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.
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.
OBJECTIVE: In people with screen-detected type 2 diabetes in primary care, (1) to assess adherence to guidelines, recommending consultation with the GP every three months and treatment initiation with an ACE inhibitor or an angiotensin-II receptor antagonist when systolic BP was > 120 mmHg and/or diastolic BP was > 80 mmHg, and (2) to identify predictors for adherence. DESIGN: Prospective follow-up of a fixed cohort of patients. SETTING: Fifty-four Danish general practices. SUBJECTS AND MAIN OUTCOME MEASURES: A total of 361 people with screen-detected type 2 diabetes were followed up for 410 days to assess planned consultations with their GP and recording of BP. Some 226 people, with BP recorded above guideline threshold(s) and where treatment was not already initiated, were followed for up to 410 days to monitor prescription redemption. RESULTS: At 3, 6, 9 and 12 months 80%, 77%, 74%, and 73% of the cohort attended a consultation. A total of 89% of the cohort attended two of the four planned consultations. The probability of redeemed prescriptions for an ACE inhibitor or an angiotensin-II receptor antagonist according to the guideline during the first year following diagnosis was 51%. High initial BP was associated with prescription redemption. No other analysed individual or organisational characteristics were found to be associated with treatment initiation. CONCLUSION: The consultation attendance was reasonably high, and treatment initiation with an ACE inhibitor or an angiotensin-II receptor antagonist according to the guideline was found in half of the cases. High initial BP increased the probability of treatment initiation.
BACKGROUND: Motivational interviewing has been shown to be broadly usable in a scientific setting in the management of behavioural problems and diseases. However, data concerning implementation and aspects regarding the use of motivational interviewing in general practice is missing. AIM:To evaluate GPs' conception of motivational interviewing in terms of methods, adherence to and aspects of its use in general practice after a course. STUDY DESIGN: In a randomised controlled trial concerning intensive treatment of newly diagnosed patients with type 2 diabetes detected by screening, the GPs were randomised to a course in motivational interviewing or not. The study also included a third group of GPs outside the randomised controlled trial, who had 2 years previously received a similar course in motivational interviewing. SETTING: General practice in Denmark. METHOD: The intervention consisted of a 1.5-day residential course in motivational interviewing with 0.5-day follow-ups, twice during the first year. Questionnaire data from GPs were obtained. RESULTS: We obtained a 100% response-rate from the GPs in all three groups. The GPs trained in motivational interviewing adhered statistically significantly more to the methods than did the control group. More than 95% of the GPs receiving the course stated that they had used the specific methods in general practice. CONCLUSION: A course in motivational interviewing seems to influence GPs professional behaviour. Based on self-reported questionnaires, this study shows that the GPs after a course in motivational interviewing seemed to change their professional behaviour in daily practice using motivational interviewing compared with the control group. GPs evaluated motivational interviewing to be more effective than 'traditional advice giving'. Furthermore, GPs stated that the method was not more time consuming than 'traditional advice giving'.
OBJECTIVE: We evaluated the association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes. RESEARCH DESIGN AND METHODS: We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n = 6,070), the Danish ADDITION study (n = 8,662), and in additional type 2 diabetic patients (n = 1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects. RESULTS: The minor alleles of rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P = 0.003), which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: 1.08 [1.03-1.14] per allele, P = 0.001). The diabetes-associated alleles also associated strongly with a higher plasma glucose at 30 and 120 min and serum insulin at 120 min during an oral glucose tolerance test (all P
OBJECTIVE: Within the frame of a randomized clinical trial to examine whether training of general practitioners (the intervention group) in intensive lifestyle modification and pharmacological treatment of patients with type 2 diabetes has a spillover effect on individuals with impaired fasting glycaemia (IFG) or impaired glucose tolerance (IGT). DESIGN: A high-risk screening study for type 2 diabetes with an intervention programme, where general practices were randomized to provide standard treatment versus intensive lifestyle modification and pharmacological treatment to newly diagnosed diabetic patients. SETTING: General practices in Denmark. SUBJECTS: Of 1821 individuals identified with IFG or IGT, results from oral glucose tolerance tests after one and three years were available in 1510 individuals. MAIN OUTCOME MEASURES: Progression rates from IFG and IGT to diabetes and effect of intervention were estimated in a regression model using interval censoring. RESULTS: A total of 442 persons developed diabetes. There was no significant overall effect of intervention on progression rates. For risk factors, no difference in rate of change was found between randomization groups, but a difference was found between general practices within the same randomization groups. CONCLUSION: General practitioners identify a high number of incident diabetes cases in individuals with IFG or IGT found by high-risk screening. Intervention at the general practitioner's level in intensive treatment type 2 diabetes does not have a significant spillover effect reducing the risk of diabetes from pre-diabetic conditions. This could indicate that intervention strategies should be specifically targeted at individuals with IFG or IGT, either by training general practitioners or directly at the individual level.
Lack of association between PKLR rs3020781 and NOS1AP rs7538490 and type 2 diabetes, overweight, obesity and related metabolic phenotypes in a Danish large-scale study: case-control studies and analyses of quantitative traits.
