RESUMEN
Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (ß=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (ß=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (ß=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (ß=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Exoma/genética , Ayuno/sangre , Predisposición Genética a la Enfermedad , Variación Genética , Tasa de Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Población Negra/genética , Diabetes Mellitus Tipo 2/sangre , Estudios de Asociación Genética , Sitios Genéticos , Receptor del Péptido 1 Similar al Glucagón/genética , Glucosa-6-Fosfatasa/genética , Humanos , Insulina/sangre , Polimorfismo de Nucleótido Simple/genética , Población Blanca/genéticaRESUMEN
An insertion in the promoter of the operon that encodes the molecular chaperone GroE was isolated as an antimutator for stationary-phase or adaptive mutation. The groE operon consists of two genes, groES and groEL; point mutations in either gene conferred the same phenotype, reducing Lac+ adaptive mutation 10- to 20-fold. groE mutant strains had 1/10 the amount of error-prone DNA polymerase IV (Pol IV). In recG+ strains, the reduction in Pol IV was sufficient to account for their low rate of adaptive mutation, but in recG mutant strains, a deficiency of GroE had some additional effect on adaptive mutation. Pol IV is induced as part of the SOS response, but the effect of GroE on Pol IV was independent of LexA. We were unable to show that GroE interacts directly with Pol IV, suggesting that GroE may act indirectly. Together with previous results, these findings indicate that Pol IV is a component of several cellular stress responses.
Asunto(s)
Proteínas Bacterianas/fisiología , ADN Polimerasa beta/metabolismo , Escherichia coli/enzimología , Regulación Bacteriana de la Expresión Génica , Proteínas de Choque Térmico/fisiología , Adaptación Biológica , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Chaperonina 10/genética , Chaperonina 10/fisiología , Chaperonina 60/genética , Chaperonina 60/fisiología , Chaperoninas , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Proteínas de Escherichia coli/fisiología , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Mutagénesis Insercional , Mutación/genética , Mutación/fisiología , Mutación Puntual , Regiones Promotoras Genéticas , Respuesta SOS en Genética , Serina Endopeptidasas/fisiologíaRESUMEN
An insertion in rpoS, which encodes the general stress response sigma factor sigma 38, was isolated as an antimutator for 'stationary-phase' or 'adaptive' mutation. In the rpoS mutant strain the levels of error-prone DNA polymerase Pol IV were reduced. Pol IV is encoded by the dinB gene, and the amount of its transcript was also reduced in rpoS mutant cells. In wild-type cells, the levels of Pol IV increased in late stationary phase and stayed elevated for several days of continuous incubation, whereas in rpoS defective cells Pol IV was not induced and declined during prolonged incubation. Even in cells missing LexA, the repressor of dinB, maximum Pol IV expression required RpoS. These results suggest that induction of Pol IV is part of a cellular response to starvation and other stresses.