RESUMO
Variants of vitamin D metabolism-genes may predispose to type 2 diabetes (T2D). This study investigated the impact of these variants on disease susceptibility, Vitamin D, parathyroid hormone, C-peptide and HbA1c levels before and after cholecalciferol supplementation in patients with T2D.Twelve polymorphisms within CYP2R1, CYP27B1, DBP, VDR and CYP24A1 were genotyped in 553 T2D patients and 916 controls. In addition 65 patients receiving either cholecalciferol or placebo were analyzed during 6 months intervention and 6 months follow-up.T2D risk alleles are VDR rs7975232 "G" (pc=0.031), rs1544410 "G" (pc=0.027) and CYP2R1 rs10741657 "A" (pc=0.016). Patients with genotypes CYP27B1 rs10877012 "CC" (pc=4x10-5), DBP rs7041 "GG" (pc=0.003), rs4588 "CC" (pc = 3x10-4), CYP24A1 rs2585426 "CG" (pc=0.006) and rs2248137 "CG" (pc=0.001) showed lower 25(OH)D3 and DBP rs4588 "CC" lower 1,25(OH)2D3 levels (pc=0.005). Whereas DBP rs4588 "CC" (pc=0.009), CYP27B1 rs10877012 "AC" (pc=0.059), VDR rs7975323 "AG" (pc=0.033) and rs1544410 "GG" (pc=0.013) are associated with higher 25(OH)D3 levels at 6 months' follow-up. Significant PTH suppression was detected for CYP2R1 "AG" (pc=0.002), DBP rs4588 "CC" (pc<0.001), VDR rs110735810 "CT" (pc<0.001) and CYP24A1 rs2248137 "GG" (pc=0.021).Genetic variants of the vitamin D system predispose to type 2 diabetes and regulate - partially - vitamin D metabolism, concentrations and the vitamin D status. Vitamin D insufficiency is a T2D risk factor. The response to cholecalciferol supplementation can be measured as 25(OH)D3 increment and PTH suppression. This process is regulated by genes of the vitamin D system conferring modest T2D risk.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Deficiência de Vitamina D/genética , Vitamina D/uso terapêutico , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Colestanotriol 26-Mono-Oxigenase/genética , Estudos de Coortes , Família 2 do Citocromo P450/genética , Diabetes Mellitus Tipo 2/metabolismo , Suplementos Nutricionais , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Testes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Dados Preliminares , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Calcitriol/genética , Resultado do Tratamento , Vitamina D/metabolismo , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/metabolismo , Proteína de Ligação a Vitamina D/genética , Vitamina D3 24-Hidroxilase/genéticaRESUMO
Rett Syndrome (RTT) is caused in more than 60% of cases by nonsense mutations in the MECP2 gene. So far, no curative therapy for RTT has become available. In other genetic disorders, it has been shown that aminoglycosides can cause a read-through of nonsense mutations with an efficiency of up to 20%. The aim of this study was to evaluate if this therapeutic concept is applicable to RTT. HeLa cells were transfected with eukaryotic expression vectors carrying mutant alleles of frequently occurring MECP2 nonsense mutations that were N-terminally fused to a FLAG tag. Transfected cells were incubated 24 h in the presence of gentamicin. The expression of full-length protein was analyzed by Western blotting and immunofluorescent cell staining. In the presence of gentamicin a read-through varying between 10 and 21.8% was found, depending on the nucleotide sequence context of the nonsense mutations. The full-length protein was located correctly in the nucleus. We have shown that aminoglycoside-mediated read-through of nonsense mutations in the MECP2 gene can be achieved in vitro with efficiency comparable with that seen in other disorders.