Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the γ-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells

A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes (T2D). In human umbilical vein endothelial cells (HUVECs), the risk allele 'C' is associated with lower expression of the adjacent gene GLUL encoding glutamine synthase, converting glutamic acid to glutamine. To further investigate the mechanisms through which this locus affects CHD risk, we measured 35 intracellular metabolites involved in glutamic acid metabolism and γ-glutamyl cycle in 62 HUVEC strains carrying different rs10911021 genotypes. Eight metabolites were positively associated with the risk allele (17%-58% increase/allele copy, p=0.046-0.002), including five γ-glutamyl amino acids, β-citryl-glutamate, N-acetyl-aspartyl-glutamate, and ophthalmate - a marker of γ-glutamyl cycle malfunction. Consistent with these findings, the risk allele was also associated with decreased glutathione/glutamate ratio (-9%, p=0.012), decreased S-lactoylglutathione (-41%, p=0.019), and reduced detoxification of the atherogenic compound methylglyoxal (+54%, p=0.008). GLUL down-regulation by shRNA caused a 40% increase in methylglyoxal level, which was completely prevented by glutamine supplementation. In summary, we have identified intracellular metabolic traits associated with the 1q25 risk allele in HUVECs, including impairments of the γ-glutamyl cycle and methylglyoxal detoxification. Glutamine supplementation abolishes the latter abnormality, suggesting that such treatment may prevent CHD in 1q25 risk allele carriers.