).
This study involved 182 Japanese SSc patients (discovery cohort) and 178 healthy controls. Four SNPs (rs11549465, rs11549467, rs1957757, and rs12434438) of the HIF1A gene were genotyped using specific TaqMan probes. We also employed another SSc cohort (N = 135) to validate the significant results of SNPs found in the discovery SSc cohort.
The frequencies of the four SNPs did not show any significant differences between the SSc and healthy control groups. The AA genotype at rs12434438 was significantly higher in SSc patients with PAH than in those without PAH (P = .012). These results were validated using another SSc cohort (N = 135, P = .006). Moreover, the AA genotype was significantly associated with the severity of PAH.
Although HIF1A gene polymorphisms were not associated with susceptibility to SSc, the AA genotype at rs12434438 was associated with a subset of SSc patients with severe PAH, suggesting that the rs12434438 SNP may contribute to the development of PAH with SSc.
缺氧诱导因子（HIF）1α 在缺氧条件下由内皮细胞诱导产生，提示 HIF1α 可能参与系统性硬化症（SSc）患者的血管损伤。本研究旨在评估 HIF1A 基因的单核苷酸多态性（SNP）是否与 SSc 及其并发症（包括肺动脉高压（PAH））的易感性相关。
本研究纳入了 182 名日本 SSc 患者（发现队列）和 178 名健康对照。使用特异性 TaqMan 探针检测 HIF1A 基因的四个 SNP（rs11549465、rs11549467、rs1957757 和 rs12434438）的基因型。我们还采用了另一个 SSc 队列（N = 135）来验证在发现的 SSc 队列中发现的 SNP 的显著结果。
这四个 SNP 的频率在 SSc 组和健康对照组之间没有显示出任何显著差异。rs12434438 处的 AA 基因型在患有 PAH 的 SSc 患者中显著高于未患 PAH 的患者（P = 0.012）。这些结果在另一个 SSc 队列（N = 135，P = 0.006）中得到了验证。此外，AA 基因型与 PAH 的严重程度显著相关。
虽然 HIF1A 基因多态性与 SSc 的易感性无关，但 rs12434438 处的 AA 基因型与一部分患有严重 PAH 的 SSc 患者相关，提示 rs12434438 SNP 可能促成 SSc 合并 PAH 的发生。
