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 of GCKR, 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]). GCKR Leu446 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.
journal_name
Diabetesjournal_title
Diabetesauthors
Cheung CYY,Tang CS,Xu A,Lee CH,Au KW,Xu L,Fong CHY,Kwok KHM,Chow WS,Woo YC,Yuen MMA,Cherny SS,Hai J,Cheung BMY,Tan KCB,Lam TH,Tse HF,Sham PC,Lam KSLdoi
10.2337/db16-1384subject
Has Abstractpub_date
2017-06-01 00:00:00pages
1723-1728issue
6eissn
0012-1797issn
1939-327Xpii
db16-1384journal_volume
66pub_type
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