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- Brito, Ema C, 1961-
(författare)
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Gene x lifestyle interactions in type 2 diabetes mellitus and related traits
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Type 2 diabetes is thought to result from interactions between genetic and lifestyle factors, but few robust examples exist. The overarching aim of this thesis was to discover such interactions by studying cohorts of white youth and adults from northern Europe in which physical activity, genotypes, and diabetes-related traits or diabetes incidence had been ascertained. Methods: The thesis includes four papers. In Paper I, we investigated associations and interactions between 35 common PPARGC1A polymorphisms and cardiovascular and metabolic disease traits in 2,101 Danish and Estonian children from the European Youth Heart Study (EYHS). Paper II used the same cohort to test associations and interactions on cardiometabolic traits for the diabetes-predisposing TCF7L2 polymorphism. In Paper III, we assessed associations for 17 type 2 diabetes gene polymorphisms on impaired glucose regulation (IGR) or incident type 2 diabetes, and tested whether these effects are modified by physical activity in a prospective cohort study of ~16,000 initially non-diabetic Swedish adults – the Malmö Preventive Project (MPP). Paper IV aimed to replicate main genetic effects and gene x physical activity interactions for an FTO polymorphism on obesity in 18,435 primarily non-diabetic Swedish (MPP) and Finnish (Prevalence, Prediction and Prevention of Diabetes in Botnia) adults. Results: In Paper I, nominally significant associations were observed for BMI (rs10018239, P=0.039), waist circumference (rs7656250, P=0.012; rs8192678 [Gly482Ser], P=0.015; rs3755863, P=0.02; rs10018239, P=0.043), systolic blood pressure (rs2970869, P=0.018) and fasting glucose concentrations (rs11724368, P=0.045). Stronger associations were observed for aerobic fitness (rs7656250, P=0.005; rs13117172, P=0.008) and fasting glucose concentrations (rs7657071, P=0.002). None remained significant after correcting for multiple statistical comparisons. We proceeded by testing for gene × physical activity interactions for the polymorphisms that showed statistical evidence of association (P<0.05) in the main effect models, but none was statistically significant. In Paper II, the minor T allele at the rs7903146 variant was associated with higher glucose levels in older (beta=–0.098 mmol/l per minor allele copy, P=0.029) but not in younger children (beta=–0.001 mmol/l per minor allele copy, P=0.972). A significant inverse association between the minor allele at rs7903146 and height was evident in boys (beta=–1.073 cm per minor allele copy, P=0.001), but not in girls. The test of interaction between the TCF7L2 rs7903146 variant and physical activity on HOMA-B was nominally statistically significant (beta=0.022, Pinteraction=0.015), whereby physical activity reduced the effect of the risk allele on estimated beta-cell function. In Paper III, tests of gene x physical activity interactions on IGR-risk for three polymorphisms were nominally statistically significant: CDKN2A/B rs10811661 (Pinteraction=0.015); HNF1B rs4430796 (Pinteraction=0.026); PPARG rs1801282 (Pinteraction=0.04). Consistent interactions were observed for the CDKN2A/B (Pinteraction=0.013) and HNF1B (Pinteraction=0.0009) variants on 2 hr glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed and this was for the HNF1B rs4430796 variant (Pinteraction=0.0004). The interaction effects for HNF1B on 2 hr glucose and incident diabetes remained significant after correction for multiple testing (Pinteraction=0.015 and 0.0068, respectively). In Paper IV, the minor A allele at rs9939609 was associated with higher BMI (P<0.0001). The tests of gene x physical activity interaction on BMI were not statistically significant in either cohort (Sweden: P=0.71, Finland: P=0.18). Conclusions: Variation at PPARGC1A is unlikely to have a major impact on cardiometabolic health in European children, but physical activity may modify the effect of the TFC7L2 variants on beta-cell function in this cohort. In Swedish adults, physical activity modifies the effects of common HNF1B and CDKN2A/B variants on risk of IGR and also modifies the effect of the HNF1B on type 2 diabetes risk. In Swedish and Finnish adults, we were unable to confirm previous reports of an interaction between FTO gene variation and physical activity on obesity predisposition.
