Core--Human phenotyping

这个核心的具体目标是利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， 特别是了解这些位点的等位基因变异是否影响交感神经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秒到秒的调节器，因此血压。自主神经活动不仅在已确诊的高血压患者中紊乱，而且在其血压仍然正常的后代中也紊乱;因此，自主神经特性作为？中间表型？（O？康纳等人，2000; Dao等人，1998; Kailasam等人，1996，2000; Lacy等人，1998; Brinton等人，1996; Song等人，2000）在高血压（一种具有非孟德尔（复杂）遗传的常见疾病）中的作用（Schork和Lander，1994）。由于人类表型分析在很大程度上起着假设生成（而不是假设检验）的作用，并且由于来自人类表型分析的材料（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），因此先前的人类表型分析项目已被重组以形成新的核心C，？人类表型分析？（O？康纳和齐格勒）。以前的领导人的系谱表型现在已经转移到一个新的一系列额外的临床职责，在肾脏病（病房，咨询和诊所）在圣地亚哥退伍军人医疗中心。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<http://medicine.ucsd.edu/hypertension/twins.html>，该项目已经招募了n=245个基于人类MZ和DZ双胞胎对的核心家庭（也确定了可用的同胞和父母），表型和基因型如下所述，以及额外的n=69个基于同胞三人组的核心家庭。这些核心家庭已经产生了n=573个同胞对。双胞胎对允许估计遗传力（h2），这反过来又使我们能够确定任何人类性状（生物化学或生理学）对遗传研究的易处理性。父母的DNA可在 这些双胞胎和兄弟姐妹（大约45%的父母）。先前的表型项目还确定了n=69个核心家庭的基础上先证者原发性高血压（一级亲属研究;平均同胞大小3 [高血压患者的后代]）。 来自这些兄弟姐妹对和父母的基因组DNA已经进行了n=777的基因组测序。 微卫星（约5 cM）基因组扫描，由James L. NHLBI的韦伯马什菲尔德诊所的哺乳动物基因分型服务。这个基因组扫描在2004年4月完成。在HL 58120更新申请的总体前言中介绍了核心C研究的人类受试者（尤其是双胞胎）研究的主要结果。

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.