Browsing by Subject "CDKAL1"

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  • Deshmukh, Harshal A.; Madsen, Anne Lundager; Vinuela, Ana; Have, Christian Theil; Grarup, Niels; Tura, Andrea; Mahajan, Anubha; Heggie, Alison J.; Koivula, Robert W.; De Masi, Federico; Tsirigos, Konstantinos K.; Linneberg, Allan; Drivsholm, Thomas; Pedersen, Oluf; Sorensen, Thorkild I. A.; Astrup, Arne; Gjesing, Anette A. P.; Pavo, Imre; Wood, Andrew R.; Ruetten, Hartmut; Jones, Angus G.; Koopman, Anitra D. M.; Cederberg, Henna; Rutters, Femke; Ridderstrale, Martin; Laakso, Markku; McCarthy, Mark; Frayling, Tim M.; Ferrannini, Ele; Franks, Paul W.; Pearson, Ewan R.; Mari, Andrea; Hansen, Torben; Walker, Mark (2021)
    Context: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. Objective: To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. Design: We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. Results: Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 x 10(-9)) and rs9368219 in the CDKAL1 (P value = 3.15 x 10(-9)) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. Conclusion: We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.
  • Cosentino, Cristina; Toivonen, Sanna; Villamil, Esteban Diaz; Atta, Mohamed; Ravanat, Jean-Luc; Demine, Stephane; Schiavo, Andrea Alex; Pachera, Nathalie; Deglasse, Jean-Philippe; Jonas, Jean-Christophe; Balboa, Diego; Otonkoski, Timo; Pearson, Ewan R.; Marchetti, Piero; Eizirik, Decio L.; Cnop, Miriam; Igoillo-Esteve, Mariana (2018)
    Transfer RNAs (tRNAs) are non-coding RNA molecules essential for protein synthesis. Post-transcriptionally they are heavily modified to improve their function, folding and stability. Intronic polymorphisms in CDKAL1, a tRNA methylthiotransferase, are associated with increased type 2 diabetes risk. Loss-of-function mutations in TRMT10A, a tRNA methyltransferase, are a monogenic cause of early onset diabetes and microcephaly. Here we confirm the role of TRMT10A as a guanosine 9 tRNA methyltransferase, and identify tRNA(Gln) and tRNA(iMeth) as two of its targets. Using RNA interference and induced pluripotent stem cell-derived pancreatic beta-like cells from healthy controls and TRMT10A-deficient patients we demonstrate that TRMT10A deficiency induces oxidative stress and triggers the intrinsic pathway of apoptosis in beta-cells. We show that tRNA guanosine 9 hypomethylation leads to tRNA(Gln) fragmentation and that 5'-tRNA(Gln) fragments mediate TRMT10A deficiency-induced beta-cell death. This study unmasks tRNA hypomethylation and fragmentation as a hitherto unknown mechanism of pancre-atic beta-cell demise relevant to monogenic and polygenic forms of diabetes.