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

摘要 虽然心血管疾病（CVD）传统上被认为是男性的高风险疾病，但它是一种高风险疾病。 也是女性死亡的主要原因。性别对CVD病理生理学的影响 出现作为一个重要的临床问题，但其分子机制知之甚少。路口 性，性别和心血管疾病是强调最近的观察，变性人经历性别 肯定性激素治疗（GHT）是在增加心血管疾病的风险。胰岛素抵抗的性别差异 主要的心血管疾病风险因素可能是这些观察结果的基础，因为胰岛素抵抗来自脂肪，这是一种性因素 对性激素高度敏感的二型组织。不幸的是，治疗胰岛素抵抗的方法- 以性和性别相关方式介导的CVD风险有限，尤其是在女性中。比如说， 噻唑烷二酮类药物（TZDs）是唯一一种特异性靶向脂肪胰岛素抵抗的药物， 增加绝经后妇女骨质疏松性骨折的风险。从分子角度理解 染色体性别、性激素和性别对胰岛素抵抗的发展是需要加强的 筛查和开发女性和变性人CVD的新治疗选择。 一种确定胰岛素抵抗的分子决定因素的方法，特别是在女性中 进行按性别分层的胰岛素抵抗的遗传关联研究（GWAS）。然而，隔离 染色体性别、性激素和性别的相对影响，并建立一种机械关系 表型和已鉴定的遗传变异之间的差异仍然是一个重大挑战。 在此，我们建议： 1)通过利用性别之间的自然“交叉”实验， 染色体，激素和性别发生在transwomen和男性接受GHT;和 2)直接测试的影响，干扰puppet致病基因对心血管疾病的风险，在妇女中使用高 用于胰岛素抵抗的通量测定，以功能性地表征 273，000名女性。 这项工作将系统地确定性别和性别特异性胰岛素抵抗基因，并为几个顶级- 排名基因，通过将遗传变异与功能相关， 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.