Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2

• DOI: 10.1371/journal.pgen.1008107
• Publication Date: 2019-06-13T17:28:10Z
• Authors: Heli Tiensuu; Antti M. Haapalainen; Minna K. Karjalainen; Anu Pasanen; Johanna M. Huusko; Riitta Marttila; Marja Ojaniemi; Louis J. Muglia; Mikko Hallman; Mika Rämet
• Keywords: Trophoblast

Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on population Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) 419 term controls (GA 38-41 weeks). The strongest signal came within gene encoding slit guidance ligand 2 (SLIT2; rs116461311, minor allele frequency 0.05, p = 1.6×10-6). Pathway analysis revealed top-ranking pathway was axon guidance, which includes SLIT2. In 172 very preterm-born <32 weeks), rs116461311 clearly overrepresented (odds ratio 4.06, 1.55×10-7). SLIT2 variants were associated in another European comprised 260 9,630 controls. To gain functional insight, we used immunohistochemistry visualize its receptor ROBO1 placentas from spontaneous births. located villous decidual trophoblasts embryonic origin. Based qRT-PCR, mRNA levels higher basal plate compared those or elective deliveries. addition, births, placental expression correlated variations growth. Knockdown trophoblast-derived HTR8/SVneo cells by siRNA indicated it regulate several pregnancy-specific beta-1-glycoprotein (PSG) genes involved inflammation. Our results show variant both placenta trophoblast may be susceptibility SLIT2-ROBO1 signaling linked regulation inflammation, PSG genes, decidualization propose this receptor-ligand couple component network promotes