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.

FIG. 1.

Regional association plots of the five SNP-metabolite associations in the RISC cohort. In each plot, the top panel shows the name and location of genes in the UCSC Genome Browser. The –log 10 of P values of the imputed SNPs are plotted on the y-axis against genomic position (NCBI Build 36) on the x-axis. The top signal is represented by a diamond. Estimated recombination rates (taken from HapMap) are plotted to reflect the local linkage disequilibrium structure around the associated SNPs and their correlated proxies (according to a gray scale from r² = 0 to 1, based on pairwise r² values from HapMap Phase II CEU). chr, chromosome. (A high-quality color representation of this figure is available in the online issue.)

FIG. 2.

Schematics of metabolic pathways relevant to SNP-metabolite associations. PSAT, phosphoserine aminotransferase.

FIG. 3.

Links between glycine, serine, folate, homocysteine, and betaine in folate metabolism and homocysteine metabolism. Enzymes (1): dihydrofolate reductase (2), serine hydroxymethyltransferase (3), glycine synthase (also called glycine cleavage enzyme) (4), methylenetetradydrofolate reductase (5), methionine synthase (the other name of 5-methyltetrahydrofolate-homocysteine methyltransferase) (6), and betaine-homocysteine methyltransferase. Modified from House et al. (44) and Van Tellingen et al. (45). (A high-quality color representation of this figure is available in the online issue.)