Stepanian Alain, Alcaïs Alexandre, de Prost Dominique, Tsatsaris Vassilis, Dreyfus Michel, Treluyer Jean-Marc, Mandelbrot Laurent
Service d'Hématologie Biologique, Hôpital Lariboisière, Paris, France.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, U1163, Imagine Institute, Paris, France; University Paris Descartes, Sorbonne Paris Cité, Paris, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, United States of America; INSERM CIC P0901, Paris, France.
PLoS One. 2014 Dec 4;9(12):e113176. doi: 10.1371/journal.pone.0113176. eCollection 2014.
Preeclampsia is a frequent medical complication during pregnancy. Corin, a serine protease which activates pro-atrial natriuretic peptide, has recently been shown to be involved in the pathophysiology of preeclampsia. The aim of this study was to search for CORIN gene variations and their association to preeclampsia in Caucasian and African women. Our study population was composed of 571 pregnant women (295 with preeclampsia and 276 normotensive controls) matched for maternal and gestational age, and ethnic origin. The 22 exons of the CORIN gene were sequenced in a discovery sample (n = 260), where 31 single nucleotide polymorphisms were identified. In a replication sample (n = 311), 4 single nucleotide polymorphisms were tested. Two minor alleles (C for rs2271036 and G for rs2271037) were significantly associated to preeclampsia. Adjusted odds ratios [95% confidence interval] were 2.5 [1.2-3.8] (p = 0.007) and 2.3 [1.5-3.5] (p = 1.3 × 10(-4)), respectively. These associations were ethnic-specific, as only found in the Caucasian of subjects (odds ratio = 3.5 [1.8-6.6], p = 1.1 × 10(-4); odds ratio = 3.1 [1.7-5.8], p = 2.1 × 10(-4), for each single nucleotide polymorphism, respectively). The two single nucleotide polymorphisms are in almost perfect linkage disequilibrium (r(2) = 0.93). No specific association was found with severe preeclampsia, early-onset preeclampsia nor fetal growth retardation. In conclusion, this is the first report of a highly significant association between these two single nucleotide polymorphisms in CORIN gene and preeclampsia. Our findings further support the probability of a critical role of corin in preeclamspia pathophysiology at the uteroplacental interface.
子痫前期是孕期常见的医学并发症。Corin是一种可激活心钠素原的丝氨酸蛋白酶，最近研究表明它参与了子痫前期的病理生理过程。本研究旨在探寻高加索和非洲女性中CORIN基因变异及其与子痫前期的关联。我们的研究对象包括571名孕妇（295名单纯子痫前期患者和276名血压正常的对照者），她们在母亲年龄、孕周及种族方面相匹配。对CORIN基因的22个外显子在一个发现样本（n = 260）中进行测序，共识别出31个单核苷酸多态性。在一个重复样本（n = 311）中，对4个单核苷酸多态性进行检测。两个次要等位基因（rs2271036的C和rs2271037的G）与子痫前期显著相关。校正后的比值比[95%置信区间]分别为2.5 [1.2 - 3.8]（p = 0.007）和2.3 [1.5 - 3.5]（p = 1.3×10⁻⁴）。这些关联具有种族特异性，仅在高加索人群中发现（每个单核苷酸多态性的比值比分别为3.5 [1.8 - 6.6]，p = 1.1×10⁻⁴；3.1 [1.7 - 5.8]，p = 2.1×10⁻⁴）。这两个单核苷酸多态性几乎完全连锁不平衡（r² = 0.93）。未发现与重度子痫前期、早发型子痫前期或胎儿生长受限有特定关联。总之，这是首次报道CORIN基因中的这两个单核苷酸多态性与子痫前期之间存在高度显著关联。我们的研究结果进一步支持了corin在子宫胎盘界面子痫前期病理生理过程中起关键作用的可能性。
