Approved research

Understanding the role of alpha-Klotho in health and disease

Lay summary

Alpha-Klotho is an aging-suppressor gene that when disrupted in mice results in symptoms of premature aging (soft tissue calcification, atherosclerosis, skin atrophy, hyperphosphatemia, osteoporosis, thymic atrophy and shortened lifespan). A circulatory soluble form of aKlotho has been identified that may have beneficial hormonal actions. We will examine whether individuals with a particular genetic form (variant haplotype, KLVS) resulting in increased levels of circulating aKlotho have a beneficial phenotype. Past studies with limited population size have shown an association of this ?protective? haplotype with reduced heart disease, improved cardiovascular function, improved age-independent cognition, improved renal health and longevity. The aim of this proposal is to determine the relationship of Klotho haplotype KL-VS to human disease and normal aging. The large population size of the UKBB database will provide a unique opportunity to investigate the impact of hormonal klotho on multiple health outcomes using imaging and non-imaging data. Human studies performed to date, while encouraging, have been limited by sample size and physiological assessment. Since the allele frequency of the protective haplotype is ~15% of the general population, there will be sufficient numbers of subjects to confirm initial published observations and investigate novel correlations. Genotyping data for the KLVS haplotype are available in the UKBB database. We will compare KLVS-carriers to the rest of the general population using a bioinformatic approach. We will use existing imaging and physiology data to identify the characteristics of KLVS-carriers compared to the non-carriers (for example, changes in brain volume using MRI imaging, differences in functional cardiac and skeletal muscle measures, alterations in fat distribution and content among others). This approach will test for correlations between the known genetic variant and measures of human health from the data already acquired as part of the UKBB initiative. This will be a population based study of the KLVS haplotype and requires genetic, imaging and physiological parameters that are already part of the UKBB baseline study database (500,000) and imaging study cohort (9,000 individuals, to date). As the cohort of scanned subjects increases we would expect subsequent data release to be incorporated into the overall analysis. For the initial screen, raw images will not be requested and no samples will be requested. Individuals will be identified by Klotho haplotype and age.