Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes

TY - JOUR

T1 - Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes

AU - Xie, Weijia

AU - Wood, Andrew R

AU - Lyssenko, Valeriya

AU - Weedon, Michael N

AU - Knowles, Joshua W

AU - Alkayyali, Sami

AU - Assimes, Themistocles L

AU - Quertermous, Thomas

AU - Abbasi, Fahim

AU - Paananen, Jussi

AU - Häring, Hans

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Smith, Ulf

AU - Laakso, Markku

AU - Dekker, Jacqueline M

AU - Nolan, John J

AU - Groop, Leif

AU - Ferrannini, Ele

AU - Adam, Klaus-Peter

AU - Gall, Walter E

AU - Frayling, Timothy M

AU - Walker, Mark

AU - MAGIC Investigators

PY - 2013/6

Y1 - 2013/6

N2 - 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.

AB - 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.

U2 - 10.2337/db12-0876

DO - 10.2337/db12-0876

M3 - Journal article

C2 - 23378610

SN - 0012-1797

VL - 62

SP - 2141

EP - 2150

JO - Diabetes

JF - Diabetes

IS - 6

ER -