The longevity gene Klotho and its cerebrospinal fluid protein profiles as a modifier for Parkinson´s disease

Background Parkinson´s disease (PD) has a large phenotypic variability, which may, at least partly, be genetically driven including alterations of gene products. Candidates might not only be proteins associated with disease risk but also pathways that play a role in aging. Objective To evaluate phenotype‐modifying effects of genetic variants in Klotho, a longevity gene. Methods We analyzed two longitudinal cohorts: one local cohort comprising 459 PD patients who underwent genotyping for the KL‐VS haplotype in Klotho including a subgroup of 125 PD patients and 50 healthy controls who underwent biochemical cerebrospinal fluid (CSF) analyses of Klotho and fibroblast growth factor 23 as well as vitamin D metabolites. The second cohort comprised 297 patients from the Parkinsonʼs Progression Markers Initiative (PPMI) for validation of genetic−clinical findings. Results PD patients carrying the KL‐VS haplotype demonstrated a shorter interval between PD onset and onset of cognitive impairment (both cohorts) and higher Unified Parkinson´s Disease Rating Scale part III (UPDRS III) scores (PPMI). CSF protein levels of Klotho and fibroblast growth factor 23 were lower in PD patients irrespective of gender compared to controls. Moreover, low CSF levels of Klotho were associated with higher scores in the UPDRS III and Hoehn and Yahr Scale. Conclusions Our results indicate that genetic variants in Klotho together with its corresponding CSF protein profiles are associated with aspects of disease severity in PD. These findings suggest that pathways associated with aging might be targets for future biomarker research in PD. Low CSF levels of the longevity protein Klotho were associated with higher scores in Unified Parkinson's Disease Rating scale part II (UPDRS III). Patients with Parkinson's disease (PD) carrying the genetic “KL‐VS”‐variant demonstrated a shorter interval between PD onset and onset of cognitive impairment and higher UPDRS III scores. Genetic variants in Klotho along with its corresponding CSF protein profiles are associated with aspects of disease severity in PD.