Female reproductive factors and risk of cardiovascular disease and mortality among women with diabetes

糖尿病患者罹患威胁生命的血管并发症的风险增加，如冠心病、中风和其他糖尿病的大血管和微血管并发症。虽然男性患心血管疾病的绝对风险更高，但女性糖尿病患者患冠心病、中风和心力衰竭的相对风险高于男性糖尿病患者。这些性别相关风险背后的潜在机制在很大程度上仍不清楚。近年来，妇女特有的风险因素，如不良妊娠结局(先兆子痫、妊娠期高血压、妊娠糖尿病、早产)和生育并发症与心脏代谢风险有关。此外，妊娠期糖尿病与高血压和其他心血管疾病的长期风险之间的联系已经确立，即使是有妊娠期糖尿病病史但没有发展为明显糖尿病的女性也是如此。然而，在患有2型糖尿病和/或妊娠期糖尿病的女性中，女性生殖风险因素与心血管疾病之间的关系尚未被探索。这项研究项目的目的是调查女性生殖因素与患有2型糖尿病和/或妊娠期糖尿病的女性心血管疾病风险和死亡率的关系。我的假设如下：在糖尿病女性中，女性生殖因素(月经初潮和绝经早期、不孕不育、未生育等)与心血管风险和死亡风险之间存在关联。此外，这些关系是通过代谢途径和代谢中间产物(代谢物)的改变来调节的。为了验证这些假设，我将使用来自两个护士健康研究的大约14,000名患有2型糖尿病的妇女和5,000名有妊娠期糖尿病病史的妇女的前瞻性数据。哈佛大学公共卫生学院的护士健康研究已经进行了40多年，是对女性慢性病风险因素进行的规模最大、持续时间最长的前瞻性调查之一。暴露(生殖和生活方式因素、饮食和其他)和新诊断的疾病，包括糖尿病、冠心病和中风，每两年更新一次。将使用机器学习方法识别与女性生殖因素(如母乳喂养、口服避孕药的使用和月经初潮早期)相关的代谢物和代谢组特征。这项提案的研究结果将为糖尿病和糖尿病相关心血管疾病易感性女性的初级、一级、二级和三级预防提供证据基础。

People with diabetes are at increased risk of developing life-threatening vascular comorbidities such as coronary heart disease (CHD), stroke, and other macrovascular and microvascular complications of diabetes. Although men are at a higher absolute risk of cardiovascular disease, the relative risk of CHD, stroke, and heart failure is higher in women with diabetes than in men with diabetes. The underlying mechanisms behind these sex-specific risks are still largely unknown. In recent years, women-specific risk factors such as adverse pregnancy outcome (preeclampsia, gestational hypertension, gestational diabetes, preterm birth) and fertility complications have been linked with cardiometabolic risk. In addition, the association between gestational diabetes and long-term risk of hypertension and other cardiovascular diseases is well established and holds true even for women with a history of gestational diabetes who do not progress to overt diabetes. However, the associations between female reproductive risk factors and cardiovascular disease in women with type 2 diabetes and/or gestational diabetes have not been explored yet. The aim of this research project is to investigate the relationships between female reproductive factors and risk of cardiovascular disease and mortality in women with type 2 diabetes and/or gestational diabetes. I hypothesize the following: There is an association between female reproductive factors (early menarche and early menopause, infertility, nulliparity, and others) and cardiovascular and mortality risks in women with diabetes. Furthermore, these relationships are mediated by alterations in metabolic pathways and metabolic intermediates (metabolites). To test these hypotheses, I will use the prospective data from approximately 14 000 women with type 2 diabetes and 5 000 women with a history of gestational diabetes from the two Nurses' Health Studies. The Nurses' Health Studies have been ongoing for more than 40 years at the Harvard School of Public Health and are among the largest and longest prospective investigations into risk factors for chronic diseases in women. Exposures (reproductive and lifestyle factors, diet, and others) and newly diagnosed diseases, including diabetes, CHD, and stroke, are updated every two years. Metabolites and metabolomic signatures associated with female reproductive factors such as breastfeeding, oral contraceptive use, and early menarche will be identified using machine learning approaches. The research findings from this proposal will provide an evidence base for primordial, primary, secondary, and tertiary prevention in women with diabetes and a predisposition to diabetes-related cardiovascular disease.