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

通过胰岛素抵抗的性别特异性基因组研究鉴定女性新的心血管疾病基因

基本信息

批准号：
10308343
负责人：
Amit Majithia
金额：
$ 55.3万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10308343
关键词：
Adipocytes Adipose tissue Alleles Biological Assay Cardiovascular Diseases Cardiovascular system Cause of Death Cells Cellular Assay Clinical Code Communities Credentialing Data Development Diabetes Mellitus Disease Dose Environmental Risk Factor Estrogens Event Female Fracture Functional disorder Gender Gene Expression Gene Proteins General Population Genes Genetic Code Genetic Risk Genome engineering Genomic approach Genomics Genotype Gonadal Steroid Hormones HDL-triglyceride Health Heritability High Density Lipoproteins Hormones Human Individual Insulin Insulin Resistance Investigation Laboratories Mediating Medical Medical Research Menopause Metabolic Diseases Molecular Mus Mutation Myocardial Infarction Ovarian PPARG gene Participant Persons Pharmaceutical Preparations Pharmacology Phenotype Physiological Population Postmenopause Proteins RNA Sequences Research Risk Risk Factors Role Series Severities Sex Chromosomes Sex Differentiation Stroke System Testing Thiazolidinediones Tissue Donors Tissue Sample Tissues Variant Vulnerable Populations Woman Work biobank cardiovascular disorder risk causal variant cis-female clinical effect clinical phenotype differential expression exome sequencing experimental study gene discovery gene function genetic analysis genetic association genetic variant genotypic sex health record high risk high throughput screening hormone therapy insulin sensitivity insulin sensitizing drugs loss of function male men novel novel therapeutics osteoporosis with pathological fracture predictive marker premature prevent prospective resistance gene response screening sex sexual dimorphism side effect targeted treatment therapeutic gene transcriptome transcriptome sequencing transgender transgender women

项目摘要

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.

抽象的尽管传统上将心血管疾病（CVD）视为男性的较高风险状况，但它是也是妇女死亡的主要原因。性别和性别对CVD病理生理学的影响出现是一个重要的临床问题，但其分子机制知之甚少。十字路口性别，性别和CVD的近期观察表明，经历性别的人确认的性马内治疗（GHT）的CVD风险增加。胰岛素抵抗的性别分化，一个主要的CVD风险因素，可能是这些观察结果的基础高度易受性激素的双态组织。不幸的是，治疗胰岛素抵抗的选择 - 与性别相关的方式中的介导的CVD风险在女性中受到限制。例如，噻唑烷二酮（TZDS），唯一针对脂肪中胰岛素耐药性的药物类别，增加绝经后妇女骨质疏松性骨折的风险。对角色的分子理解需要增强胰岛素抵抗发展的染色体性，性恐怖和性别在妇女和跨性别者中筛选和开发CVD的新治疗选择。鉴定胰岛素抵抗的分子确定的一种方法是为通过性别分层的胰岛素抵抗进行遗传关联研究（GWAS）。但是，隔离染色体性别，性恐怖和性别的相对影响和建立机械关系在表型和确定的遗传变异之间仍然是一个主要挑战。在这里，我们建议： 1）通过利用性别之间的自然“交叉”实验来利用集成的基因组方法染色体，激素和性别发生在经历GHT的男性中；和 2）直接通过使用高的扰动性毒性基因对CVD风险的扰动的影响通过高胰岛素抵抗的吞吐量测定在功能上表征蛋白质编码遗传变异体 273,000名妇女。这项工作将系统地识别性别和性别特异性胰岛素抵抗基因，并适用于几个顶部排名的基因，通过将遗传变异的功能与女性的CVD评估对CVD的临床影响表型。