title: Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.
abstract: Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.
authors: Genetics of Complex Traits, Peninsula School of Medicine, University of Exeter, Exeter, UK.
authors: Weijia
authors: W
authors: Xie
authors: Andrew R
authors: AR
authors: Wood
authors: Valeriya
authors: V
authors: Lyssenko
authors: Michael N
authors: MN
authors: Weedon
authors: Joshua W
authors: JW
authors: Knowles
authors: Sami
authors: S
authors: Alkayyali
authors: Themistocles L
authors: TL
authors: Assimes
authors: Thomas
authors: T
authors: Quertermous
authors: Fahim
authors: F
authors: Abbasi
authors: Jussi
authors: J
authors: Paananen
authors: Hans
authors: H
authors: Häring
authors: Torben
authors: T
authors: Hansen
authors: Oluf
authors: O
authors: Pedersen
authors: Ulf
authors: U
authors: Smith
authors: Markku
authors: M
authors: Laakso
authors: Jacqueline M
authors: JM
authors: Dekker
authors: John J
authors: JJ
authors: Nolan
authors: Leif
authors: L
authors: Groop
authors: Ele
authors: E
authors: Ferrannini
authors: Klaus-Peter
authors: KP
authors: Adam
authors: Walter E
authors: WE
authors: Gall
authors: Timothy M
authors: TM
authors: Frayling
authors: Mark
authors: M
authors: Walker
mesh_terms: D000328:Adult; D001622:Betaine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012694:Serine / Q000378:metabolism
chemical_list: D001622:Betaine; D012694:Serine; D005998:Glycine
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