Core--Human phenotyping

核心——人类表型分析

• 批准号: 7844963
• 负责人: DANIEL T O'CONNOR
• 金额: $ 24.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844963
• 关键词: Autonomic nervous system; Biochemical; Biological; Blood Circulation; Blood Pressure; Clinic; Clinical; Complex; Consultations; Coupled; DNA; Disease; Essential Hypertension; First Degree Relative; Genetic; Genome Scan; Genomics; Genotype; Heritability; Human; Hypertension; Investigation; Medical center; Microsatellite Repeats; Nephrology; Neuroeffector Junction; Nuclear Family; Parents; Patients; Phenotype; Physiological; Play; Recruitment Activity; Role; Sampling; Series; Services; Siblings; Testing; Twin Multiple Birth; Variant; base; genetic pedigree; human subject; normotensive; offspring; proband; trait; ward

The specific aim of this Core is to use the power of twin and sibling pairs, coupled with SNP and microsatellite genotyping at candidate loci, to establish the significance or effect of such loci, in particular to understand whether allelic variation at such loci influences autonomic function in either the sympathetic or parasympathetic branches. The autonomic nervous system is the key second-to-second regulator of the circulation, and hence of blood pressure. Autonomic activity is deranged not only in patients with established hypertension, but also in their still-normotensive offspring; thus, autonomic traits are valuable as ?intermediate phenotypes? (O?Connor et al, 2000; Dao et al, 1998; Kailasam et al, 1996, 2000; Lacy et al, 1998; Brinton et al, 1996; Song et al, 2000) in hypertension, a common disease with non-Mendelian (complex) inheritance (Schork and Lander, 1994). Since Human phenotyping plays a role that is largely hypothesis generating (rather than hypothesis testing), and since the materials from Human phenotyping (biological samples, DNA, phenotypes, genotypes) now flow systematically to all Projects and Cores (see Diagram), the previous Project on Human phenotyping has been retooled to form new Core C, ?Human phenotyping? (O?Connor and Ziegler). The previous leader of pedigree phenotyping has now moved on to a new series of additional clinical duties in nephrology (wards, consultations, and clinics) at the San Diego VA Medical Center. This change should facilitate interactions among all Projects and Cores. Core C utilizes the San Diego Twin Project <http://medicine.ucsd.edu/hypertension/twins.html>, which has already recruited n=245 nuclear families based on human MZ and DZ twin pairs (also ascertaining available sibs and parents), phenotyped and genotyped as outlined below, as well as an additional n=69 nuclear families based on sib trios. These nuclear families already give rise to n=573 sib pairs. Twin pairs allow estimation of heritability (h2), which in turn allows us to determine the tractability of any human trait (biochemical or physiological) to genetic investigation. Parental DNA is available on these twinships and sibships (from approximately 45% of parents). The previous phenotyping Project also ascertained n=69 nuclear families based on probands with essential hypertension (first degree relatives studied; average sibship size 3 [offspring of the hypertensive patient]). Genomic DNAs from these sibling pairs, and parents, have already been subjected to a n=777 microsatellite (approximately 5 cM) genome scan, performed by James L. Weber at the NHLBI?s Mammalian Genotyping Service at Marshfield Clinic. This genome scan was completed in April of 2004. Major results emerging from studies employing the human subjects (especially twin pairs) studied by Core C are presented in the overall Preamble to the HL58120 renewal application.

这个核心的具体目标是使用双胞胎和兄弟姐妹对的力量，再加上SNP和 候选基因座的微卫星基因分型，以确定这些基因座的意义或作用，在 特别是了解这些基因座的等位基因变异是否会影响交感或副交感神经分支的自主神经功能。自主神经系统是循环的关键的秒级调节器，因此也是血压的调节器。不仅高血压患者的自主神经活动紊乱，他们的血压仍然正常的后代也是如此；因此，自主神经特征作为中间表型有价值。(O？Connor等人，2000；Dao等人，1998；Kailasam等人，1996,2000；Lacy等人，1998；Brinton等人，1996；Song等人，2000)高血压，一种具有非孟德尔(复杂)遗传的常见病(Schork和Lander，1994)。由于人类表型在很大程度上是产生假设(而不是假设检验)的角色，而且由于来自人类表型的材料(生物样本、DNA、表型、基因型)现在系统地流向所有项目和核心(见图)，以前的人类表型项目已经被重组，以形成新的核心C，？人类表型？(O？Connor和Ziegler)。这位以前的系谱表型鉴定负责人现在已经在圣地亚哥退伍军人医学中心承担了一系列新的肾病临床职责(病房、会诊和诊所)。这一变化应促进所有项目和核心之间的互动。核心C利用圣地亚哥双胞胎项目&lt；http://medicine.ucsd.edu/hypertension/twins.html&gt；，，该项目已经招募了基于人类MZ和DZ双胞胎对的n=245个核心家庭(还确定了可用的同胞和双亲)，如下所述的表型和基因分型，以及另外n=69个基于同胞三人组的核心家庭。这些核心家族已经产生了n=573对同胞。双胞胎配对可以估计遗传力(H2)，这反过来又允许我们确定任何人类特征(生化或生理)对遗传研究的可控性。父母的DNA可在 这些双胞胎和兄弟姐妹关系(来自大约45%的父母)。先前的表型项目也确定了n=69个基于高血压先证者的核心家庭(研究对象为一级亲属；平均亲属大小为3[高血压患者的后代])。 来自这些兄弟姐妹和双亲的基因组DNA已经经历了n=777 微卫星(约5厘米)基因组扫描，由詹姆斯·L·韦伯在马什菲尔德诊所NHLBI？S哺乳动物基因分型服务执行。这次基因组扫描是在2004年4月完成的。核心C研究的人类受试者(特别是双胞胎对)的主要研究结果显示在HL58120更新申请的总体序言中。