Genetics of Microangiopathic Brain Injury

高血压影响着5000万美国人，是导致大脑、心脏和肾脏疾病的最大危险因素。脑皮层下白质的缺血性损伤是与高血压和中风相关的脑小动脉硬化的一种遗传性并发症，并有助于晚年的认知障碍。动脉病变遗传流行病学网络（GENOA）和国家心肺血液研究所家庭血压计划（NHLBI-FBPP）正在完成多种族群体的联系和关联分析，以表征影响血压和高血压心脏和肾脏并发症的基因。这项热那亚辅助研究将通过识别导致大脑皮层下白质缺血性损伤的基因（称为白质病变）来扩展这些努力。脑磁共振成像（MRI）将用于通过高血压兄弟姐妹确定已经明确的非裔美国人和非西班牙裔热那亚白人兄弟姐妹的白质变体积的非侵入性定量。目的1将使用方差成分连锁方法来确定跨越基因组的387个多态性标记位点（已经由热那亚测量）是否与650多名非裔美国人和650名非西班牙裔白人热那亚兄弟姐妹中影响白质病变MRI体积的基因有关。Aim 2将使用基于家族的关联分析来确定选定候选基因中的双等位基因DNA多态性（包括热那亚确定的影响血压测量的基因）是否也影响700多名非裔美国人和700名非西班牙裔白人热那亚参与者白质变的MRI体积。了解导致缺血性脑损伤和认知障碍易感性的基因将提高对这些疾病的分子基础的理解，并导致更好的方法来识别和治疗高危个体，这些个体将从早期干预中受益。

GENETICS OF MICROANGIOPATHIC BRAIN INJURY Hypertension affects 50 million Americans and is the single greatest risk factor contributing to diseases of the brain, heart, and kidneys. Ischemic injury to subcortical white matter of the brain is a heritable complication of cerebral arteriolosclerosis associated with hypertension and stroke, and contributes to cognitive impairment late in life. The Genetic Epidemiology Network of Arteriopathy (GENOA) and the National Heart Lung and Blood Institute Family Blood Pressure Program (NHLBI-FBPP) are completing linkage and association analyses in multiple racial groups to characterize genes influencing blood pressure and the cardiac and renal complications of hypertension. This GENOA ancillary study will extend those efforts by identifying genes contributing to ischemic damage to the subcortical white matter of the brain, referred to as leukoaraiosis. Magnetic resonance imaging (MRI) of the brain will be used to non-invasively quantitate the volume of leukoaraiosis in already well-characterized African-American and non-Hispanic white GENOA sibships ascertained through hypertensive sibling pairs. Aim 1 will use variance components linkage methods to determine whether any of 387 polymorphic marker loci spanning the genome (already measured by GENOA) are linked to genes influencing the MRI volume of leukoaraiosis in more than 650 African-American and 650 non-Hispanic white GENOA sibling pairs. Aim 2 will use family-based association analyses to determine whether biallelic DNA polymorphisms in selected candidate genes, including those determined by GENOA to influence measures of blood pressure, also influence the MRI volume of leukoaraiosis in more than 700 African-American and 700 non-Hispanic white GENOA participants. Knowledge of genes that contribute to ischemic brain injury and predispose to cognitive impairment will improve understanding of the molecular basis of these disorders and lead to better methods of identifying and treating at-risk individuals who will benefit from early intervention.