Department of Molecular Epidemiology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Institute of Advanced Biomedical Engineering and Science, The Public Health Research Foundation, Tokyo, Japan.
BMC Med. 2021 Nov 4;19(1):260. doi: 10.1186/s12916-021-02131-0.
Low birth weight (LBW) and fetal growth restriction are associated with the development of cardio-metabolic diseases later in life. A recent Mendelian randomization study concluded that the susceptibility of LBW infants to develop hypertension during adulthood is due to the inheritance of hypertension genes from the mother and not to an unfavorable intrauterine environment. Therein, a negative linear association has been assumed between genetically estimated maternal blood pressure (BP) and birth weight, while the observed relationship between maternal BP and birth weight is substantially different from that assumption. As many hypertension genes are likely involved in vasculature development and function, we hypothesized that BP-increasing genetic variants could affect birth weight by reducing the growth of the placenta, a highly vascular organ, without overtly elevating the maternal BP.
Using a birth cohort in the Japanese population possessing time-series fetal growth velocity data as a target and a GWAS summary statistics of BioBank Japan as a base data, we performed polygenic score (PGS) analyses for systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure. A causal mediation analysis was performed to assess the meditation effect of placental weight on birth weight reduced by maternal BP-increasing PGS. Maternal genetic risk score constituted of only "vasculature-related" BP single nucleotide polymorphisms (SNPs) was constructed to examine the involvement of vascular genes in the mediation effect of placental weight. We identified gestational week in which maternal SBP-increasing PGS significantly decreased fetal growth velocity.
We observed that maternal SBP-increasing PGS was negatively associated with offspring birth weight. A causal mediation analysis revealed that a large proportion of the total maternal PGS effect on birth weight was mediated by placental weight. The placental mediation effect was remarkable when genetic risk score was constituted of "vasculature-related" BP SNPs. The inverse association between maternal SBP PGS and fetal growth velocity only became apparent in late gestation.
Our study suggests that maternal hypertension genes are strongly associated with placental growth and that fetal growth inhibition is induced through the intrauterine environment established by the placenta.
低出生体重（LBW）和胎儿生长受限与成年后患心血管代谢疾病有关。最近一项孟德尔随机化研究得出结论，LBW 婴儿在成年后患高血压的易感性是由于从母亲那里遗传了高血压基因，而不是由于宫内环境不利。在此，假设遗传估计的母亲血压（BP）与出生体重之间存在负线性关联，而观察到的母亲 BP 与出生体重之间的关系与该假设大不相同。由于许多高血压基因可能参与血管发育和功能，我们假设，增加血压的遗传变异可能通过减少胎盘的生长来影响出生体重，而胎盘是一个高度血管化的器官，而不会明显升高母亲的血压。
我们使用日本人群中的一个出生队列作为目标，该队列具有时间序列胎儿生长速度数据，以及日本生物银行的 GWAS 汇总统计数据作为基础数据，对收缩压（SBP）、舒张压、平均动脉压和脉压进行多基因评分（PGS）分析。进行因果中介分析，以评估由增加母亲血压的 PGS 导致的胎盘重量对出生体重的降低的中介作用。构建仅由“血管相关”BP 单核苷酸多态性（SNP）组成的母体遗传风险评分，以检验血管基因在胎盘重量中介作用中的作用。我们确定了母体 SBP 增加的 PGS 显著降低胎儿生长速度的妊娠周数。
我们观察到母体 SBP 增加的 PGS 与后代出生体重呈负相关。因果中介分析表明，母体 PGS 对出生体重的总影响中有很大一部分是由胎盘重量介导的。当遗传风险评分由“血管相关”BP SNP 组成时，胎盘的中介作用非常显著。只有在妊娠晚期，母体 SBP PGS 与胎儿生长速度之间的负相关才变得明显。
我们的研究表明，母体高血压基因与胎盘生长密切相关，通过胎盘建立的宫内环境诱导胎儿生长抑制。
