A variant on chromosome 1q25 (rs10911021) has been previously associated with coronary artery disease (CAD) in individuals with T2D. In human umbilical vein endothelial cells (HUVECs), the 1q25 risk allele (‘C’) was found to be associated with decreased expression of the adjacent gene GLUL encoding the enzyme glutamine synthase converting glutamate to glutamine. To further investigate the mechanisms through which the 1q25 locus modulates CAD risk in T2D, we performed a global metabolomics study (LC-MS, Metabolon) in 62 HUVECs (TT=11, CT=21, CC=30). Among 597 metabolites detected in HUVEC lysates, 23 attained p<0.005 for association with the 1q25 risk allele. Through an unbiased hierarchical cluster analysis, these 23 metabolites could be subdivided into four clusters - two upregulated and two downregulated in carriers of the risk allele. The two upregulated clusters included a group of γ-glutamyl amino acids (γ-glutamylthreonine, γ-glutamylleucine, and γ-glutamylvaline) and a heterogeneous group of metabolites including isoleucylglycine and tyrosylglycine. The two downregulated clusters included a group of polyunsaturated fatty acid (PUFA) derivatives, such as DHA-choline and N-arachidonoyl taurine, and a cluster of several sphingomyelins. Consistent with the higher γ-glutamyl amino acids, the risk allele was associated with increased ophthalmate (p=0.04), a marker of γ-glutamyl cycle malfunction, and decreased S-lactoylglutathione (p=0.016), a possible sign of defective detoxification of the AGE-precursor methylglyoxal.
In summary, we have identified several metabolic pathways potentially mediating the 1q25 locus effect on CAD risk in T2D. These include impairment of the γ-glutamyl cycle, possibly increasing susceptibility to oxidative stress, and downregulation of PUFA derivatives and sphingomyelins. Further studies of these pathways may lead to the identification of novel therapeutic targets to reduce CAD risk in T2D.
C. Pipino: None. H. Shah: None. K. Park: None. S. Monti: None. C. Mendonca: None. G.L. King: Research Support; Self; Sanofi. A. Pandolfi: None. A. Doria: Research Support; Self; Sanofi-Aventis.