title: FGF21 signalling pathway and metabolic traits - genetic association analysis.
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.
authors: Department of Cardiovascular Sciences, University of Leicester, Glenfield General Hospital, Leicester, UK.
authors: Bernhard M
authors: BM
authors: Kaess
authors: Timothy A
authors: TA
authors: Barnes
authors: Klaus
authors: K
authors: Stark
authors: Fadi J
authors: FJ
authors: Charchar
authors: Dawn
authors: D
authors: Waterworth
authors: Kijoung
authors: K
authors: Song
authors: William Y S
authors: WY
authors: Wang
authors: Peter
authors: P
authors: Vollenweider
authors: Gerard
authors: G
authors: Waeber
authors: Vincent
authors: V
authors: Mooser
authors: Ewa
authors: E
authors: Zukowska-Szczechowska
authors: Nilesh J
authors: NJ
authors: Samani
authors: Christian
authors: C
authors: Hengstenberg
authors: Maciej
authors: M
authors: Tomaszewski
mesh_terms: D000328:Adult; D001483:Base Sequence; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000235:genetics; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019655:Quantitative Trait, Heritable; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2