Common genetic variation at the Klotho gene locus and its relationship to age-related phenotypes

Abstract

The proportion of older adults in Western populations is increasing and there is, therefore, a need to define factors affecting the maintenance of physical and cognitive health in old age. Klotho, an FGF-23 co-receptor, has been shown to increase the lifespan in mice and there are numerous reports of common variants at the Klotho gene locus, particularly those that make up the KL-VS haplotype, being associated with age-related phenotypes. However, these reports are based on small sample sizes and are consequently under-powered. The work described in this thesis uses a candidate gene association approach to evaluate the previously reported associations between common genetic variants at the Klotho gene locus and age-related phenotypes in the UK Biobank, a large prospective cohort study of half a million participants. There was preliminary evidence for the following associations: rs2283368 and rs9536338 with longevity; rs495392 with HbA1c; rs141113969, rs2227122 and rs676046 with memory; and rs71436501 and rs78425544 with melanoma survival. However, none of these associations could be adequately replicated and are likely to be unreliable. These results show that the previous reports of associations between Klotho variants and longevity, cognitive function, cardiometabolic disease and cancer are likely to be false positives, which leads to two overall conclusions: one, there is insufficient evidence that common variation at the Klotho gene locus is associated with age-related phenotypes; and two, there is a need for well-powered replication studies.