Methods and means are described for diagnosing a disease or a predisposition to disease by genotyping a klotho gene from an individual and identifying the presence of one or more risk polymorphisms. These risk polymorphisms are associated either directly or indirectly with predisposition to a range of chronic diseases including osteoporosis, skin disorders, age-related disease, lung dysfunction and metabolic syndrome. Methods of treatment, kits for diagnostic purposes and an isolated klotho gene including all or some of a range of polymorphisms are also described as well as methods of isolating molecules that modulate a klotho gene.