GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating α-Klotho levels
| Autor: | Nazanin Mirza-Schreiber, Louise Falk, George Davey Smith, Till F. M. Andlauer, Winfried März, Bertram Müller-Myhsok, Ingrid Gergei, Jonathan H Tobias, Vincent Brandenburg, Daniel Richard, Bernhard K. Krämer, Jakob Voelkl, Jie Zheng, Claes Ohlsson, Sofia Movérare-Skrtic |
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| Rok vydání: | 2021 |
| Předmět: |
kl gene
Fibroblast growth factor 23 medicine.medical_specialty Genome-wide association study Biology urologic and male genital diseases Phosphates symbols.namesake Internal medicine Genetics medicine Vitamin D and neurology genetics Longitudinal Studies Molecular Biology Klotho Proteins Genetics (clinical) Glucuronidase genome-wide association study Protein turnover FGF19 General Medicine Mendelian Randomization Analysis Phenotype mendelian randomization analysis female genital diseases and pregnancy complications Fibroblast Growth Factors Endocrinology Meta-analysis Mendelian inheritance symbols Genome-Wide Association Study |
| Zdroj: | HUMAN MOLECULAR GENETICS Gergei, I, Zheng, J, Andlauer, T F M, Brandenburg, V, Mirza-Schreiber, N, Müller-Myhsok, B, Krämer, B K, Richard, D, Falk, L, Moverare-Skrtic, S, Ohlsson, C, Davey Smith, G, März, W, Voelkl, J & Tobias, J H 2021, ' GWAS META-analysis followed by MENDELIAN randomisation revealed potential control mechanisms for circulating α-klotho levels ', Human Molecular Genetics . https://doi.org/10.1093/hmg/ddab263 |
| ISSN: | 1460-2083 |
| DOI: | 10.1093/hmg/ddab263 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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