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The G-250A Promoter Polymorphism of the Hepatic Lipase Gene Predicts the Conversion from Impaired Glucose Tolerance to Type 2 Diabetes Mellitus: The Finnish Diabetes Prevention Study

Department of Medicine (B.T., A.K., J.P., M.L.) and Department of Clinical Nutrition (M.U.), University of Kuopio, 70210 Kuopio; Department of Epidemiology and Health Promotion (J.L., J.E., T.T.V., J.T.), Diabetes and Genetic Epidemiology Unit, National Public Health Institute, 00300 Helsinki; Research Department (H.H.), Social Insurance Institution, 20720 Turku; Department of Medicine (P.I.-P.), Finnish Diabetes Association and Tampere University Hospital, 33014 Tampere; Department of Public Health Science and General Practice (S.K.-K.), University of Oulu, Oulu University Hospital and Department of Sport Medicine (S.K.-K.), Oulu Deaconess Institute, 90220 Oulu; and Department of Public Health (J.T.), University of Helsinki, 00300 Helsinki, Finland

Address all correspondence and requests for reprints to: Markku Laakso, M.D., Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail: markku.laakso{at}kuh.fi.

In population-based studies, dyslipidemia related to insulin resistance (high triglyceride level and low high-density lipoprotein cholesterol level) is a risk factor for type 2 diabetes. Therefore, variants in genes regulating lipid and lipoprotein metabolism are potential candidate genes for diabetes. We investigated whether the G-250A polymorphism of the hepatic lipase gene (LIPC) predicts the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. This study randomized subjects to either the intervention group (lifestyle modification aimed at weight loss, such as changes in diet and increased physical exercise) or the control group. Genotyping at position –250 of the LIPC gene was performed with PCR amplification, DraI enzyme digestion, and gel electrophoresis in 490 subjects with IGT whose DNA was available. In the entire study population, the conversion rate to type 2 diabetes was 17.8% among subjects with the G-250G genotype and 10.7% among subjects with the –250A allele (P = 0.032). In univariate analysis, the odds ratio for the G-250G genotype to predict the conversion from IGT to type 2 diabetes was 1.80 (95% confidence interval, 1.05–3.10; P = 0.034). In multivariate logistic regression analysis, the G-250G genotype predicted the conversion to diabetes independently of the study group (control or intervention), gender, weight, waist circumference at baseline, and change in weight and waist circumference. In the intervention group, 13.0% of subjects with the G-250G genotype and 1.0% of the subjects with the –250A allele converted to diabetes (P = 0.001). We conclude that the G-250G genotype of the LIPC gene is a risk factor for type 2 diabetes. Therefore, genes regulating lipid and lipoprotein metabolism may be potential candidate genes for type 2 diabetes.

This work was supported by grants from the Academy of Finland (38387 and 46558 to J.T., and 40758 to M.U.), the EVO fund of the Kuopio University Hospital (5106 to M.U.), the Ministry of Education, the Finnish Diabetes Research Foundation, and the European Union (QLG1-CT-1999-00674 to M.L.).

Abbreviations: BMI, Body mass index; DPS, Diabetes Prevention Study; HDL-C, high-density lipoprotein cholesterol; HL, hepatic lipase; IGT, impaired glucose tolerance; LDL, low-density lipoprotein; LIPC, hepatic lipase gene.

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