Genome-Wide Association Studies in Sickle Cell Anemia and in Centenarians

描述(由申请人提供)： 镰状细胞性贫血(HbSS)是一种典型的孟德尔疾病，由单一的β-血红蛋白基因突变引起。其臭名昭著的表型可变性表明，其他基因调节其许多亚型。在候选的基于基因的关联研究中，我们发现单核苷酸多态(SNPs)与包括中风在内的HbSS的特定亚型相关，并与“全球”严重程度指数相关。我们还发现了与其他人发现的与长寿有关的基因的关联。新英格兰百岁老人研究(CS)指出，异常长寿(EL)很可能是一种复杂的遗传特征，可归因于相对缺乏易患与年龄相关的疾病的遗传和环境变异，特别是心脏病、高血压和中风。此外，存活可能归因于防止衰老的基因变异，并可能推迟与年龄相关的疾病的发生。在这个提案中，我们关注这两个独特群体的全基因组关联研究(GWA)。我们的假设是，HbSS患者和CS参与者的独立GWA将提供关于这两个独特和不同人群的表型易感性的广泛信息。此外，对这两个小组的分析进行比较，突出不同和相似之处，其次，与2007年公开提供的弗雷明翰心脏研究的GWA数据进行额外的比较，将进一步加强和验证我们的发现。GWA和新的生物信息学方法将有助于开发一种超越种群起源的表型/疾病风险模型，从而代表影响人类固有疾病风险的关键遗传因素。具体地说，我们将：对-1800名HbSS患者和-1000名无关的百岁老人进行GWA；为了验证目的，使用317K Illumina SNP基因分型分析，大约300名无关的百岁后代，200名后代对照和125名额外的HbSS患者。利用现代关联分析和新的生物信息学，我们将比较与HbSS的临床特征的相关性，包括血压、存活率、中风、骨坏死、异常勃起、腿部溃疡和疾病严重程度的综合衡量标准，并选择反映HbSS病理生理因素的实验室指标，包括乳酸脱氢酶和胎儿血红蛋白。在CS受试者中，我们将研究遗传与临床特征的关系，包括身体和认知功能、功能状态和与年龄相关的疾病(包括高血压、中风、心血管疾病和痴呆症)的发病年龄。使用新的先进网络建模技术，我们计划描绘在中风和高血压等疾病中发挥关键作用的基因和途径。(摘要结束)

DESCRIPTION (provided by applicant): Sickle cell anemia (HbSS), a classical Mendelian disease is caused by a single beta-hemoglobin gene mutation. Its notorious phenotypic variability suggests that other genes modulate its many subphenotypes. In candidate gene-based association studies, we showed that single nucleotide polymorphisms (SNPs) were associated with selected subphenotypes of HbSS, including stroke, and with a 'global" severity index. We also found an association with genes others have found to be related to longevity. Exceptional longevity, (EL) has been noted by the New England Centenarian Study (CS) to very likely be a complex genetic trait that can be attributed to a relative lack of genetic and environmental variations that predispose to age-related diseases, particularly heart disease, hypertension and stroke. In addition, survival may be attributed to genetic variations that are protective against aging and that may delay the onset of age-related diseases. In this proposal, we focus on genome-wide association studies (GWA) in these 2 unique populations. Our hypothesis is that independent GWA in HbSS patients and the CS participants will provide extensive information about predisposition to phenotypes in these two unique and diverse populations. Moreover, a comparison of the analyses of these two groups, highlighting differences and similarities, and secondarily, additional comparisons with GWA data from the Framingham Heart Study to be publicly available in 2007 will further enhance and validate our findings. GWA and novel bioinformatic approaches will facilitate development of a model of phenotype/disease risk that transcends population origin and thus, represents key genetic factors affecting disease risk that are inherent to mankind. Specifically we will: perform GWA in -1800 patients with HbSS and -1000 unrelated centenarians; and for validation purposes, ~ 300 unrelated centenarian offspring, 200 offspring cohort controls and 125 additional HbSS patients, using the 317K Illumina SNP genotyping assay. With contemporary association analysis and novel bioinformatics we will compare associations with clinical features of HbSS including blood pressure, survival, stroke, osteonecrosis, priapism, leg ulcers and an integrated measure of disease severity and also selected laboratory measurements including lactic dehydrogenase and fetal hemoglobin that reflect pathophysiological elements of HbSS. In CS subjects, we will examine genetic associations with clinical features including physical and cognitive function, functional status and age at onset of age-related conditions including hypertension, stroke, cardiovascular disease and dementia. Using novel advanced network modeling techniques we plan to delineate genes and pathways that play crucial roles in diseases like stroke and hypertension. (End of Abstract)