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GWAS META-analysis ...
GWAS META-analysis followed by MENDELIAN randomisation revealed potential control mechanisms for circulating α-klotho levels.
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Gergei, Ingrid (author)
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Zheng, Jie (author)
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Andlauer, Till F M (author)
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Brandenburg, Vincent (author)
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Mirza-Schreiber, Nazanin (author)
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Müller-Myhsok, Bertram (author)
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Krämer, Bernhard K (author)
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Richard, Daniel (author)
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Falk, Louise (author)
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- Movérare-Skrtic, Sofia (author)
- Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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- Ohlsson, Claes, 1965 (author)
- Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
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Smith, George Davey (author)
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März, Winfried (author)
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Voelkl, Jakob (author)
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Tobias, Jonathan H (author)
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(creator_code:org_t)
- 2021-09-20
- 2022
- English.
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 31:5
- Related links:
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https://academic.oup...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
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- 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.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.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.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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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- art (subject category)
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- By the author/editor
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Gergei, Ingrid
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Zheng, Jie
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Andlauer, Till F ...
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Brandenburg, Vin ...
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Mirza-Schreiber, ...
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Müller-Myhsok, B ...
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show more...
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Krämer, Bernhard ...
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Richard, Daniel
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Falk, Louise
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Movérare-Skrtic, ...
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Ohlsson, Claes, ...
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Smith, George Da ...
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März, Winfried
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Voelkl, Jakob
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Tobias, Jonathan ...
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
- Articles in the publication
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Human molecular ...
- By the university
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University of Gothenburg