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：
10677618
负责人：
Amit Majithia
金额：
$ 53.15万
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/10677618
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 Disparity Dose Environmental Risk Factor Estrogens Event Exclusion Female Fracture Functional disorder Gender Gene Expression General Population Genes Genetic Code Genome engineering Genomic approach Genomics Genotype Gonadal Steroid Hormones Health Heritability High Density Lipoproteins Hormones Human Individual Insulin Insulin Resistance Investigation Laboratories Lipodystrophy Mediating Medical Medical Research Metabolic Diseases Molecular Mus Mutation Myocardial Infarction Ovarian PPARG gene Participant Persons Pharmaceutical Preparations Phenotype Physiological Population Postmenopause Predisposition Production Proteins RNA Sequences Research Risk Risk Factors Role Series Severities Sex Chromosomes Sex Differentiation Stroke System Testing Thiazolidinediones Tissue Donors Tissue Sample Tissues Triglycerides Variant Vulnerable Populations Woman Work biobank cardiovascular disorder risk causal variant cis-female clinical effect clinical phenotype differential expression exome sequencing experimental study gender affirmation gender affirming hormone therapy gene discovery gene function genetic analysis genetic association genetic risk factor genetic variant genome wide association study genotypic sex health record high risk high throughput screening hormone therapy insulin sensitivity loss of function male men novel novel therapeutics osteoporosis with pathological fracture pharmacologic 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.

抽象的尽管心血管疾病 (CVD) 传统上被认为是男性的高危疾病，但它性别和性别对 CVD 病理生理学的影响也是女性死亡的主要原因。已成为一个重要的临床问题，但其分子机制尚不清楚。最近的观察结果强调了性别、性别和心血管疾病之间的关系，即跨性别者经历性别确认性激素治疗 (GHT) 会增加 CVD 风险，这是胰岛素抵抗的性别差异。主要的 CVD 危险因素，可能是这些观察结果的基础，因为胰岛素抵抗源于脂肪，而脂肪是一种性行为不幸的是，对性激素高度敏感的二态性组织是治疗胰岛素抵抗的选择。与性别相关的 CVD 风险尤其有限，例如，噻唑烷二酮类 (TZD) 是唯一专门针对脂肪胰岛素抵抗的药理学类别，增加绝经后妇女骨质疏松性骨折的风险。从分子角度理解其作用。染色体性别、性激素和性别对胰岛素抵抗发展的影响需要加强筛查和开发女性和跨性别者心血管疾病的新治疗方案。一种确定胰岛素抵抗分子决定因素的方法，特别适用于女性是进行按性别分层的胰岛素抵抗的遗传关联研究（GWAS）。染色体性别、性激素和性别的相对影响并建立机械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，我们倡议： 1) 利用性别之间自然的“交叉”实验，采用综合基因组方法接受 GHT 的跨性别女性和男性的染色体、激素和性别；以及 2) 使用高浓度直接测试干扰假定致病基因对女性 CVD 风险的影响胰岛素抵抗的通量测定，以功能性地表征在中鉴定的蛋白质编码遗传变异 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以及几个顶级的对基因进行排序，通过将基因变异与功能联系起来，评估对女性 CVD 的临床影响表型。