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Genetics/Genomes/Proteomics/Metabolomics

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

  1. Caterina Pipino1,2,3,
  2. Hetal Shah1,2,
  3. Sabrina Prudente4,
  4. Natalia Di Pietro3,
  5. Lixia Zeng5,
  6. Kyoungmin Park1,2,
  7. Vincenzo Trischitta6,7,
  8. Subramanian Pennathur5,
  9. Assunta Pandolfi3 and
  10. Alessandro Doria1,2⇑
  1. 1Research Division, Joslin Diabetes Center, Boston, MA
  2. 2Department of Medicine, Harvard Medical School, Boston, MA
  3. 3Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology - CAST (ex CeSI-MeT), University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
  4. 4Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  5. 5Division of Nephrology, Department of Medicine, University of Michigan, Ann Arbor, MI
  6. 6Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  7. 7Department of Experimental Medicine, Sapienza University, Rome, Italy
  1. Corresponding author: Alessandro Doria, alessandro.doria{at}joslin.harvard.edu
Diabetes 2020 Oct; 69(10): 2206-2216. https://doi.org/10.2337/db20-0475
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Abstract

A chromosome 1q25 variant (rs10911021) has been associated with coronary heart disease (CHD) in type 2 diabetes. 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 the 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-to-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 downregulation by shRNA caused a 40% increase in the 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.

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.12616442.

  • Received May 5, 2020.
  • Accepted July 3, 2020.
  • © 2020 by the American Diabetes Association
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Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the γ-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells
Caterina Pipino, Hetal Shah, Sabrina Prudente, Natalia Di Pietro, Lixia Zeng, Kyoungmin Park, Vincenzo Trischitta, Subramanian Pennathur, Assunta Pandolfi, Alessandro Doria
Diabetes Oct 2020, 69 (10) 2206-2216; DOI: 10.2337/db20-0475

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Association of the 1q25 Diabetes-Specific Coronary Heart Disease Locus With Alterations of the γ-Glutamyl Cycle and Increased Methylglyoxal Levels in Endothelial Cells
Caterina Pipino, Hetal Shah, Sabrina Prudente, Natalia Di Pietro, Lixia Zeng, Kyoungmin Park, Vincenzo Trischitta, Subramanian Pennathur, Assunta Pandolfi, Alessandro Doria
Diabetes Oct 2020, 69 (10) 2206-2216; DOI: 10.2337/db20-0475
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