Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Maternal genetic risk of hypertension is associated with reduced placental weight, inhibiting fetal growth and contributing to future cardio-metabolic abnormalities

Evidence Rating Level: 2 (Good)

Study Rundown:

Low birth weight (LBW) and/or fetal growth restriction (FGR) are associated with various cardio-metabolic diseases, including hypertension, later in life. A recent Mendelian Randomization (MR) study found that the susceptibility of LBW infants to develop hypertension in adulthood is due to the inheritance of hypertension genes from the mother. As many hypertension genes are likely involved in vasculature development and function, this prospective cohort study hypothesized that BP-increasing genetic variants may reduce the growth of the placenta, a highly vascular organ, resulting in lower birth weight and increased incidence of future cardio-metabolic abnormalities. Using a Japanese birth cohort, the authors performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP). The mediation effect of placental weight on birth weight reduced by maternal BP-increasing PGS was assessed and the involvement of vascular genes in the aforementioned mediation effect was examined. The gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity was identified. It was found that maternal genetic risk of hypertension is associated with reduced placental weight, inhibiting fetal growth and contributing to the development of future hypertension in LBW offspring. The authors suggested that maternal SBP-PGS in particular may be a useful screening tool in late-onset FGR high-risk groups, regardless of the presence or absence of maternal hypertension. Overall, this provides evidence that maternal hypertension genes are strongly associated with placental growth and further research in this area may improve our understanding of the prenatal origin of certain diseases.

In-Depth [Retrospective cohort study]:

This study analyzed two cohorts. A total of 993 participants were recruited from a retrospective cohort of women who gave birth at TMDU Hospital from 2013 to 2017. Additionally, clinical information and genotype data of 93 mother-child pairs of Japanese ancestry were obtained from the Birth Cohort Gene and ENvironment Interaction Study of Tokyo Medical and Dental University (TMDU) (BC-GENIST) project. The relationship between observational BP and birth weight was analyzed using the TMDU pregnant women cohort. BP was measured at periodic prenatal check-ups and was used to calculate MAP and PP. The mean value of SBP, DBP, MAP, and PP at each of three gestational periods (i.e., [1] early, gestational age < 20 weeks, [2] middle, 20 ≤ gestational age < 34 weeks, and [3] late, 34 weeks ≤ gestational age) was determined and used for analysis. Birth weight and placental weight were adjusted for gestational age, fetal sex, and parity and estimated fetal growth velocity was calculated. The BC-GENIST cohort was used to compare the genetic effect size across all phenotypes. The DNA was extracted from maternal peripheral blood and cord blood and genotyped. A classic clumping and thresholding method was used to derive individual polygenic scores. Subsequently, two distinct genetic risk scores were constructed, one from only “vasculature-related” single nucleotide polymorphisms (SNPs) and the other from “unlikely related” SNPs. There were no differences between the TMDU pregnant women and BC-GENIST cohorts. It was found that high maternal PGS for each BP phenotype (SBP, DBP, MAP, and PP) was negatively associated with birth weight. Among all four phenotypes, SBP-PGS (111 SNPs, GWAS p value threshold = 1.00 × 10−5) demonstrated the highest significance (estimated regression coefficient [Est.; 95% CI] = − 0.340 [− 0.509, − 0.171], p = 1.29 × 10−4). Additionally, a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight [Est.; 0.661 [95% CI 0.50, 0.82] (p value =1.7 × 10−12). Approximately 86% of the effect of maternal SBP-increasing PGS on birth weight was mediated by placental weight. Furthermore, “vasculature-related” PGS was more strongly associated with birth weight than the “unlikely related” PGS (Est. (change in birth weight z score per 1 SD increase of PGS) = − 0.26 [− 0.44, − 0.09]; p = 3.6 × 10−3). Causal mediation analysis estimated 96% of the “vasculature-related” PGS effect was mediated by the placental weight. The inverse correlation between maternal SBP-PGS and fetal growth velocity appeared in late gestation, specifically towards 36 weeks.

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