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.
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