Stress, Inflammation, and Genetics of Human Longevity
Clinical, experimental, and genetic data suggest the importance of inflammation and thrombosis pathways in modulating the rate of age-related tissue damage and organ dysfunction, and longevity. In the Cardiovascular Health Study (CHS), inflammatory and thrombotic markers such as C-reactive protein (CRP) and D-dimer predict all-cause mortality. Preliminary data from CHS also suggest that common variants in two genes involved in the regulation of fibrinolytic activity, PAI-1 and TAFI, may be associated with longevity in men. The application of candidate gene SNP discovery and use of haplotype information in the full CHS cohort is the next logical step in the assessment of genetic associations with longevity. The availability of high-quality human genomic sequence variation data from the University of Washington Variation Discovery Resource allows us to assess genetic associations, using on average, ~6 SNPs per gene, that efficiently capture the common haplotype patterns of 40 candidate genes that comprise inflammation and thrombosis pathways. CHS is a cohort study of nearly 6,000 adults aged 65 at baseline, followed prospectively for over 12 years with extensive data on longevity and aging outcomes, and intermediate phenotypes related to inflammation and thrombosis.
The clinical endpoints to be studied in this proposal include overall survival, cardiovascular and cancer-related mortality, and years of healthy life (YHL), a measure that combines duration of survival with quality of life. Other study outcome measures include quantitative traits that reflect age-related inflammation and thrombotic responses, including plasma levels of CRP, IL-6, D-dimer, and non-invasive measures of subclinical vascular disease. Our analytic approach involves several recently described statistical genetic and computational methodologies, and will allow assessment of single-locus and multi-locus genotypes, haplotypes, as well as gene-environment and gene-gene interaction. Once putative genetic associations with human longevity have been identified in CHS, we plan to apply for additional Consortium funds to validate our findings in other human cohorts. The ability to validate immediately any apparent associations is an important component of this proposal. We expect this multi-disciplinary approach to enable the detection of common genetic variants that modulate organismal inflammatory response and adaptation to stress, and thereby influence human longevity.