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The -250G>A promoter variant in hepatic lipase associates with elevated fasting serum high-density lipoprotein cholesterol modulated by interaction with physical activity in a study of 16,156 Danish subjects.

https://arctichealth.org/en/permalink/ahliterature85800
Source
J Clin Endocrinol Metab. 2008 Jun;93(6):2294-9
Publication Type
Article
Date
Jun-2008
Author
Grarup Niels
Andreasen Camilla H
Andersen Mette K
Albrechtsen Anders
Sandbaek Annelli
Lauritzen Torsten
Borch-Johnsen Knut
Jørgensen Torben
Schmitz Ole
Hansen Torben
Pedersen Oluf
Author Affiliation
Steno Diabetes Center, Niels Steensens Vej 1, Gentofte, Denmark. ngrp@steno.dk
Source
J Clin Endocrinol Metab. 2008 Jun;93(6):2294-9
Date
Jun-2008
Language
English
Publication Type
Article
Keywords
Case-Control Studies
Cholesterol, HDL - blood
Cohort Studies
Denmark
Diabetes Mellitus, Type 2 - genetics
Fasting - blood
Genetic Predisposition to Disease
Genetic Screening
Genotype
Heterozygote
Humans
Insulin Resistance
Linkage Disequilibrium
Lipase - genetics
Motor Activity - genetics - physiology
Polymorphism, Single Nucleotide
Promoter Regions (Genetics)
Abstract
CONTEXT: Hepatic lipase plays a pivotal role in the metabolism of high-density lipoprotein (HDL) and low-density lipoprotein by involvement in reverse cholesterol transport and the formation of atherogenic small dense low-density lipoprotein. OBJECTIVES: The objective was to investigate the impact of variants in LIPC on metabolic traits and type 2 diabetes in a large sample of Danes. Because behavioral factors influence hepatic lipase activity, we furthermore examined possible gene-environment interactions in the population-based Inter99 study. DESIGN: The LIPC -250G>A (rs2070895) variant was genotyped in the Inter99 study (n = 6070), the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care Denmark screening cohort of individuals with risk factors for undiagnosed type 2 diabetes (n = 8662), and in additional type 2 diabetic patients (n = 1,064) and glucose-tolerant control subjects (n = 360). RESULTS: In the Inter99 study, the A allele of rs2070895 associated with a 0.057 mmol/liter [95% confidence interval (CI) 0.039-0.075] increase in fasting serum HDL-cholesterol (HDL-c) (P = 8 x 10(-10)) supported by association in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen Detected Diabetes in Primary Care study [0.038 mmol/liter per allele (95% CI 0.024-0.053); P = 2 x 10(-7)). The allelic effect on HDL-c was modulated by interaction with self-reported physical activity (P(interaction) = 0.002) because vigorous physically active homozygous A-allele carriers had a 0.30 mmol/liter (95% CI 0.22-0.37) increase in HDL-c compared with homozygous G-allele carriers. CONCLUSIONS: We validate the association of LIPC promoter variation with fasting serum HDL-c and present data supporting an interaction with physical activity implying an increased effect on HDL-c in vigorous physically active subjects carrying the -250 A allele. This interaction may have potential implications for public health and disease prevention.
PubMed ID
18364377 View in PubMed
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Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes.

