Dieudé P, Guedj M, Wipff J, Ruiz B, Hachulla E, Diot E, Granel B, Sibilia J, Tiev K, Mouthon L, Cracowski J L, Carpentier P H, Amoura Z, Fajardy I, Avouac J, Meyer O, Kahan A, Boileau C, Allanore Y
Université Paris 7 and Service de Rhumatologie, Hôpital Bichat Claude Bernard, Assistance Publique Hôpitaux de Paris, Paris, France.
Arthritis Rheum. 2009 Aug;60(8):2472-9. doi: 10.1002/art.24688.
Systemic sclerosis (SSc) belongs to the group of connective tissue disorders (CTDs), among which are several disorders characterized by a type I interferon (IFN) signature. The recent identification of an association between IRF5 and SSc further highlights a key role for IFN. STAT4, which encodes STAT-4, contributes to IFN signaling, and its genetic variants were found to be associated with CTDs. The aim of this study was to determine whether the STAT4 rs7574865 single-nucleotide polymorphism is associated with SSc, and whether it interacts with IRF5.
Both the STAT4 rs7574865 and IRF5 rs2004640 polymorphisms were genotyped in 1,855 individuals of French Caucasian origin comprising a discovery set of 440 patients with SSc and 485 control subjects and a replication set of 445 patients with SSc and an additional 485 control subjects.
STAT4 rs7574865 was shown to be associated with SSc (P=0.001, odds ratio [OR] 1.29, 95% confidence interval [95% CI] 1.11-1.51). This association was not restricted to a particular phenotype. An additive effect of the STAT4 rs7574865 T allele and the IRF5 rs2004640 T allele was observed, resulting in a multiple increased 1.28-fold risk of SSc. The OR for SSc was 2.72 (95% CI 1.86-3.99) for combinations of genotypes with >or=3 risk alleles. An additive effect was also detected for fibrosing alveolitis: carriage of at least 3 risk alleles appeared to be an independent risk factor (P=2.2x10(-4), OR 1.97, 95% CI 1.28-3.04).
Our results establish STAT4 rs7574865 as a new SSc genetic susceptibility factor. STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis.
系统性硬化症（SSc）属于结缔组织病（CTD）组，其中几种疾病的特征是具有I型干扰素（IFN）特征。最近发现IRF5与SSc之间存在关联，这进一步凸显了IFN的关键作用。编码STAT-4的STAT4有助于IFN信号传导，并且发现其基因变异与CTD相关。本研究的目的是确定STAT4 rs7574865单核苷酸多态性是否与SSc相关，以及它是否与IRF5相互作用。
对1855名法国白种人进行STAT4 rs7574865和IRF5 rs2004640多态性基因分型，包括一个发现集，其中有440例SSc患者和485例对照，以及一个复制集，其中有445例SSc患者和另外485例对照。
STAT4 rs7574865与SSc相关（P = 0.001，优势比[OR] 1.29，95%置信区间[95%CI] 1.11 - 1.51）。这种关联不限于特定表型。观察到STAT4 rs7574865的T等位基因和IRF5 rs2004640的T等位基因具有累加效应，导致SSc风险增加1.28倍。对于具有≥3个风险等位基因的基因型组合，SSc的OR为2.72（95%CI 1.86 - 3.99）。对于肺纤维化也检测到累加效应：携带至少3个风险等位基因似乎是一个独立的风险因素（P = 2.2×10⁻⁴，OR 1.97，95%CI 1.28 - 3.04）。
我们的结果确定STAT4 rs7574865是一个新的SSc遗传易感因素。STAT4和IRF5在对SSc和SSc相关肺纤维化的易感性方面具有累加作用。
