Abstract
Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol – LDL-C, HDL-cholesterol – HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.
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Acknowledgements
This project was supported by NIH Fogarty International Research Collaboration Award (R03 TW007165; to MT). BMK's fellowship in Leicester was supported by the EU project Cardiogenics (LSHM-CT-2006-037593). TAB was supported by a British Heart Foundation project Grant (PG/06/097; to MT). NJS holds a British Heart Foundation Chair of Cardiology. This study is a part of the research portfolio supported by the Leicester NIHR Biomedical Research Unit in Cardiovascular Disease. The CoLaus study was supported by research Grants from GlaxoSmithKline and from the Faculty of Biology and Medicine of Lausanne, Switzerland, and is currently supported by the Swiss National Science Foundation (Grant no: 33CSCO-122661). We are grateful to Dr Allan Beveridge for support in bioinformatic analysis.
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Kaess, B., Barnes, T., Stark, K. et al. FGF21 signalling pathway and metabolic traits – genetic association analysis. Eur J Hum Genet 18, 1344–1348 (2010). https://doi.org/10.1038/ejhg.2010.130
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DOI: https://doi.org/10.1038/ejhg.2010.130
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