https://arctichealth.org/en/permalink/ahliterature92941
Source
Diabetes. 2008 Sep;57(9):2534-40
Publication Type
Article
Date
Sep-2008
Author
Grarup Niels
Andersen Gitte
Krarup Nikolaj T
Albrechtsen Anders
Schmitz Ole
Jørgensen Torben
Borch-Johnsen Knut
Hansen Torben
Pedersen Oluf
Author Affiliation
Steno Diabetes Center, Copenhagen, Denmark. ngrp@steno.dk
Source
Diabetes. 2008 Sep;57(9):2534-40
Date
Sep-2008
Language
English
Publication Type
Article
Keywords
ADAM Proteins - genetics
Adult
Antigens, Neoplasm - genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 1 - genetics
Cell Cycle Proteins - genetics
Cohort Studies
Denmark - epidemiology
Diabetes Mellitus, Type 2 - diagnosis - epidemiology - genetics
Female
Genomics
Glucose Tolerance Test
Humans
Insulin Resistance - genetics
Male
Membrane Glycoproteins - genetics
Middle Aged
Neoplasm Proteins - genetics
Obesity - epidemiology - genetics
Risk factors
Abstract
OBJECTIVE: We evaluated the impact on diabetes-related intermediary traits of common novel type 2 diabetes-associated variants in the JAZF1 (rs864745), CDC123/CAMK1D (rs12779790), TSPAN8 (rs7961581), THADA (rs7578597), ADAMTS9 (rs4607103), and NOTCH2 (rs10923931) loci, which were recently identified by meta-analysis of genome-wide association data. RESEARCH DESIGN AND METHODS: We genotyped the six variants in 4,516 middle-aged glucose-tolerant individuals of the population-based Inter99 cohort who were all characterized by an oral glucose tolerance test (OGTT). RESULTS: Homozygous carriers of the minor diabetes risk G-allele of the CDC123/CAMK1D rs12779790 showed an 18% decrease in insulinogenic index (95% CI 10-27%; P = 4 x 10(-5)), an 18% decrease in corrected insulin response (CIR) (8.1-29%; P = 4 x 10(-4)), and a 13% decrease in the ratio of area under the serum-insulin and plasma-glucose curves during an OGTT (AUC-insulin/AUC-glucose) (5.8-20%; P = 4 x 10(-4)). Carriers of the diabetes-associated T-allele of JAZF1 rs864745 had an allele-dependent 3% decrease in BIGTT-AIR (0.9-4.3%; P = 0.003). Furthermore, the diabetes-associated C-allele of TSPAN8 rs7961581 associated with decreased levels of CIR (4.5% [0.5-8.4]; P = 0.03), of AUC-insulin/AUC-glucose ratio (3.9% [1.2-6.7]; P = 0.005), and of the insulinogenic index (5.2% [1.9-8.6]; P = 0.002). No association with traits of insulin release or insulin action was observed for the THADA, ADAMTS9, or NOTCH2 variants. CONCLUSIONS: If replicated, our data suggest that type 2 diabetes at-risk alleles in the JAZF1, CDC123/CAMK1D, and TSPAN8 loci associate with various OGTT-based surrogate measures of insulin release, emphasizing the contribution of abnormal pancreatic beta-cell function in the pathogenesis of type 2 diabetes.
PubMed ID
18567820 View in PubMed
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Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation.

https://arctichealth.org/en/permalink/ahliterature85084
Source
Diabetes. 2008 Jan;57(1):95-101
Publication Type
Article
Date
Jan-2008
Author
Andreasen Camilla H
Stender-Petersen Kirstine L
Mogensen Mette S
Torekov Signe S
Wegner Lise
Andersen Gitte
Nielsen Arne L
Albrechtsen Anders
Borch-Johnsen Knut
Rasmussen Signe S
Clausen Jesper O
Sandbaek Annelli
Lauritzen Torsten
Hansen Lars
Jørgensen Torben
Pedersen Oluf
Hansen Torben
Author Affiliation
Steno Diabetes Center, Niels Steensens Vej 1, NLC2.13, DK-2820 Gentofte, Denmark. cila@novonordisk.com
Source
Diabetes. 2008 Jan;57(1):95-101
Date
Jan-2008
Language
English
Publication Type
Article
Keywords
Adipose Tissue - anatomy & histology
Adult
Body mass index
Denmark
Diabetes Mellitus, Type 2 - complications - genetics
Female
Genotype
Glucose Intolerance - genetics
Humans
Linkage Disequilibrium
Male
Middle Aged
Motor Activity
Obesity - complications - genetics - physiopathology
Odds Ratio
Oxo-Acid-Lyases - genetics
Polymorphism, Genetic
Reference Values
Variation (Genetics)
Abstract
OBJECTIVE: Three independent studies have shown that variation in the fat mass and obesity-associated (FTO) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined. RESEARCH DESIGN AND METHODS: The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups. RESULTS: In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of rs9939609 associated with type 2 diabetes (odds ratio 1.13 [95% CI 1.06-1.20], P = 9 x 10(-5)). This association was abolished when adjusting for BMI (1.06 [0.97-1.16], P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13-1.24], P = 1 x 10(-12)) and obesity (1.27 [1.20-1.34], P = 2 x 10(-16)). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity (P = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 +/- 0.3 kg/m(2) increase in BMI compared with homozygous T-allele carriers. CONCLUSIONS: We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore, low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation.
