RESUMEN
BACKGROUND: Genome-wide association studies in Japanese populations recently identified common variants in the KCNQ1 gene to be associated with type 2 diabetes. We examined the association of these variants within KCNQ1 with type 2 diabetes in a Dutch population, investigated their effects on insulin secretion and metabolic traits and on the risk of developing complications in type 2 diabetes patients. METHODOLOGY: The KCNQ1 variants rs151290, rs2237892, and rs2237895 were genotyped in a total of 4620 type 2 diabetes patients and 5285 healthy controls from the Netherlands. Data on macrovascular complications, nephropathy and retinopathy were available in a subset of diabetic patients. Association between genotype and insulin secretion/action was assessed in the additional sample of 335 individuals who underwent a hyperglycaemic clamp. PRINCIPAL FINDINGS: We found that all the genotyped KCNQ1 variants were significantly associated with type 2 diabetes in our Dutch population, and the association of rs151290 was the strongest (OR 1.20, 95% CI 1.07-1.35, p = 0.002). The risk C-allele of rs151290 was nominally associated with reduced first-phase glucose-stimulated insulin secretion, while the non-risk T-allele of rs2237892 was significantly correlated with increased second-phase glucose-stimulated insulin secretion (p = 0.025 and 0.0016, respectively). In addition, the risk C-allele of rs2237892 was associated with higher LDL and total cholesterol levels (p = 0.015 and 0.003, respectively). We found no evidence for an association of KCNQ1 with diabetic complications. CONCLUSIONS: Common variants in the KCNQ1 gene are associated with type 2 diabetes in a Dutch population, which can be explained at least in part by an effect on insulin secretion. Furthermore, our data suggest that KCNQ1 is also associated with lipid metabolism.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Técnica de Clampeo de la Glucosa , Hiperglucemia/metabolismo , Insulina/metabolismo , Canal de Potasio KCNQ1/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Complicaciones de la Diabetes/genética , Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Secreción de Insulina , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To identify distinct developmental patterns of diabetic retinopathy (DR) and assess the risk factor levels of patients in these clusters. RESEARCH DESIGN AND METHODS: A cohort of 3,343 patients with type 2 diabetes mellitus (T2DM) monitored and treated in the Diabetes Care System West-Friesland, the Netherlands, was followed from 2 to 6 years. Risk factors were measured, and two-field fundus photographs were taken annually and graded according to the EURODIAB study group. Latent class growth modeling was used to identify distinct developmental patterns of DR over time. RESULTS: Five clusters of patients with distinct developmental patterns of DR were identified: A, patients without any signs of DR (88.9%); B, patients with a slow regression from minimal background to no DR (4.9%); C, patients with a slow progression from minimal background to moderate nonproliferative DR (4.0%); D, patients with a fast progression from minimal or moderate nonproliferative to (pre)proliferative or treated DR (1.4%); and E, patients with persistent proliferative DR (0.8%). Patients in clusters A and B were characterized by lower risk factor levels, such as diabetes duration, HbA(1c), and systolic blood pressure compared with patients in progressive clusters (C-E). CONCLUSIONS: Clusters of patients with T2DM with markedly different patterns of DR development were identified, including a cluster with regression of DR. These clusters enable a more detailed examination of the influence of various risk factors on DR.