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

Abstract

BACKGROUND\nThe 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.\n\n\nMETHODS\nPlasma 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.\n\n\nRESULTS\nSix signals at five loci were associated with circulating α-Klotho levels at genome-wide significance (p\u2009<\u20095\u2009×\u200910-8), namely ABO, KL, FGFR1, and two post-translational modification genes, B4GALNT3 and CHST9. Together, these loci explained >\u20099% 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\u2009=\u20090.059 (95% CI 0.026, 0.093)] and low-density lipoprotein cholesterol (LDL-C) levels [-0.198, (-0.332, -0.063)] on α-Klotho.\n\n\nCONCLUSIONS\nOur 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.