application): The primary objective of this proposal is to identify and investigate genes that impact extreme longevity in human populations. The Iong-term goal is to maximize the potential for robust late-life health. The proposal is to conduct a candidate gene-association study based on cenenarians and octogenarians from China and Denmark. The first specific aim defines criteria for identifying candidate genes from categories of genes that are likely to have an effect on extreme longevity. The second specific aim describes the use of single strand conformation polymorphism methods to scan candidate genes for allelic variants. Aliele frequency differentials will be determined from analysis of Chinese and Danish centenarians and octogenarians. Candidate genes will be compared with respect to the magnitude of altele frequency differentials to decide which genes will beselected for DNA sequencing. The third specific aim focuses on sequencing regions of select candidate genes and analyzing these sequences to estimate haplotypes and evaluate the evolutionary history of genes. Sequencing is required to design genotype assays and sequence analysis is important for efficient logic-driven choices about which genotyinvestigatorng assays to conduct. The fourth specific aim describes the utility of an ELISA- oligonucleotide ligation assay to genotype thousands of very elderly individuals. This is one of the new generation of methods for genotyinvestigatorng single nucleotide substitutions and unique in,;ertions/deletions. This assay is robust, cost efficient and high throughput which makes it ideal to genotype large numbers of Danes and Chinese, The sequential design of the specific aims and large sample sizes contribute to the rigor of this association study. The centenarian candidate gene study will be conducted in a collaborative matrix that includes demographic studies on Hart Chinese and Danes, as well as an analytical methods component of the larger program project.
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