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| 3. |
- Fawcett, Katherine A, et al.
(författare)
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Detailed investigation of the role of common and low-frequency WFS1 variants in type 2 diabetes risk
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:3, s. 741-746
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Tidskriftsartikel (refereegranskat)abstract
- We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing.
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| 4. |
- Fontaine-Bisson, B., et al.
(författare)
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Evaluating the discriminative power of multi-trait genetic risk scores for type 2 diabetes in a northern Swedish population
- 2010
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 53:10, s. 2155-2162
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Tidskriftsartikel (refereegranskat)abstract
- We determined whether single nucleotide polymorphisms (SNPs) previously associated with diabetogenic traits improve the discriminative power of a type 2 diabetes genetic risk score. Participants (n = 2,751) were genotyped for 73 SNPs previously associated with type 2 diabetes, fasting glucose/insulin concentrations, obesity or lipid levels, from which five genetic risk scores (one for each of the four traits and one combining all SNPs) were computed. Type 2 diabetes patients and non-diabetic controls (n = 1,327/1,424) were identified using medical records in addition to an independent oral glucose tolerance test. Model 1, including only SNPs associated with type 2 diabetes, had a discriminative power of 0.591 (p < 1.00 x 10(-20) vs null model) as estimated by the area under the receiver operator characteristic curve (ROC AUC). Model 2, including only fasting glucose/insulin SNPs, had a significantly higher discriminative power than the null model (ROC AUC 0.543; p = 9.38 x 10(-6) vs null model), but lower discriminative power than model 1 (p = 5.92 x 10(-5)). Model 3, with only lipid-associated SNPs, had significantly higher discriminative power than the null model (ROC AUC 0.565; p = 1.44 x 10(-9)) and was not statistically different from model 1 (p = 0.083). The ROC AUC of model 4, which included only obesity SNPs, was 0.557 (p = 2.30 x 10(-7) vs null model) and smaller than model 1 (p = 0.025). Finally, the model including all SNPs yielded a significant improvement in discriminative power compared with the null model (p < 1.0 x 10(-20)) and model 1 (p = 1.32 x 10(-5)); its ROC AUC was 0.626. Adding SNPs previously associated with fasting glucose, insulin, lipids or obesity to a genetic risk score for type 2 diabetes significantly increases the power to discriminate between people with and without clinically manifest type 2 diabetes compared with a model including only conventional type 2 diabetes loci.
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| 6. |
- Franks, Paul, et al.
(författare)
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Epigenetics and obesity: the devil is in the details
- 2010
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 8
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Obesity is a complex disease with multiple well-defined risk factors. Nevertheless, susceptibility to obesity and its sequelae within obesogenic environments varies greatly from one person to the next, suggesting a role for gene x environment interactions in the etiology of the disorder. Epigenetic regulation of the human genome provides a putative mechanism by which specific environmental exposures convey risk for obesity and other human diseases and is one possible mechanism that underlies the gene x environment/treatment interactions observed in epidemiological studies and clinical trials. A study published in BMC Medicine this month by Wang et al. reports on an examination of DNA methylation in peripheral blood leukocytes of lean and obese adolescents, comparing methylation patterns between the two groups. The authors identified two genes that were differentially methylated, both of which have roles in immune function. Here we overview the findings from this study in the context of those emerging from other recent genetic and epigenetic studies, discuss the strengths and weaknesses of the study and speculate on the future of epigenetics in chronic disease research. See research article: http://www.biomedcentral.com/1741-7015/8/87/abstract
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| 7. |
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| 8. |
- Franks, Paul W, et al.
(författare)
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Childhood obesity, other cardiovascular risk factors, and premature death.
