系统性硬化症患者中Toll相互作用蛋白基因多态性：与间质性肺病、病情转归及生存率的关联
Toll interacting protein gene polymorphisms in patients with systemic sclerosis: association with interstitial lung disease, outcome, and survival.
作者信息
Schröder Niels, Andrä Jitka, Knuth-Rehr Diana, Leja Silke, Hunzelmann Nicolas, Moinzadeh Pia, Frank Konrad, Börner Eda, Bonella Francesco
机构信息
Center for Interstitial and Rare Lung Diseases, Ruhrlandklinik, Pneumonology Department, University of Duisburg-Essen, Essen, Germany.
Department of Dermatology and Venereology, University Hospital Cologne, Cologne, Germany.
出版信息
Front Med (Lausanne). 2025 May 22;12:1584014. doi: 10.3389/fmed.2025.1584014. eCollection 2025.
BACKGROUND
Pulmonary fibrosis is a leading cause of death in patients with Systemic sclerosis (SSc). Single nucleotide polymorphisms (SNPs) within Toll interacting protein () coding gene have been associated with progression and prognosis of Idiopathic Pulmonary Fibrosis (IPF). Aim of the present study was to investigate the association of SNPs with the presence, severity and outcome of interstitial lung disease (ILD) in patients with SSc.
PATIENTS AND METHODS
106 consecutive SSc patients (77 female) with ( = 53) and without ILD ( = 53) and 212 healthy controls (HC) (154 female) were genotyped for two SNPs within (rs3750920, rs5743890) by using TaqMan™ SNP Genotyping Assay (Thermo Fischer Scientific, USA). Disease progression was defined as ≥ 10% relative decline in FVC% pred. or ≥ 5 to < 10% decline in relative FVC% pred. and 15% relative decline in DLCO% pred. From baseline.
RESULTS
The rs5743890 minor Allele (C) was more frequent in HC than in SSc patients (41% vs. 16%, = 0.021). The homozygote alleles of rs5743890 were significantly overrepresented in SSc patients compared to HC (84% vs. 71%, = 0.008). Among SSc patients with ILD, those carrying the rs5743890 T/C genotype had a tendentially worse survival (158 vs. 213 months, = 0.162) and a significantly higher rate of disease progression (66% vs. 22%, = 0.003) compared to homozygotes. The rs5743890 minor allele C was an independent predictor of progression after adjustment for a number of covariates (HR 4.29, 95% CI 1.48-12.48, = 0.008). Moreover, the TC haplotype appeared to be an even stronger predictor of progression than rs5743890 alone (HR 7.71, 95% CI 1.79-33.12, = 0.006).
CONCLUSION
SNP rs5743890 genotype distribution seems to differ in SSc patients compared to HC. The rs5743890 heterozygote genotype and the TC haplotype may be associated with an increased risk of progression in patients with SSc-ILD.
背景
肺纤维化是系统性硬化症（SSc）患者的主要死亡原因。Toll相互作用蛋白（TIP）编码基因内的单核苷酸多态性（SNP）与特发性肺纤维化（IPF）的进展和预后相关。本研究的目的是调查TIP SNPs与SSc患者间质性肺病（ILD）的存在、严重程度和结局之间的关联。
患者和方法
对106例连续的SSc患者（77例女性）进行基因分型，其中有ILD（n = 53）和无ILD（n = 53），以及212名健康对照（HC）（154例女性），使用TaqMan™ SNP基因分型检测法（美国赛默飞世尔科技公司）对TIP基因内的两个SNP（rs3750920，rs5743890）进行基因分型。疾病进展定义为预计用力肺活量（FVC）百分比相对下降≥10%，或预计FVC百分比相对下降≥5%至<10%，且预计一氧化碳弥散量（DLCO）百分比相对下降15%。从基线开始计算。
结果
与SSc患者相比，HC中TIP rs5743890次要等位基因（C）的频率更高（41%对16%，P = 0.021）。与HC相比，SSc患者中rs5743890的纯合子等位基因明显过多（84%对71%，P = 0.008）。在患有ILD的SSc患者中，携带rs5743890 T/C基因型的患者与纯合子相比，生存趋势较差（158对213个月，P = 0.162），疾病进展率显著更高（66%对22%，P = 0.003）。在调整了多个协变量后，rs5743890次要等位基因C是进展的独立预测因子（风险比4.29，95%可信区间1.48 - 12.48，P = 0.008）。此外，TC单倍型似乎比单独的rs5743890更能预测疾病进展（风险比7.71，95%可信区间1.79 - 33.12，P = 0.006）。
结论
与HC相比，SSc患者中SNP rs5743890的基因型分布似乎有所不同。rs5743890杂合子基因型和TC单倍型可能与SSc - ILD患者疾病进展风险增加有关。
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