Epidemiology of Calcineurin Gene Polymorphisms, Serum Calcineurin, and LVH

描述（由申请人提供）：动物和人体研究的大量证据表明，钙调神经磷酸酶通路是左心室肥大（LVH）发病机制中的关键介质。先前的研究表明，参与该途径的基因变异有助于LVH的风险。然而，因果变异尚未确定。此外，几乎所有与LVH相关的钙调磷酸酶途径原位激活的人体研究都是基于移植心脏，没有基于人群的研究报告来评估血清钙调磷酸酶蛋白水平和酶活性是否可以作为人类心脏中激活的钙调磷酸酶途径的生物标志物。本研究的目的是评价血清钙调磷酸酶蛋白和酶活性作为人群水平LVH生物标志物的效用，并鉴定参与钙调磷酸酶途径的基因变异，这些基因变异导致LVH风险。利用高血压遗传流行病学网络收集的基因型数据和样本-左心室肥厚遗传学研究（HyperGEN-LVH），我们提出了四个目标：1）开发测量血清钙调磷酸酶蛋白水平和酶活性的测定法，将该测定法应用于1101名高血压非洲裔美国人的血清样品，并检测蛋白质水平和酶活性与LVH之间的关联; 2）对4个候选基因中的140个SNP进行遗传关联研究（CnA 1、CnA 2、CnB 1和MCIP 1）参与钙调神经磷酸酶途径与血清钙调神经磷酸酶蛋白水平和酶活性; 3）评估LVH与NFATC 4的140个SNP和另外9个SNP的相关性，NFATC 4是钙调神经磷酸酶的下游靶点，参与调节LVH，以及4）在来自FBPP-GENOA网络的非裔美国参与者中复制重要的遗传发现，这些参与者使用HyperGEN协议和阅读中心进行LVH表型分析。我们预计，这项研究的结果将提供更好的了解LVH的遗传和分子机制在人口水平上，并提供新的机会，筛选测试和新的药理学靶点，以预防或治疗高血压患者LVH。公共卫生相关性：该研究有望在人群水平上对LVH的遗传和分子机制的理解上取得突破，并为LVH中钙调神经磷酸酶通路的流行病学研究提供新的机会。该项目也可能对临床试验的设计产生重大影响，以靶向钙调磷酸酶途径预防和治疗高血压受试者的LVH。

DESCRIPTION (provided by applicant): Abundant evidence from animal and human studies suggests that the calcineurin pathway is a key mediator in the pathogenesis of left ventricular hypertrophy (LVH). Previous studies suggest that variation in genes involved in this pathway contributes to the risk of LVH. However, causal variants have not been identified. In addition, almost all human studies of in-situ activation of the calcineurin pathway in relation to LVH were based on transplant hearts and there are no reports of population-based studies to evaluate whether serum calcineurin protein level and enzymatic activity can serve as biomarkers of activated calcineurin pathways in the human heart. The objective of the proposed study is to evaluate the utility of serum calcineurin protein and enzymatic activity as biomarkers for LVH at the population level and to identify variants in genes involved in the calcineurin pathway that contribute to the risk of LVH. Utilizing genotype data and specimens collected from the Hypertension Genetic Epidemiology Network - Genetics of Left Ventricular Hypertrophy Study (HyperGEN- LVH) of the Family Blood Pressure Program (FBPP), we propose four aims 1) to develop assays to measure serum calcineurin protein level and enzymatic activity, apply the assays to serum samples of 1101 hypertensive African Americans, and test associations between protein level and enzymatic activity with LVH; 2) to conduct a genetic association study of 140 SNPs in four candidate genes (CnA1, CnA2, CnB1, and MCIP1) involved in the calcineurin pathway with serum calcineurin protein level and enzymatic activity; 3) to evaluate associations of LVH with the 140 SNPs plus another 9 SNPs of NFATC4, which is a downstream target of calcineurin and participates in regulating LVH, and 4) to replicate significant genetic findings in the African-American participants from the FBPP-GENOA network who were phenotyped for LVH using the HyperGEN protocol and reading center. We anticipate that results from this study will provide greater understanding of genetic and molecular mechanisms of LVH at the population level and provide new opportunities for screening tests and novel pharmacological targets to prevent or treat LVH in hypertensive subjects. PUBLIC HEALTH RELEVANCE: The proposed study could lead to a breakthrough in the understanding of genetic and molecular mechanisms of LVH at the population level and provide new opportunities for epidemiological studies of the calcineurin pathway in LVH. This project could also have a major impact on the design of clinical trials to pharmacologically target the calcineurin pathway to prevent and treat LVH in hypertensive subjects.