PubMed ID
17942823 View in PubMed
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Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects: validation and extension of genome-wide association studies.

https://arctichealth.org/en/permalink/ahliterature84854
Source
Diabetes. 2007 Dec;56(12):3105-11
Publication Type
Article
Date
Dec-2007
Author
Grarup Niels
Rose Chrisian S
Andersson Ehm A
Andersen Gitte
Nielsen Arne L
Albrechtsen Anders
Clausen Jesper O
Rasmussen Signe S
Jørgensen Torben
Sandbaek Annelli
Lauritzen Torsten
Schmitz Ole
Hansen Torben
Pedersen Oluf
Author Affiliation
Steno Diabetes Center, Niels Steensens Vej 1, NLC2.14, 2820 Gentofte, Denmark. ngrp@steno.dk
Source
Diabetes. 2007 Dec;56(12):3105-11
Date
Dec-2007
Language
English
Publication Type
Article
Keywords
Adult
Cohort Studies
Cyclin-Dependent Kinase Inhibitor p15 - genetics
Cyclin-Dependent Kinase Inhibitor p16 - genetics
Denmark
Diabetes Mellitus, Type 2 - genetics
European Continental Ancestry Group - genetics
Genetic Predisposition to Disease
Genome, Human
Glucose Intolerance - genetics
Homeodomain Proteins - genetics
Humans
Insulin - secretion
Insulin-Like Growth Factor Binding Protein 2 - genetics
Introns
Middle Aged
Reference Values
Reproducibility of Results
Transcription Factors - genetics
Variation (Genetics)
Abstract
OBJECTIVE: In the present study, we aimed to validate the type 2 diabetes susceptibility alleles identified in six recent genome-wide association studies in the HHEX/KIF11/IDE (rs1111875), CDKN2A/B (rs10811661), and IGF2BP2 (rs4402960) loci, as well as the intergenic rs9300039 variant. Furthermore, we aimed to characterize quantitative metabolic risk phenotypes of the four variants. RESEARCH DESIGN AND METHODS: The variants were genotyped in the population-based Inter99 cohort (n = 5,970), the ADDITION Study (n = 1,626), a population-based sample of young healthy subjects (n = 377), and in additional type 2 diabetic case (n = 2,111) and glucose-tolerant (n = 521) subjects. The case-control studies involved a total of 4,089 type 2 diabetic patients and 5,043 glucose-tolerant control subjects. RESULTS: We validated association of variants near HHEX/KIF11/IDE, CDKN2A/B, and IGF2BP2 with type 2 diabetes. Interestingly, in middle-aged people, the rs1111875 C-allele of HHEX/KIF11/IDE strongly associated with lower acute insulin response during an oral glucose tolerance test (P = 6 x 10(-7)). In addition, decreased insulin release following intravenous tolbutamide injection was observed in young healthy subjects (P = 0.02). Also, a reduced insulin release was observed for the CDKN2A/B rs10811661 T-allele after both oral and intravenous glucose challenges (P = 0.001 and P = 0.009, respectively). CONCLUSIONS: We validate that variants in the proximity of the HHEX/KIF11/IDE, CDKN2A/B, and IFG2BP2 loci associate with type 2 diabetes. Importantly, variations within the HHEX/KIF11/IDE and CDKN2A/B loci confer impaired glucose- and tolbutamide-induced insulin release in middle-aged and young healthy subjects, suggesting a role for these variants in the pathogenesis of pancreatic beta-cell dysfunction.
PubMed ID
17827400 View in PubMed
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