- 2010
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 362:6, s. 485-493
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood. METHODS: In a cohort of 4857 American Indian children without diabetes (mean age, 11.3 years; 12,659 examinations) who were born between 1945 and 1984, we assessed whether body-mass index (BMI), glucose tolerance, and blood pressure and cholesterol levels predicted premature death. Risk factors were standardized according to sex and age. Proportional-hazards models were used to assess whether each risk factor was associated with time to death occurring before 55 years of age. Models were adjusted for baseline age, sex, birth cohort, and Pima or Tohono O'odham Indian heritage. RESULTS: There were 166 deaths from endogenous causes (3.4% of the cohort) during a median follow-up period of 23.9 years. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio, 2.30; 95% confidence interval [CI], 1.46 to 3.62). Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio, 1.73; 95% CI, 1.09 to 2.74). No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale, although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio, 1.57; 95% CI, 1.10 to 2.24). CONCLUSIONS: Obesity, glucose intolerance, and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. In contrast, childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes.
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| 9. |
- Franks, Paul W, et al.
(författare)
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Invited commentary : gene X lifestyle interactions and complex disease traits-inferring cause and effect from observational data, sine qua non
- 2010
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 172:9, s. 992-997
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Tidskriftsartikel (refereegranskat)abstract
- Observational epidemiology has made outstanding contributions to the discovery and elucidation of relations between lifestyle factors and common complex diseases such as type 2 diabetes. Recent major advances in the understanding of the human genetics of this disease have inspired studies that seek to determine whether the risk conveyed by bona fide risk loci might be modified by lifestyle factors such as diet composition and physical activity levels. A major challenge is to determine which of the reported findings are likely to represent causal interactions and which might be explained by other factors. The authors of this commentary use the Bradford-Hill criteria, a set of tried-and-tested guidelines for causal inference, to evaluate the findings of a recent study on interaction between variation at the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) locus and total energy intake with respect to prevalent metabolic syndrome and hemoglobin A₁(c) levels in a cohort of 313 Japanese men. The current authors conclude that the study, while useful for hypothesis generation, does not provide overwhelming evidence of causal interactions. They overview ways in which future studies of gene × lifestyle interactions might overcome the limitations that motivated this conclusion.
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| 10. |
- Gradmark, Anna M I, 1981-, et al.
(författare)
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Computed tomography-based validation of abdominal adiposity measurements from ultrasonography, dual-energy X-ray absorptiometry and anthropometry
- 2010
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Ingår i: British Journal of Nutrition. - 0007-1145 .- 1475-2662. ; 104:4, s. 582-588
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale aetiological studies of obesity and its pathological consequences require accurate measurements of adipose mass, distribution and subtype. Here, we compared the validity of three abdominal obesity assessment methods (dual-energy X-ray absorptiometry (DXA), ultrasound and anthropometry) against the gold-standard method of computed tomography (CT) in twenty-nine non-diseased middle-aged men (BMI 26.5 (sd 3.1) kg/m(2)) and women (BMI 25.5 (sd 3.2) kg/m(2)). Assessments of adipose mass (kg) and distribution (total subcutaneous (TSAT), superficial subcutaneous (SSAT), deep subcutaneous (DSAT) and visceral (VAT)) were obtained. Spearman's correlations were performed adjusted for age and sex. VAT area that was assessed using ultrasound (r 0.79; P < 0.0001) and waist circumference (r 0.85; P < 0.0001) correlated highly with VAT from CT, as did BMI (r 0.67; P < 0.0001) and DXA (r 0.70; P < 0.0001). DXA (r 0.72; P = 0.0004), BMI (r 0.71; P = 0.0003), waist circumference (r 0.86; P < 0.0001) and ultrasound (r 0.52; P = 0.015) were less strongly correlated with CT TSAT. None of the comparison measures of DSAT was strongly correlated with CT DSAT (all r approximately 0.50; P < 0.02). BMI (r 0.76; P < 0.0001), waist circumference (r 0.65; P = 0.002) and DXA (r 0.75; P < 0.0001) were all fairly strongly correlated with the CT measure of SSAT, whereas ultrasound yielded a weaker yet statistically significant correlation (r 0.48; P = 0.03). Compared with CT, visceral and subcutaneous adiposity can be assessed with reasonable validity using waist circumference and BMI, respectively. Ultrasound or DXA does not generally provide substantially better measures of these traits. Highly valid assessments of DSAT do not appear to be possible with surrogate measures. These findings may help guide the selection of measures for epidemiological studies of obesity.
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