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

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.