[文献分享] 孕妇咖啡饮用与出生结局：孟德尔随机化研究

文献来源：Brito Nunes C, Huang P, Wang G, et al. Mendelian randomization study of maternal coffee consumption and its influence on birthweight, stillbirth, miscarriage, gestational age and pre-term birth [published online ahead of print, 2022 Jun 9]. Int J Epidemiol. 2022;dyac121. doi:10.1093/ije/dyac121

目录

1. 基本信息

2. 主要内容概览：

3. 主要结果和内容

3.1.  Study 1: Two-sample MR analyses

3.1.1. 各人群研究的样本量

3.1.2. 遗传工具变量的筛选

 3.1.3.  MR 相关的Statistical analysis

3.1.4. 两样本MR主要结果

 3.1.5. 两样本MR敏感性分析

  3.1.6. 水平多效性和异质性检验

3.2. Individual-level data MR analysis using GRS (ALSPAC and UKBB)

3.2.1.UKBB

3.2.2. ALSPAC

3.3.Study 3: Associations between self-reported coffee consumption and pregnancy outcomes in the ALSPAC study

4. 结论

---

1. 基本信息

期刊：International journal of epidemiology

影响因子2021：9.685

中科院分区：一区Top

机构：澳大利亚昆士兰大学

发表时间：2022年6月

一句话介绍：孕妇咖啡消费与出生结局（出生体重，死产，流产，胎龄和早产）进行因果推断: 两样本MR、基因风险评分的个体数据水平的MR、传统的队列研究

2. 主要内容概览：

Three studies (Fig. 1 and Table S1) to investigate:

3. 主要结果和内容

3.1.  Study 1: Two-sample MR analyses

3.1.1. 各人群研究的样本量

3.1.2. 遗传工具变量的筛选

如下步骤，研究者依次筛选了3个SNP的集合（数目分别为8个，6个，3个）

 3.1.3.  MR 相关的Statistical analysis

Two-sample inverse-variance weighted (IVW) MR analysis: Estimate the causal relationship

Cochran’s Q: A heterogeneity test of causal effect estimates

MR–Egger intercept: Directional pleiotropy

MR–Egger regression, weighted median, weighted and simple mode estimation approaches: Sensitivity analyses

I2GX: Assess the potential for weak instrument bias in the MR–Egger regression

Bonferroni correction of P-value for the two-sample MR analysis was 0.05/5 phenotypes tested = 0.01 controlling for latent horizontal pleiotropy

3.1.4. 两样本MR主要结果

基本没有发现咖啡消费与这几个关注的妊娠结局有因果关系，除了6SNP set的BW有统计学差异。

 3.1.5. 两样本MR敏感性分析

  3.1.6. 水平多效性和异质性检验

3.2. Individual-level data MR analysis using GRS (ALSPAC and UKBB)

3.2.1.UKBB

3.2.1.1. UKBB人群的基本情况

UKBB is a large prospective population-based cohort containing ∼500 000 individuals (aged 37–73 years; 54% female), representing 5.5% of those who were invited to participate.

3.2.1.2. 遗传工具变量

还是两样本MR中的3个IV集合，这里的GRS用了weighted和unweighted两种

Both weighted and unweighted GRSs using the three sets of SNPs mentioned above in the two-sample MR section, resulting in six different GRSs for coffee consumption.

The weighted risk scores were created by multiplying the coffee-increasing alleles by their effect size from the exposure GWAS, whereas the unweighted risk scores were obtained by adding the number of coffee consumption increasing alleles together.

3.2.1.3. 母亲咖啡消费GRSs与自报告的咖啡消费量的关系

Linear regression analyses were used to assess the relationship between the maternal GRSs for coffee consumption (both weighted and unweighted) and self-reported and maternal coffee intake (cups/day) in addition to the number of spontaneous miscarriages, number of stillbirths and birthweight of the first offspring, adjusting for maternal age at birth.

做这一步是因为这8个SNP是来自于全人群（男性和女性），能否代表母体的还不清楚，这里是为了验证这8个SNP是否适用于母亲

 An association was found between coffee consumption and the different unweighted and weighted GRSs, suggesting that having more coffee consumption increasing alleles identified in the sample of both men and women would increase a woman’s coffee consumption.

3.2.1.4. 母亲咖啡消费GRSs与出生结局的关系

Linear regression analyses were used to assess the relationship between the maternal GRSs for coffee consumption (both weighted and unweighted) and self-reported and maternal coffee intake (cups/day) in addition to the number of spontaneous miscarriages, number of stillbirths and birthweight of the first offspring, adjusting for maternal age at birth.

3.2.1.5. Mother–offspring pairs

研究者为什么要做这个工作呢？下面给出了回答：

Maternal genome is correlated 0.5 with the offspring genome.

This means that using maternal SNPs in MR studies of maternal exposures and offspring outcomes without conditioning on offspring genotype could violate core assumptions relating to horizontal pleiotropy and complicate interpretation of results. We, therefore, leveraged the mother-offspring pairs in the UKBB.

结果是Not able to detect any associations between maternal GRS and offspring birthweight in these analyses

3.2.2. ALSPAC

3.2.2.1. ALSPAC研究介绍

ALSPAC is a longitudinal birth cohort study established to understand how genetic and environmental factors influence health and development in parents and children.

 3.2.2.2. 在ALSPAC人群中验证GRS与每日咖啡摄入量有关而与其他混杂因素无关

•Examined the Association between the GRSs and maternal coffee intake (cups/day) at Week 32 during pregnancy.    √

(GRSs of eight and six SNPs account for 0.37% and 0.35% of the variance, respectively; P<0.003)

确实与每日咖啡摄入量有关

•Examined the association between maternal GRS quartiles and two potential confounders (alcohol drinking and smoking during pregnancy) using chi-square tests. ×

与混杂因素吸烟饮酒无关

3.2.2.3. 在ALSPAC人群中验证GRS与妊娠结局关系（BW, GA, PTB）

 Q:   Is there any association between the GRSs of coffee consumption and three pregnancy outcomes (BW, GA, PTB) with and without conditioning on child’s unweighted GRS or individual SNPs ?

A: Maternal GRSs were not associated with offspring BW, GA or PTB either with or without adjusting for offspring genetics

3.3.Study 3: Associations between self-reported coffee consumption and pregnancy outcomes in the ALSPAC study

这一部分就是传统的队列研究

 目的：

To explore whether previous observational associations regarding coffee consumption and BW were applicable to ALSPAC, the phenotypic association between maternal coffee intake at Week 32 during pregnancy and the three pregnancy outcomes were examined.

结果：

Outcomes	Adjusting	effect size / OR
birthweight	no	−9.63 grams/cups, 95% CI: −17.57, −1.69
	yes	−4.52 grams/cups, 95% CI: −14.92, 5.88
pre-term birth	no	1.11, 95% CI: 1.03, 1.19
	yes	1.08, 95% CI: 1.02, 1.14
gestational age	no	−0.03 weeks/cups, 95% CI: −0.07, 0.01
	yes	−0.02 weeks/cups, 95% CI: −0.05, 0.01

Covariates: maternal age, maternal smoking and alcohol intake during pregnancy, and child’s sex.

4. 结论

这项研究工作量还是比较大的，包含了多个人群数据，虽然结果基本是阴性的。另外有两个作者是本杂志的副主编。个人认为把第3个传统的队列研究放到第一个可能更好一些，不清楚研究者这样叙述的目的。

感兴趣可阅读原文。