Genetics of Bone and Vascular Calcium in Type 2 Diabetes

描述（由申请人提供）： 广泛的长期目标是改善健康和减少死亡， 患有骨质疏松症、心血管疾病和2型糖尿病的人。具体目标是 研究的重点是导致血管病变的遗传和环境因素， 钙化（VC）和骨矿化（BM）在2型糖尿病家族。 与健康相关的是，心血管疾病（CVD）是头号 在美国，心血管疾病的风险显著增加， 2型糖尿病患者的饮食习惯骨质疏松症是目前在10万 估计还有1800万人骨质疏松。这是一 2型亚临床心血管疾病的遗传流行病学"的辅助建议 糖尿病”（HL67348）也称为“糖尿病心脏研究”或DHS。国土安全部使用 一项家族研究设计和CVD表型的定量测量， 并鉴定导致同胞亚临床动脉粥样硬化的基因 与2型糖尿病一致的配对。生活方式和环境的影响 通过BM和VC测量的亚临床疾病的基因表达， 测定在这项建议中，测量骨矿化和主动脉VC 将被添加到我们现有的CVD表型阵列中，其中包括血管 冠状动脉和颈动脉的钙（VC）。我们将使用额外的 BM的定量测量（QCT，DXA，QUS和生物标志物），以了解 BM、VC、CVD、骨质疏松症与2型糖尿病的遗传关系。 具体目的是：1）测量和描述高风险人群中的BM和VC CVD人群，兄弟姐妹对与2型糖尿病一致的家庭 和未受影响的家庭成员。2)测量关联强度， 血管钙和骨矿化-进一步表征 与2型糖尿病的存在或不存在、种族和性别相关。 3)估计BM和VC的家族聚集性和遗传力， 糖尿病心脏研究家族。4）调查候选基因多态性， 先前确定的BM和VC，与主要表型相关 在DHS中测量。5)确定特定的染色体区域， 数量性状基因座（QTL），影响BM和VC，使用全基因组 屏幕6)进行精细绘图，进行关联和单倍型分析， 并确定新的候选基因的染色体区域与强 与主要表型BM、VC和CVD相关的证据。一个既定 和活跃的多学科研究团队，使用先进的方法， 表型定量、分子遗传学和遗传流行病学将 进行这项研究。

DESCRIPTION (provided by applicant): The broad long-term objectives are to improve health and reduce deaths in people from osteoporosis, CVD and type 2 diabetes. The specific aims are focused on the genetic and environmental factors that contribute to vascular calcification (VC) and bone mineralization (BM) in type 2 diabetic families. The health relatedness is that cardiovascular disease (CVD) is the number one cause of death in the U.S. and the risk of CVD is significantly increased in individuals with type 2 diabetes. Osteoporosis is present in 10 million citizens with another 18 million estimated to have low bone mass. This is an ancillary proposal to the "Genetic Epidemiology of Subclinical CVD in Type 2 Diabetes" (HL67348) also know as the "Diabetes Heart Study" or DHS. DHS uses a family study design and quantitative measurement of CVD phenotypes to locate and identify genes contributing to subclinical atherosclerosis in sibling pairs concordant for type 2 diabetes. The impact of lifestyle and environment on gene expression for subclinical disease as measured by BM and VC will be determined. In this proposal, measures of bone mineralization and aortic VC will be added to our existing array of CVD phenotypes, which include vascular calcium (VC) of the coronary and carotid arteries. We will use the additional quantitative measures of BM (QCT, DXA, QUS & Biomarkers) to understand the genetic relation between BM, VC, CVD, osteoporosis and type 2 diabetes. The Specific Aims are: 1) Measure and describe BM & VC in a high-risk population for CVD, families with sibling pairs concordant for type 2 diabetes and unaffected family members. 2) Measure the strength of association between vascular calcium and bone mineralization - further characterize the association by presence or absence of type 2 diabetes, ethnicity, and gender. 3) Estimate the familial aggregation and heritability of BM & VC in the Diabetes Heart Study families.4) Investigate if candidate gene polymorphisms, previously identified for BM & VC, are associated with the primary phenotypes measured in DHS. 5) Identify specific chromosomal regions containing quantitative trait loci (QTLs), which influence BM &VC, using the genome-wide screen. 6) Perform fine mapping, conduct association and haplotype analyses, and identify novel candidate genes for chromosomal regions with strong evidence for linkage to the primary phenotypes, BM, VC and CVD. An established and active multidisciplinary team of investigators using advanced methods of phenotype quantification, molecular genetics, and genetic epidemiology will conduct this research.