BACKGROUND: Several studies in multiple ethnicities have reported linkage to type 2 diabetes on chromosome 1q21-25. Both PKLR encoding the liver pyruvate kinase and NOS1AP encoding the nitric oxide synthase 1 (neuronal) adaptor protein (CAPON) are positioned within this chromosomal region and are thus positional candidates for the observed linkage peak. The C-allele of PKLR rs3020781 and the T-allele of NOS1AP rs7538490 are reported to strongly associate with type 2 diabetes in various European-descent populations comprising a total of 2,198 individuals with a combined odds ratio (OR) of 1.33 [1.16-1.54] and 1.53 [1.28-1.81], respectively. Our aim was to validate these findings by investigating the impact of the two variants on type 2 diabetes and related quantitative metabolic phenotypes in a large study sample of Danes. Further, we intended to expand the analyses by examining the effect of the variants in relation to overweight and obesity. METHODS: PKLR rs3020781 and NOS1AP rs7538490 were genotyped, using TaqMan allelic discrimination, in a combined study sample comprising a total of 16,801 and 16,913 individuals, respectively. The participants were ascertained from four different study groups; the population-based Inter99 cohort (nPKLR = 5,962, nNOS1AP = 6,008), a type 2 diabetic patient group (nPKLR = 1,873, nNOS1AP = 1,874) from Steno Diabetes Center, a population-based study sample (nPKLR = 599, nNOS1AP = 596) from Steno Diabetes Center and the ADDITION Denmark screening study cohort (nPKLR = 8,367, nNOS1AP = 8,435). RESULTS: In case-control studies we evaluated the potential association between rs3020781 and rs7538490 and type 2 diabetes and obesity. No significant associations were observed for type 2 diabetes (rs3020781: pAF = 0.49, OR = 1.02 [0.96-1.10]; rs7538490: pAF = 0.84, OR = 0.99 [0.93-1.06]). Neither did we show association with overweight or obesity. Additionally, the PKLR and the NOS1AP genotypes were demonstrated not to have a major influence on diabetes-related quantitative metabolic phenotypes. CONCLUSION: We failed to provide evidence of an association between PKLR rs3020781 and NOS1AP rs7538490 and type 2 diabetes, overweight, obesity or related quantitative metabolic phenotypes in large-scale studies of Danes.
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.
BACKGROUND: The INSIG2 rs7566605 and PFKP rs6602024 polymorphisms have been identified as obesity gene variants in genome-wide association (GWA) studies. However, replication has been contradictory for both variants. The aims of this study were to validate these obesity-associations through case-control studies and analyses of obesity-related quantitative traits. Moreover, since environmental and genetic factors may modulate the impact of a genetic variant, we wanted to perform such interaction analyses. We focused on physical activity as an environmental risk factor, and on the GWA identified obesity variants in FTO (rs9939609) and near MC4R (rs17782313) as genetic risk factors. MATERIALS AND METHODS: The four variants were genotyped in a combined study sample comprising a total of 18,014 subject ascertained from, the population-based Inter99 cohort (n = 6,514), the ADDITION screening cohort (n = 8,662), a population-based study sample (n = 680) and a type 2 diabetic patient group (n = 2,158) from Steno Diabetes Center. RESULTS: No association with overweight, obesity or obesity-related measures was shown for either the INSIG2 rs7566605 or the PFKP rs6602024 variants. However, an interaction between the INSIG2 rs7566605 variant and the level of self-reported physical activity (p(Int) = 0.004) was observed. A BMI difference of 0.53 (SE 0.42) kg/m(2) was found when comparing physically passive homozygous C-allele carriers with physically passive G-allele carriers. No interactions between the two variants and FTO rs9939609 and MC4R rs17782313 were observed. CONCLUSIONS: The INSIG2 rs7566605 and PFKP rs6602024 polymorphisms play no apparent role in the development of common forms of obesity in the Danish population. However, if replicated, the INSIG2 rs7566605 may influence the level of BMI in combination with the level of physical activity.
BACKGROUND: The prevalence of type 2 diabetes is increasing, but the exact prevalence of the disease and its accompanying late complications are unknown. In the Anglo-Danish-Dutch study of Intensive Treatment in People with Screen-detected Diabetes in Primary Care (ADDITION study), patients with hitherto undiagnosed type 2 diabetes are identified using a stepwise screening strategy in selected general practices. This article reports the occurrence of diabetic retinopathy in this population. METHODS: In Arhus and Copenhagen counties, a total of 12,708 of the persons invited by mail were screened for diabetes mellitus. Consequently, 763 persons with type 2 diabetes were identified; 670 of these (335 from each of the two centres) underwent a general physical examination (including measurement of blood pressure and HbA1c) and an ophthalmological examination (including measurement of visual acuity and fundus photography). Retinopathy was graded from the photographs by counting all retinopathy lesions. RESULTS: Forty-five (6.8%) of the examined patients had any retinopathy, of which the majority was minimal. No patients had severe non-proliferative or proliferative diabetic retinopathy. There was no significant difference between age, sex and visual acuity among patients with and without retinopathy. However, the patients with retinopathy had significantly higher HbA1c and systolic and diastolic blood pressure than the patients without retinopathy. CONCLUSION: Patients with screen-detected diabetes have a low prevalence of diabetic retinopathy and no vision-threatening lesions. Screening for diabetic retinopathy should be focused on those patients who have already been diagnosed with type 2 diabetes during routine clinical practice.
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.
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.