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风险因素。 脑皮质下白色物质的缺血性损伤是与高血压和中风相关的脑小动脉硬化症的遗传性并发症，并导致晚年的认知障碍。 动脉病遗传流行病学网络（GENOA）和国家心肺和血液研究所家庭血压计划（NHLBI-FBPP）正在完成多个种族群体的连锁和关联分析，以表征影响血压和高血压心脏和肾脏并发症的基因。这项GENOA辅助研究将通过鉴定导致大脑皮质下白色物质缺血性损伤的基因来扩展这些努力，称为脑白质疏松症。 将使用脑部磁共振成像（MRI）对通过高血压同胞对确定的已充分表征的非裔美国人和非西班牙裔白色GENOA同胞中的脑白质疏松体积进行非侵入性定量。目的1将使用方差分量连锁方法，以确定是否有任何387多态性标记基因座跨越基因组（已测量的GENOA）的基因影响脑白质疏松症的MRI体积在超过650个非洲裔美国人和650个非西班牙裔白色GENOA同胞对。目标2将使用基于家族的关联分析，以确定是否双等位基因DNA多态性在选定的候选基因，包括那些由GENOA确定的影响血压的措施，也影响MRI体积的脑白质疏松症在超过700名非洲裔美国人和700名非西班牙裔白色GENOA参与者。对导致缺血性脑损伤和易患认知障碍的基因的了解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将受益于早期干预的高危个体。

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.