Gergei, Ingrid, Zheng, Jie, Andlauer, Till FM, Brandenburg, Vincent, Mirza-Schreiber, Nazanin, Mueller-Myhsok, Bertram 
ORCID: 0000-0002-0719-101X, Kraemer, Bernhard K, Richard, Daniel, Falk, Louise, Moverare-Skrtic, Sofia et al (show 5 more authors)
(2022)
GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating alpha-Klotho levels.
HUMAN MOLECULAR GENETICS, 31 (5).
pp. 792-802.
|
Text
GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating α-Klotho levels.pdf - Published version Download (642kB) | Preview |
Abstract
The protein α-Klotho acts as transmembrane co-receptor for fibroblast growth factor 23 (FGF23) and is a key regulator of phosphate homeostasis. However, α-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 α-Klotho levels. Plasma α-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 α-Klotho levels at genome-wide significance (P < 5 × 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 α-Klotho levels. MR analyses revealed no causal relationships between α-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 α-Klotho. Our GWAS findings suggest that two enzymes involved in post-translational modification, B4GALNT3 and CHST9, contribute to genetic influences on α-Klotho levels, presumably by affecting protein turnover and stability. Subsequent evidence from MR analyses on α-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: α-Klotho as a transmembrane protein is well investigated along the endocrine FGF23-α-Klotho pathway. However, the role of the circulating form of α-Klotho, which is generated by cleavage of transmembrane α-Klotho, remains incompletely understood. Genetic analyses might help to elucidate novel regulatory and functional mechanisms. The identification of genetic factors related to circulating α-Klotho further enables MR to examine causal relationships with other factors. The findings from the first GWAS meta-analysis of circulating α-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 α-Klotho levels, presumably by affecting protein turnover and stability.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Phosphates, Glucuronidase, Fibroblast Growth Factors, Longitudinal Studies, Genome-Wide Association Study, Mendelian Randomization Analysis, Klotho Proteins |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Population Health |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 16 May 2022 10:24 |
| Last Modified: | 18 Jan 2023 21:02 |
| DOI: | 10.1093/hmg/ddab263 |
| Open Access URL: | https://doi.org/10.1093/hmg/ddab263 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3154881 |
Dimensions
Dimensions
