A Functional Missense Variant of the Glucokinase Regulator Gene (GCKR) Is Associated with Raised FGF21 Levels in an Exome-Chip Association Study Amongst Chinese Individuals

Presentation Number: SAT 598
Date of Presentation: April 1st, 2017

Karen SL Lam*1, Chloe YY Cheung2, Paul CH Lee1, Clara S Tang1, Aimin Xu3, Ka-Wing Au1, Lin Xu1, Carol HY Fong3, Kelvin HM Kwok1, Wing-Sun Chow4, Yu Cho Woo4, Michele MA Yuen3, Stacey S Cherny1, Jojo SH Hai1, Bernard MY Cheung5, Kathryn CB Tan1, Tai-Hing Lam1, Hung-Fat Tse3 and Pak-Chung Sham6
1The University of Hong Kong, Hong Kong, 2The University of Hong Kong, Hong Kong, China, 3University of Hong Kong, Hong Kong, Hong Kong, 4The University of Hong Kong, Hong Kong, Hong Kong, 5The Univeristy of Hong Kong, Hong Kong, 6The University of Hong, Hong Kong

Abstract

Fibroblast growth factor 21 (FGF21) is increasingly recognized as an important metabolic hormone with beneficial effects on glucose and lipid metabolism. Here, we conducted an exome-chip association analysis by genotyping 5169 Chinese individuals, using a custom Illumina HumanExome BeadChip, to detect genetic determinants influencing circulating FGF21 levels. Single-variant association analysis interrogating 73,648 single nucleotide polymorphisms with minor allele frequencies ≥0.1% identified a novel locus, GCKR, significantly associated with circulating FGF21 levels. A common missense variant of GCKR, rs1260326 (p.Pro446Leu), showed an association with FGF21 levels at genome-wide significance with adjustment for age and sex (P =7.42x10-15; β[SE]: 0.15[0.02]). This association remained significant after adjustment for body mass index (P =1.05x10-15; β[SE]: 0.16[0.02]), indicating an adiposity-independent effect of this variant. The GCKR Leu446 variant 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 have 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.

 

Nothing to Disclose: CYYC, CHL, CST, AX, KWA, LX, CHYF, KHMK, WSC, YCW, MMAY, SSC, JSHH, BMYC, KCBT, THL, HFT, PCS, KSLL

 

Nothing to Disclose: KSL, CYC, PCL, CST, AX, KWA, LX, CHF, KHK, WSC, YCW, MMY, SSC, JSH, BMC, KCT, THL, HFT, PCS