FGF21 signalling pathway and metabolic traits - genetic association analysis

Maciej Tomaszewski (1) , Bernhard M Kaess (1) , Timothy A Barnes (1) , Fadi J Charchar (1) , Klaus Stark (1) , Dawn Waterworth (1) , Kijoung Song (1) , Peter Vollenweider (1) , Gerard Waeber (1) , Vincent Mooser (1) , Ewa Zukowska-Szczechowska (1) , Nilesh J. Samani (1) , Christian Hengstenberg (1) , William Ys Wang (1)

1 Cardiovascular Sciences

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), FGF receptor 2 (FGFR2) and FGF receptor 3 (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 5 genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and 4 metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol, triglycerides and body mass index - BMI) in 629 individuals from Silesian Hypertension Study. Replication analyses were performed in 5,478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3,030 directly genotyped individuals of the German Myocardial Infarction Family Study. Of 54 SNPs that met quality control criteria after genotyping in Silesian Hypertension Study, four (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 one (rs2608819 in KLB) was associated with BMI (p=0.011); all - false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both the CoLaus cohort (p=0.009) and men from the German Myocardial Infarction Family Study (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 variation in FGFR2 may be associated with LDL-C in subjects of white European ancestry.

Mots clés: fibroblast growth factor receptor 2; LDL cholesterol; single nucleotide polymorphism

Maciej Tomaszewski, Bernhard M Kaess, Timothy A Barnes, Fadi J Charchar, Klaus Stark, et al.. FGF21 signalling pathway and metabolic traits - genetic association analysis. European Journal of Human Genetics, 2010, ⟨10.1038/ejhg.2010.130⟩. ⟨hal-00567033⟩