Abruptio Placentae Risk and Genetic Variations in Mitochondrial Biogenesis and Oxidative Phosphorylation: Replication of a Candidate Gene Association Study.
familial aggregation; genetic association; mitochondria; mitochondrial genome; separation of the placenta
BACKGROUND: Abruptio placentae is a complex multifactorial disease associated with maternal and neonatal mortality and morbidity. Abruptio placentae's high recurrence rate, high prevalence of heritable trompbophilia among women with abruptio placentae, and aggregation of cases in families of women with the disease, support the possibility of a genetic predisposition. Previous genome-wide and candidate gene association studies have identified single nucleotide polymorphisms (SNPs) in mitochondrial biogenesis and oxidative phosphorylation genes that are potentially associated with abruptio placentae risk. Perturbations in mitochondrial biogenesis and oxidative phosphorylation, resulting in mitochondrial dysfunction, can lead to the impairment of differentiation and invasion of the trophoblast, leading to several obstetrical complications including abruptio placentae.
OBJECTIVE: To determine whether the results of a candidate genetic association study indicating a link between DNA variants (implicated in mitochondrial biogenesis and oxidative phosphorylation) and abruptio placentae could be replicated.
STUDY DESIGN: and Methods: The study was conducted among participants (507 abruptio placentae cases and 1,090 controls) of the Placental Abruption Genetic Epidemiology (PAGE) study. Weighted genetic risk scores were calculated using abruptio placentae risk-increasing alleles of 11 SNPs in nine mitochondrial biogenesis and oxidative phosphorylation genes (CAMK2B, NR1H3, PPARG, PRKCA, THRB, COX5A, NDUFA10, NDUFA12 and NDUFC2), previously reported in the Peruvian Abruptio Placentae Epidemiology study, a study with similar design and study population to the PAGE study. Logistic regression models were fit to examine associations of weighted genetic risk scores (quartile 1: <25
RESULTS: Abruptio placentae cases were more likely to have preeclampsia, shorter gestational age and lower infant birthweight. Participants in quartile 2 (score:12.6-13.8), quartile 3 (score:13.9-15.0) and quartile 4 (score≥15.1) genetic risk score had a 1.45-fold (95% confidence interval [CI]:1.04,2.02 ; p-value [p]=0.03), a 1.42-fold (95% CI:1.02,1.98; p=0.04), and a 1.75-fold (95%CI:1.27,2.42; p=7.0E-04) higher odds of abruptio placentae, respectively, compared to those in quartile 1 (score
CONCLUSIONS: In this study, we replicated previous findings and provide strong evidence for DNA variants encoding for genes involved in mitochondrial biogenesis and oxidative phosphorylation pathways, conferring risk for abruptio placentae. These results shed light on the mechanisms, implicating DNA variants encoding for proteins in mitochondrial function that are responsible for abruptio placentae risk. Therapeutic efforts to reduce risk of AP can be enhanced by improved biological understanding of maternal mitochondrial biogenesis/oxidative phosphorylation pathways as well as identification of women who would be at high risk for AP.
Women & Children
Obstetrics & Gynecology
Workalemahu, Tsegaselassie; Enquobahrie, Daniel A; Gelaye, Bizu; Thornton, Timothy A; Tekola-Ayele, Fasil; Sanchez, Sixto E; Garcia, Pedro J; Palomino, Henry G; Hajat, Anjum; Romero, Roberto; Ananth, Cande V; and Williams, Michelle A, "Abruptio Placentae Risk and Genetic Variations in Mitochondrial Biogenesis and Oxidative Phosphorylation: Replication of a Candidate Gene Association Study." (2018). Articles, Abstracts, and Reports. 748.