title: An Exome-Chip Association Analysis in Chinese Subjects Reveals a Functional Missense Variant ofGCKRThat Regulates FGF21 Levels.
abstract: Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic regulator of glucose homeostasis. Here, we conducted an exome-chip association analysis by genotyping 5,169 Chinese individuals from a community-based cohort and two clinic-based cohorts. A custom Asian exome-chip was used to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 70,444 single nucleotide polymorphisms identified a novel locus,GCKR, significantly associated with circulating FGF21 levels at genome-wide significance. In the combined analysis, the common missense variant ofGCKR, rs1260326 (p.Pro446Leu), showed an association with FGF21 levels after adjustment for age and sex (P= 1.61 × 10-12; β [SE] = 0.14 [0.02]), which remained significant on further adjustment for BMI (P= 3.01 × 10-14; β [SE] = 0.15 [0.02]).GCKRLeu446 may influence FGF21 expression via its ability to increase glucokinase (GCK) activity. This can lead to enhanced FGF21 expression via elevated fatty acid synthesis, consequent to the inhibition of carnitine/palmitoyl-transferase by malonyl-CoA, and via increased glucose-6-phosphate-mediated activation of the carbohydrate response element binding protein, known to regulate FGF21 gene expression. Our findings shed new light on the genetic regulation of FGF21 levels. Further investigations to dissect the relationship between GCKR and FGF21, with respect to the risk of metabolic diseases, are warranted.
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chloe Y Y
authors.initials: CYY
authors.lastname: Cheung
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Clara S
authors.initials: CS
authors.lastname: Tang
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.|The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.|Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chi-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Ka-Wing
authors.initials: KW
authors.lastname: Au
authors.affiliation: School of Public Health, The University of Hong Kong, Hong Kong, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Carol H Y
authors.initials: CHY
authors.lastname: Fong
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Kelvin H M
authors.initials: KHM
authors.lastname: Kwok
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Wing-Sun
authors.initials: WS
authors.lastname: Chow
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yu-Cho
authors.initials: YC
authors.lastname: Woo
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Michele M A
authors.initials: MMA
authors.lastname: Yuen
authors.affiliation: Department of Psychiatry, The University of Hong Kong, Hong Kong, China.
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: JoJo
authors.initials: J
authors.lastname: Hai
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Bernard M Y
authors.initials: BMY
authors.lastname: Cheung
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Kathryn C B
authors.initials: KCB
authors.lastname: Tan
authors.affiliation: School of Public Health, The University of Hong Kong, Hong Kong, China.
authors.forename: Tai-Hing
authors.initials: TH
authors.lastname: Lam
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China ksllam@hku.hk pcsham@hku.hk hftse@hkucc.hku.hk.|Hong Kong-Guangdong Joint Laboratory on Stem Cell and Regenerative Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Hung-Fat
authors.initials: HF
authors.lastname: Tse
authors.affiliation: Department of Psychiatry, The University of Hong Kong, Hong Kong, China ksllam@hku.hk pcsham@hku.hk hftse@hkucc.hku.hk.|Centre for Genomic Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.|The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China.
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China ksllam@hku.hk pcsham@hku.hk hftse@hkucc.hku.hk.|The State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.|Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Karen S L
authors.initials: KSL
authors.lastname: Lam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase; D059472:Exome; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D005941:Glucokinase / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D006801:Humans; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D008875:Middle Aged; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; C485100:GCKR protein, human; C116385:MLXIPL protein, human; C414620:fibroblast growth factor 21; D008316:Malonyl Coenzyme A; D019298:Glucose-6-Phosphate; D005346:Fibroblast Growth Factors; D002334:Carnitine O-Palmitoyltransferase; D005941:Glucokinase