| First Author | Gergei I | Year | 2022 |
| Journal | Hum Mol Genet | Volume | 31 |
| Issue | 5 | Pages | 792-802 |
| PubMed ID | 34542150 | Mgi Jnum | J:333356 |
| Mgi Id | MGI:7380491 | Doi | 10.1093/hmg/ddab263 |
| Citation | Gergei I, et al. (2022) GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating alpha-Klotho levels. Hum Mol Genet 31(5):792-802 |
| abstractText | The protein alpha-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, alpha-Klotho also exists in a circulating form, with pleiotropic, but incompletely understood functions and regulation. Therefore, we undertook a genome-wide association study (GWAS) meta-analysis followed by Mendelian randomization (MR) of circulating alpha-Klotho levels. Plasma alpha-Klotho levels were measured by enzyme-linked immunosorbent assay (ELISA) in the Ludwigshafen Risk and Cardiovascular Health and Avon Longitudinal Study of Parents and Children (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. Six signals at five loci were associated with circulating alpha-Klotho levels at genome-wide significance (P < 5 x 10-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >9% of the variation in circulating alpha-Klotho levels. MR analyses revealed no causal relationships between alpha-Klotho and renal function, FGF23-dependent factors such as vitamin D and phosphate levels, or bone mineral density. The screening for genetic correlations with other phenotypes followed by targeted MR suggested causal effects of liability of Crohn's disease risk [Inverse variance weighted (IVW) beta = 0.059 (95% confidence interval 0.026, 0.093)] and low-density lipoprotein cholesterol levels [-0.198 (-0.332, -0.063)] on alpha-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on alpha-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on alpha-Klotho levels suggest regulation by mechanisms besides phosphate-homeostasis and raise the possibility of cross-talk with FGF19- and FGF21-dependent pathways, respectively. Significance statement: alpha-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-alpha-Klotho pathway. However, the role of the circulating form of alpha-Klotho, which is generated by cleavage of transmembrane alpha-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating alpha-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating alpha-Klotho levels identified six genome-wide significant signals across five genes. Given the function of two of the genes identified, B4GALNT3 and CHST9, it is tempting to speculate that post-translational modification significantly contributes to genetic influences on alpha-Klotho levels, presumably by affecting protein turnover and stability. |
