RESUMEN
Preeclampsia is a serious complication of pregnancy, affecting both maternal and fetal health. In genome-wide association meta-analysis of European and Central Asian mothers, we identify sequence variants that associate with preeclampsia in the maternal genome at ZNF831/20q13 and FTO/16q12. These are previously established variants for blood pressure (BP) and the FTO variant has also been associated with body mass index (BMI). Further analysis of BP variants establishes that variants at MECOM/3q26, FGF5/4q21 and SH2B3/12q24 also associate with preeclampsia through the maternal genome. We further show that a polygenic risk score for hypertension associates with preeclampsia. However, comparison with gestational hypertension indicates that additional factors modify the risk of preeclampsia.
Asunto(s)
Predisposición Genética a la Enfermedad , Hipertensión Inducida en el Embarazo/genética , Herencia Multifactorial , Preeclampsia/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Asia Central/epidemiología , Presión Sanguínea/genética , Estudios de Casos y Controles , Conjuntos de Datos como Asunto , Europa (Continente)/epidemiología , Femenino , Factor 5 de Crecimiento de Fibroblastos/genética , Sitios Genéticos/genética , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión Inducida en el Embarazo/epidemiología , Proteína del Locus del Complejo MDS1 y EV11/genética , Persona de Mediana Edad , Preeclampsia/epidemiología , Embarazo , Estudios ProspectivosRESUMEN
Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10-11) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.
Asunto(s)
Feto , Predisposición Genética a la Enfermedad , Preeclampsia/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Genoma Humano , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Embarazo , Proteínas Gestacionales/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
Caffeine is a commonly consumed drug during pregnancy with the potential to affect the developing fetus. Findings from previous studies have shown inconsistent results. We recruited a cohort of 2,643 pregnant women, aged 18-45 years, attending two UK maternity units between 8 and 12 weeks gestation from September 2003 to June 2006. We used a validated tool to assess caffeine intake at different stages of pregnancy and related this to late miscarriage and stillbirth, adjusting for confounders, including salivary cotinine as a biomarker of smoking status. There was a strong association between caffeine intake in the first trimester and subsequent late miscarriage and stillbirth, adjusting for confounders. Women whose pregnancies resulted in late miscarriage or stillbirth had higher caffeine intakes (geometric mean = 145 mg/day; 95% CI: 85-249) than those with live births (103 mg/day; 95% CI: 98-108). Compared to those consuming < 100 mg/day, odds ratios increased to 2.2 (95% CI: 0.7-7.1) for 100-199 mg/day, 1.7 (0.4-7.1) for 200-299 mg/day, and 5.1 (1.6-16.4) for 300+ mg/day (P (trend) = 0.004). Greater caffeine intake is associated with increases in late miscarriage and stillbirth. Despite remaining uncertainty in the strength of association, our study strengthens the observational evidence base on which current guidance is founded.
