GWAS meta-analysis followed by Mendelian randomization revealed potential control mechanisms for circulating α-Klotho levels.

Ingrid Gergei, Jie Zheng, Till F M Andlauer, Vincent Brandenburg, Nazanin Mirza-Schreiber, Bertram Müller-Myhsok, Bernhard K Krämer, Daniel Richard, Louise Falk, Sofia Movérare-Skrtic, Claes Ohlsson, George Davey Smith, Winfried März, Jakob Voelkl, Jonathan H Tobias

Journal: Human molecular genetics 2022;31(5):792-802

PMID: 34542150

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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.

Address: Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim 69117, Germany.; Therapeutic Area Cardiovascular Medicine, Boehringer Ingelheim International GmbH, Ingelheim 06877, Germany.; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.; Population Health Science, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK.; Max Planck Institute of Psychiatry, Munich 80804, Germany.; Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich 80333, Germany.; Department of Cardiology and Nephrology, Rhein-Maas Klinikum Würselen, Würselen 52146, Germany.; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg 85764, Germany.; Max Planck Institute of Psychiatry, Munich 80804, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich 2145, Germany.; Institute of Translational Medicine, University of Liverpool, Liverpool 11341, UK.; Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim 69117, Germany.; European Center for Angioscience ECAS, Medical Faculty Mannheim, University of Heidelberg, Mannheim 69117, Germany.; Center for Preventive Medicine and Digital Health Baden-Württemberg (CPDBW), Medical Faculty Mannheim, Heidelberg University, Mannheim 69117, Germany.; Department of Human Evolutionary Biology, Harvard University, Cambridge 02138, MA, USA.; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.; Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Sahlgrenska Osteoporosis Centre, CBAR, Institute of Medicine, Gothenburg 41296, Sweden.; Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Sahlgrenska Osteoporosis Centre, CBAR, Institute of Medicine, Gothenburg 41296, Sweden.; Department of Drug Treatment, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg 7163, Sweden.; Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim 69117, Germany.; SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim 24496, Germany.; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8010, Austria.; Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Linz 4040, Austria.; Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin 10117, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin 10623, Germany.; MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.; Musculoskeletal Research Unit, Translational Health, Learning and Research Building, Level 1 , Southmead Hospital, Bristol BS10 5NB, UK.

DOI: 10.1093/hmg/ddab263

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MeSH Terms: Fibroblast Growth Factors, Genome-Wide Association Study, Glucuronidase, Klotho Proteins, Longitudinal Studies, Mendelian Randomization Analysis, Phosphates