Credentialing novel cardiovascular disease genes in women by sex-specific genomic investigation of insulin resistance

摘要 尽管心血管疾病(CVD)传统上被认为是男性的高危疾病，但它是 也是女性死亡的主要原因。性别和性别对脑血管病病理生理学的影响 已经成为一个重要的临床问题，但其分子机制尚不清楚。交叉口 最近的观察强调了性、性别和心血管疾病的关系，最近的观察表明，变性人正在经历性别 肯定性激素治疗(GHT)会增加心血管疾病的风险。胰岛素抵抗的性别分化，a 主要的心血管疾病危险因素，可能是这些观察的基础，因为胰岛素抵抗是由脂肪引起的，性行为 对性激素高度敏感的二态组织。不幸的是，治疗胰岛素抵抗的选择- 以性别和性别相关的方式调节的心血管疾病风险是有限的，特别是在妇女中。例如, 噻唑烷二酮(TZDS)是唯一一种专门针对脂肪中的胰岛素抵抗的药物， 增加绝经后妇女骨质疏松性骨折的风险。对角色的分子理解 染色体性别、性激素和性别对胰岛素抵抗的发展需要加强 筛查和开发女性和变性人心血管疾病的新治疗选择。 识别胰岛素抵抗的分子决定因素的一种方法在女性中具有特异性 对胰岛素抵抗进行性别分层的遗传关联研究。然而，将 染色体性别、性激素和性别的相对影响及建立机制关系 表型和已识别的遗传变异之间的关系仍然是一个重大挑战。 在此，我们建议： 1)利用整合的基因组方法，利用性别之间的自然“交叉”实验 染色体、激素和性别发生在接受GHT的变性女性和男性中；以及 2)直接测试扰动推定原因基因对女性心血管疾病风险的影响 胰岛素抵抗的吞吐能力分析以确定编码蛋白质的基因变异的功能 273,000名女性。 这项工作将系统地识别性别和性别特异性的胰岛素抵抗基因，并针对几个顶级- 对基因进行排序，通过将基因变异与功能联系起来评估女性心血管疾病的临床效果 表型。

Abstract Although cardiovascular disease (CVD) has traditionally been regarded as a higher risk condition in men, it is also the leading cause of death in women. The impact of sex and gender on the pathophysiology of CVD has emerged as an important clinical issue but its molecular mechanisms are poorly understood. The intersection of sex, gender and CVD is underscored by recent observations that transgender individuals undergoing gender affirming sex hormone therapy (GHT) are at increased CVD risk. Sex-differentiation of insulin resistance, a major CVD risk factor, may underlie these observations since insulin resistance arises from adipose, a sexually dimorphic tissue that is highly susceptible to sex hormones. Unfortunately, options to treat insulin resistance- mediated CVD risk in a sex- and gender-relevant fashion are limited particularly in women. For example, thiazolidinediones (TZDs), the only pharmacologic class that specifically targets insulin resistance in adipose, increase the risk of osteoporotic fractures in post-menopausal women. A molecular understanding of the roles of chromosomal sex, sex hormones and gender on the development of insulin resistance is needed to enhance screening and develop new therapeutic options for CVD in women and transgender individuals. One approach to identifying the molecular determinants of insulin resistance specifically operational in women is to conduct genetic association studies (GWAS) of insulin resistance stratified by sex. However, isolating the relative impacts of chromosomal sex, sex hormones, and gender and establishing a mechanistic relationship between phenotype and identified genetic variants remains a major challenge. Here, we propose to: 1) Utilize an integrative genomic approach by leveraging the natural “crossover” experiment between sex chromosomes, hormones and gender that occurs in transwomen and men undergoing GHT; and 2) Directly test the impact of perturbing putatively causal genes on CVD risk in women by using high throughput assays for insulin resistance to functionally characterize protein-coding genetic variants identified in 273,000 women. This work will systematically identify sex- and gender-specific insulin resistance genes and for several top- ranked genes, assess the clinical effect on CVD in women by relating genetic variants to function to phenotype.