Genetic Variants Associated with CVD Risk and Hormone Therapy Interactions

与 CVD 风险和激素治疗相互作用相关的遗传变异

• 批准号: 8890877
• 负责人: Paul L. Auer
• 金额: $ 12.39万
• 依托单位: UNIVERSITY OF WISCONSIN MILWAUKEE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890877
• 关键词: Accounting; Address; African American; American; Americas; Biological; Biological Assay; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cholesterol; Clinical; Colorectal Cancer; Complex; Coronary heart disease; Data; Dementia; Diabetes Mellitus; Disease; Disease Pathway; Dyslipidemias; Estrogens; European; Evaluation; Event; Fracture; Gene Frequency; Genes; Genetic; Genetic Variation; Genetic screening method; Genetic study; Genome; Genotype; Gonadal Steroid Hormones; Health; High Density Lipoprotein Cholesterol; Hispanic Americans; Hormones; Hypertriglyceridemia; Individual; Intervention Studies; Knowledge; LDL Cholesterol Lipoproteins; Left; Lipids; Menopause; Minor; Plasma; Play; Population; Positioning Attribute; Postmenopause; Prevention; Progesterone; Progestins; Randomized Clinical Trials; Recording of previous events; Risk; Role; Side; Stroke; Testing; Therapeutic Intervention; United States; United States National Institutes of Health; Variant; Venous; Woman; Women' s Health; base; cardiovascular disorder risk; cardiovascular risk factor; clinical practice; disability; exome; genetic variant; genome wide association study; genome-wide; health data; hormone therapy; insight; malignant breast neoplasm; novel; population based; receptor; response; screening; targeted treatment

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is a major cause of death and disability in the United States. An individual's risk for CVD contains a substantial genetic component. Along with being highly heritable, plasma lipid concentrations are also strong determinants of CVD risk. Recently, there have been several large, concerted efforts to investigate the genetics of plasma lipid levels and CVD in population based studies. However successful these studies have been, approximately 70% of the genetic variance in plasma lipid levels remains unexplained. A popular hypothesis states that rare genetic variants that were un-assayed in previous studies may account for a significant portion of this unexplained variation. Sex steroid hormones and their receptors are also critical determinants of plasma lipid levels and CVD risk. An important unresolved question is whether genetic variability influences the effect of estrogen and/or progesterone in modifying lipid levels and risk for CVD. We will use genetic data, health histories, lipid concentrations, and data from a randomized clinical trial on hormone-therapy (HT) from the Women's Health Initiative (WHI) to: (1) identify rare genetic variants associated with plasma lipid levels in European America (EA) and African American (AA) postmenopausal women; and (2) identify rare genetic variants that interact with HT to modify plasma lipid levels and risk for CVD in EA and AA postmenopausal women. Information generated from this study will be critical in determining the impact of genetic variants on women's health and to prioritize them for intervention studies aimed to maximize overall clinical benefit of HT and minimize their associated cardiovascular risk. Findings may also provide valuable insights into disease pathways and mechanisms, and identify novel targets for screening, prevention, and treatment of dyslipidemia and CVD in postmenopausal women.

描述（由申请人提供）：心血管疾病（CVD）是美国死亡和残疾的主要原因。个人患心血管疾病的风险包含大量的遗传成分。除了高度遗传外，血浆脂质浓度也是心血管疾病风险的重要决定因素。最近，在基于人群的研究中，有几个大型的、一致的努力来研究血浆脂质水平和心血管疾病的遗传学。无论这些研究多么成功，大约70%的血脂水平遗传变异仍未得到解释。一种流行的假设认为，在以前的研究中未检测到的罕见遗传变异可能是这种无法解释的变异的重要原因。性类固醇激素及其受体也是血脂水平和心血管疾病风险的关键决定因素。一个重要的未解决的问题是遗传变异是否影响雌激素和/或孕激素在调节脂质水平和心血管疾病风险方面的作用。我们将使用来自妇女健康倡议（WHI）的遗传数据、健康史、脂质浓度和激素治疗（HT）随机临床试验的数据：(1)确定与欧美（EA）和非裔美国（AA）绝经后妇女血浆脂质水平相关的罕见遗传变异；(2)确定与HT相互作用的罕见遗传变异，以改变EA和AA绝经后妇女的血脂水平和心血管疾病的风险。这项研究产生的信息对于确定遗传变异对女性健康的影响至关重要，并将其优先用于干预研究，旨在最大限度地提高激素疗法的总体临床效益，并将其相关的心血管风险降至最低。研究结果还可能为疾病途径和机制提供有价值的见解，并为绝经后妇女血脂异常和心血管疾病的筛查、预防和治疗确定新的靶点。

项目成果

Discovery and refinement of genetic loci associated with cardiometabolic risk using dense imputation maps.

使用密集的插图地图发现与与心脏代谢风险相关的遗传基因座的发现和完善。

• DOI: 10.1038/ng.3668
• 发表时间: 2016-11
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Iotchkova V;Huang J;Morris JA;Jain D;Barbieri C;Walter K;Min JL;Chen L;Astle W;Cocca M;Deelen P;Elding H;Farmaki AE;Franklin CS;Franberg M;Gaunt TR;Hofman A;Jiang T;Kleber ME;Lachance G;Luan J;Malerba G;Matchan A;Mead D;Memari Y;Ntalla I;Panoutsopoulou K;Pazoki R;Perry JRB;Rivadeneira F;Sabater-Lleal M;Sennblad B;Shin SY;Southam L;Traglia M;van Dijk F;van Leeuwen EM;Zaza G;Zhang W;UK10K Consortium;Amin N;Butterworth A;Chambers JC;Dedoussis G;Dehghan A;Franco OH;Franke L;Frontini M;Gambaro G;Gasparini P;Hamsten A;Issacs A;Kooner JS;Kooperberg C;Langenberg C;Marz W;Scott RA;Swertz MA;Toniolo D;Uitterlinden AG;van Duijn CM;Watkins H;Zeggini E;Maurano MT;Timpson NJ;Reiner AP;Auer PL;Soranzo N
• 通讯作者: Soranzo N

Rare variant association studies: considerations, challenges and opportunities.

• DOI: 10.1186/s13073-015-0138-2
• 发表时间: 2015
• 期刊: Genome medicine
• 影响因子: 12.3
• 作者: Auer PL;Lettre G
• 通讯作者: Lettre G