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Gergei, I.* ; Zheng, J.* ; Andlauer, T.F.M.* ; Brandenburg, V.* ; Mirza-Schreiber, N. ; Müller-Myhsok, B.* ; Krämer, B.K.* ; Richard, D.* ; Falk, L.* ; Movérare-Skrtic, S.* ; Ohlsson, C.* ; Smith, G.D.* ; März, W.* ; Voelkl, J.* ; Tobias, J.H.*

GWAS META-analysis followed by MENDELIAN randomisation revealed potential control mechanisms for circulating α-klotho levels.

Hum. Mol. Genet., DOI: 10.1093/hmg/ddab263 (2021)
Open Access Green: Postprint online available 10/2022
BACKGROUND: The protein α-Klotho acts as transmembrane the co-receptor for fibroblast growth factor 23 (FGF-23) 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 GWAS meta-analysis followed by Mendelian randomisation (MR) of circulating α-Klotho levels. METHODS: Plasma α-Klotho levels were measured by ELISA in the LURIC and ALSPAC (mothers) cohorts, followed by a GWAS meta-analysis in 4376 individuals across the two cohorts. RESULTS: 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, FGF-23-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 [IVW beta = 0.059 (95% CI 0.026, 0.093)] and low-density lipoprotein cholesterol (LDL-C) levels [-0.198, (-0.332, -0.063)] on α-Klotho. CONCLUSIONS: 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Genome-wide Association; Ld Score Regression; Inflammatory Cytokines; Receptor; Disease; Kidney; Beta-4galnac-t3; Specificity; Expression; Protein
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status Peer reviewed
Grants Diabetes UK
University of Bristol
UK Medical Research Council
UK Medical Research Council Integrative Epidemiology Unit
Shanghai Thousand Talents Program
Academy of Medical Sciences (AMS) Springboard Award
Government Department of Business, Energy and Industrial Strategy (BEIS)
British Heart Foundation
Wellcome Trust