STUDY QUESTION

研究问题

Are impaired glucose tolerance (as measured by fasting glucose, glycated hemoglobin, and fasting insulin) and cardiovascular disease risk (as measured by low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and diastolic blood pressure) causally related to infertility?

糖耐量受损（通过检测空腹血糖、糖化血红蛋白和空腹胰岛素）和发生心血管疾病的风险（通过检测低密度脂蛋白、高密度脂蛋白、甘油三酯及测量收缩压和舒张压）与不孕症有因果关系吗？

SUMMARY ANSWER

结论摘要

Genetic instruments suggest that higher fasting insulin may increase infertility in women.

基因工具表明，较高的空腹胰岛素水平可能会增加女性不孕的风险。

WHAT IS KNOWN ALREADY

已知信息

Observational evidence suggests a shared etiology between impaired glucose tolerance, cardiovascular risk, and fertility problems.

观察证据表明糖耐量受损、发生心血管疾病风险和生育问题之间存在共同的病因。

STUDY DESIGN, SIZE, DURATION

研究设计、规模、持续时间

This study included two-sample Mendelian randomization (MR) analyses, in which we used genome-wide association summary data that were publicly available for the biomarkers of impaired glucose tolerance and cardiovascular disease, and sex-specific genome-wide association studies (GWASs) of infertility conducted in the Norwegian Mother, Father, and Child Cohort Study.

本研究包括两个样本的孟德尔随机化 (MR) 分析，其中我们使用公开的糖耐量受损和心血管疾病的生物标志物的全基因组关联汇总数据以及性别特异性的挪威母亲、父亲和子女队列研究中进行的不孕不育全基因组的关联分析 (GWAS)。

PARTICIPANTS/MATERIALS, SETTING, METHODS

参与者/材料、地点、方法

There were 68 882 women (average age 30, involved in 81 682 pregnancies) and 47 474 of their male partners (average age 33, 55 744 pregnancies) who had available genotype data and who provided self-reported information on time-to-pregnancy and use of ARTs. Of couples, 12% were infertile (having tried to conceive for ≥12 months or used ARTs to conceive). We applied the inverse variance weighted method with random effects to pool data across variants and a series of sensitivity analyses to explore genetic instrument validity. (We checked the robustness of genetic instruments and the lack of unbalanced horizontal pleiotropy, and we used methods that are robust to population stratification.) Findings were corrected for multiple comparisons by the Bonferroni method (eight exposures: P-value < 0.00625).

共有68 882名女性（平均年龄 30 岁，涉及 81 682 次妊娠）和 47 474 名男性伴侣（平均年龄 33 岁，涉及 55 744 次妊娠），提供了可用的基因型数据，并提供了关于怀孕时间和辅助生殖技术使用的自我报告信息。其中12%夫妇患有不孕症（即试孕12 个月或使用 ART 助孕）。我们应用具有随机效应的逆方差加权方法来汇集跨变体的数据，并进行一系列敏感性分析来探索遗传学研究的有效性。（我们检查了遗传学研究的稳健性和缺乏不平衡的水平多效性，并且我们使用了对群体分层稳健的方法）通过 Bonferroni 方法对多重比较结果进行了修正（八个暴露因素：P 值 < 0.00625）。

MAIN RESULTS AND THE ROLE OF CHANCE

主要结果和机会的作用

In women, increases in genetically determined fasting insulin levels were associated with greater odds of infertility (+1 log(pmol/l): odds ratio 1.60, 95% CI 1.17 to 2.18, P-value = 0.003). The results were robust in the sensitivity analyses exploring the validity of MR assumptions and the role of pleiotropy of other cardiometabolic risk factors. There was also evidence of higher glucose and glycated hemoglobin causing infertility in women, but the findings were imprecise and did not pass our P-value threshold for multiple testing. The results for lipids and blood pressure were close to the null, suggesting that these did not cause infertility.

在女性中，基因决定的空腹胰岛素水平增加与不孕的可能性增加相关（±1 log(pmol/l)：优势比1.60，95% CI ：1.17 至 2.18，P =0.003）。在探索 MR 假设的有效性和其他心脏代谢危险因素的多效性作用的敏感性分析中，结果是稳健的。证据同时表明，较高的血糖和糖化血红蛋白会导致女性不孕，但研究结果并不精确，并且没有通过我们多次测试的 P 值阈值。血脂和血压的结果接近零，表明这两者不会导致不孕。

LIMITATIONS, REASONS FOR CAUTION

局限性和审慎的原因

We did not know if underlying causes of infertility were in the woman, man, or both. Our analyses only involved couples who had conceived. We did not have data on circulating levels of cardiometabolic risk factors, and we opted to conduct an MR analysis using GWAS summary statistics. No sex-specific genetic instruments on cardiometabolic risk factors were available. Our results may be affected by selection and misclassification bias. Finally, the characteristics of our study sample limit the generalizability of our results to populations of non-European ancestry.

我们不知道不孕症的潜在原因是女性、男性还是两者都有。不知道不孕不育的根本原因是在女性、男性或两者身上。我们的分析仅涉及已怀孕的夫妇。我们没有心脏代谢危险因素循环水平的数据，因此我们选择使用 GWAS 摘要统计数据进行 MR 分析。我们也没有可用的关于心脏代谢危险因素的性别特异性遗传学分析方法。我们的结果可能会受到选择和错误分类偏差的影响。最后，我们研究样本的特征限制了我们的结果对于非欧洲人群的普遍适用性。

WIDER IMPLICATIONS OF THE FINDINGS

研究结果的更广泛意义

Treatments for lower fasting insulin levels may reduce the risk of infertility in women.

降低空腹胰岛素水平的治疗可能会降低女性不孕的风险。

参考文献：

Álvaro Hernáez, Yunsung Lee, Christian M Page, Karoline H Skåra, Siri E Håberg, Per Magnus, Pål R Njølstad, Ole A Andreassen, Elizabeth C Corfield, Alexandra Havdahl, Abigail Fraser, Stephen Burgess, Deborah A Lawlor, Maria C Magnus, Impaired glucose tolerance and cardiovascular risk factors in relation to infertility: a Mendelian randomization analysis in the Norwegian Mother, Father, and Child Cohort Study, Human Reproduction, Volume 39, Issue 2, February 2024, Pages 436–441, https://doi.org/10.1093/humrep/dead234