The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Australia.
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Int J Epidemiol. 2019 Oct 1;48(5):1457-1467. doi: 10.1093/ije/dyz160.
The intrauterine environment is critical for fetal growth and development. However, observational associations between maternal gestational lipid concentrations and offspring birth weight (BW) have been inconsistent and ascertaining causality is challenging.
We used a novel two-sample Mendelian randomization (MR) approach to estimate the causal effect of maternal gestational high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride concentrations on offspring BW. Single nucleotide polymorphisms (SNPs) associated with serum HDL-C, LDL-C and triglyceride concentrations identified in the Global Lipids Genetics Consortium genome-wide association study meta-analysis (n = 188 577 European-ancestry individuals; sample 1) were selected as instrumental variables. The effects of these SNPs on offspring BW were estimated using a structural equation model in the UK Biobank and Early Growth Genetics consortium (n = 230 069 European-ancestry individuals; sample 2) that enabled partitioning of the genetic associations into maternal- (intrauterine) and fetal-specific effects.
We found no evidence for a causal effect of maternal gestational HDL-C, LDL-C or triglyceride concentrations on offspring BW [standard deviation change in BW per standard deviation higher in HDL-C = -0.005 (95% confidence interval: -0.039, 0.029), LDL-C = 0.014 (-0.017, 0.045), and triglycerides = 0.014 (-0.025, 0.052)].
Our findings suggest that maternal gestational HDL-C, LDL-C and triglyceride concentrations play a limited role in determining offspring BW. However, we cannot comment on the impact of these and other lipid fractions on fetal development more generally. Our study illustrates the power and flexibility of two-sample MR in assessing the causal effect of maternal environmental exposures on offspring outcomes.
子宫内环境对胎儿的生长和发育至关重要。然而，母体妊娠脂质浓度与后代出生体重（BW）之间的观察性关联一直不一致，确定因果关系具有挑战性。
我们使用一种新的两样本孟德尔随机化（MR）方法来估计母体妊娠期间高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）和甘油三酯浓度对后代 BW 的因果效应。在全球脂质遗传学联合会全基因组关联研究荟萃分析（n=188577 名欧洲血统个体；样本 1）中确定的与血清 HDL-C、LDL-C 和甘油三酯浓度相关的单核苷酸多态性（SNP）被选为工具变量。这些 SNP 对后代 BW 的影响使用 UK Biobank 和早期生长遗传学联盟（n=230069 名欧洲血统个体；样本 2）中的结构方程模型进行估计，该模型能够将遗传关联分为母体（子宫内）和胎儿特异性效应。
我们没有发现母体妊娠 HDL-C、LDL-C 或甘油三酯浓度对后代 BW 有因果影响的证据[HDL-C 每标准差升高时 BW 的标准差变化=-0.005（95%置信区间：-0.039，0.029），LDL-C=0.014（-0.017，0.045），和甘油三酯=0.014（-0.025，0.052）]。
我们的研究结果表明，母体妊娠 HDL-C、LDL-C 和甘油三酯浓度在决定后代 BW 方面作用有限。然而，我们不能评论这些和其他脂质成分对胎儿发育的总体影响。我们的研究说明了两样本 MR 在评估母体环境暴露对后代结局的因果效应方面的强大功能和灵活性。
