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Low-frequency variants in genes involved in glutamic acid metabolism and γ-glutamyl cycle and risk of coronary artery disease in type 2 diabetes
Background: A common genetic variant at the glutamate-ammonia ligase (GLUL) locus has been previously associated with an increased risk of coronary artery disease (CAD) as well as alterations of glutamic acid metabolism and the γ-glutamyl cycle in individuals with type 2 diabetes (T2D). Here we investigated whether less frequent variants in GLUL and 15 additional genes in these pathways are associated with differences in CAD risk in T2D.
Methods: Coding sequences and regulatory elements of these genes were sequenced in 2,394 individuals with T2D from three CAD case/control sets.
Results: Ninety-six variants with minor allele frequency [MAF]< 0.05 were identified as being nominally associated with CAD status. One of these variants (rs62447457, MAF 0.025), placed in a non-coding region flanking the γ-glutamylcyclotransferase (GGCT) gene, showed nominal evidence of replication in two other cases-control se ts (n = 1,132), with summary OR of 0.54 (p = 2.5 × 10–4). Another variant (rs145322388, MAF = 0.039), flanking the dipeptidase 2 (DPEP2) gene, showed association with CAD status across discovery and replications sets (summary OR 0.61, p = 2.5 × 10–4). A third variant (rs1238275622, MAF 0.004), flanking the GLUL gene, was associated with increased risk of CAD (summary OR 1.84, p-value 2.1 × 10–3). Based on their Regulome scores (2b, 2a, and 3a, respectively), all three variants are very likely to have regulatory functions. Conclusions: In summary, we have identified low-frequency variants associated with CAD in T2D at two loci involved in glutamic acid metabolism and the γ-glutamyl cycle. These findings provide further evidence for a role of these pathways in the link between T2D and CAD. Graphical Abstract: (Figure presented.) © The Author(s) 2024.
Authors : Giuffrida F.M.A.; Rai S.K.; Tang Y.; Mendonça C.; Frodsham S.G.; Shah H.S.; Pezzolesi M.G.; Sun Q.; Doria A.
Source : BioMed Central Ltd
Article Information
| Year | 2024 |
| Type | Article |
| DOI | 10.1186/s12933-024-02442-5 |
| ISSN | 14752840 |
| Volume | 23 |
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