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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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| 2. |
- 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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| 3. |
- Franks, Paul W.
(författare)
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Body Weight and Risk of Early Death
- 2013
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Ingår i: Obesity. - : Wiley-Blackwell. - 1930-7381 .- 1930-739X. ; 21:9, s. 1743-1743
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
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| 5. |
- Franks, Paul W., et al.
(författare)
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Interaction Between Exercise and Genetics in Type 2 Diabetes Mellitus : An Epidemiological Perspective
- 2011
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Ingår i: Exercise Genomics. - TOTOWA : Humana Press. - 9781607613541 - 9781607613558 ; , s. 73-100
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Type 2 diabetes mellitus is a heterogeneous disease characterized by an inability to transport glucose from the blood into the cells. The disease has genetic and lifestyle determinants and probably results from the interaction of these risk factors. While this notion is widely accepted and endorsed, the available evidence is far from concrete. In this chapter the evidence that implicates physical inactivity and common genetic variation in type 2 diabetes risk will be described. Then, the fundamental concepts of gene × exercise interactions in type 2 diabetes will be defined by summarizing the evidence from epidemiological studies and clinical trials that have tested related hypotheses. The penultimate section of this chapter discusses the strengths and limitations of existing studies of interaction and outlines some of the common methodological hurdles inherent when testing hypotheses of gene × exercise interactions. The chapter concludes with a short section looking forward to where this field of research is heading and the possibilities for clinical translation.
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| 7. |
- Gradmark, Anna, 1981-, et al.
(författare)
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Physical activity, sedentary behaviors, and estimated insulin sensitivity and secretion in pregnant and non-pregnant women
- 2011
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aims Overweight and obesity during pregnancy raise the risk of gestational diabetes and birth complications. Lifestyle factors such as physical activity may decrease these risks through beneficial effects on systemic glucose homeostasis. Here we examined physical activity patterns and their relationships with measures of glucose homeostasis in late pregnancy compared to non-pregnant women. Methods Normal weight and overweight women without diabetes (N=108; aged 25-35 years) were studied; 35 were pregnant (in gestational weeks 28-32) and 73 were non-pregnant. An oral glucose tolerance test was conducted from which insulin sensitivity and β-cell response were estimated. Physical activity was measured during 10-days of free-living using a combined heart rate sensor and accelerometer. Total (TEE), resting (REE), and physical activity (PAEE) energy expenditure were measured using doubly-labeled water and expired gas indirect calorimetry. Results Total activity (counts/day) was associated with a reduced first-phase insulin response in both pregnant (r=-0.47; 95% CI: -0.70- to -0.15) and non-pregnant women (r=-0.36; 95% CI: -0.56- to -0.12). Pregnant women were estimated to have secreted more insulin (p=0.002) and had lower fasting glucose than non-pregnant women (p<0.0001). Measures of overall physical activity intensity were similar in both groups (p=0.547), but pregnant women spent more time sedentary (p<0.0001), less time in moderate-to-vigorous intensity activity (p<0.0001), had lower objectively measured total activity, and had lower physical activity energy expenditure (PAEE) than non-pregnant women (p=0.045). Conclusions Our findings suggest that physical activity conveys similar benefits on glucose homeostasis in pregnant and non-pregnant women, despite differences in subcomponents of physical activity.
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| 8. |
- Gradmark, Anna, 1981-
(författare)
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Validation and application of objective measures of obesity and physical activity : studies in pregnant and non-pregnant adults and in infants
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Excess adipose tissue and low physical activity are two major determinants for chronic diseases such as type 2 diabetes and cardiovascular disease. Understanding these relationships requires accurate and precise measures of body composition and physical activity, and most existing observational studies lack such measures. Paper I to III in this thesis addresses the validity of measures of physical activity and abdominal adipose mass. In paper IV and V, we explore the relationships between obesity and physical activity on metabolic health in non-pregnant and pregnant women and their offspring. Methods and Results Two hundred men and women representative of the Northern Sweden EPIC cohort were recruited for Paper I. A questionnaire on physical activity (PAQ) was validated against objectively measured physical activity energy expenditure (PAEE). A categorical physical activity index (Cambridge index) calculated from PAQ showed strongest correlation with PAEE (r=0.33 p<0.05). In Paper II, abdominal adiposity were assessed in 29 adult men and women using anthropometric measurements, dual energy x-ray absorptiometry (DXA) and ultrasound and were compared to computed tomography (CT). Waist circumference showed the highest correlation with CT-assessed visceral (r=0.85, p<0.0001) and subcutaneous adipose tissue (r=0.86, p<0.0001). Adipose thickness was best assessed with ultrasound. In Paper III, the validity of a wrist-worn triaxial accelerometer was assessed in 32 pregnant and 74 non-pregnant women using double-labeled water method (DLW) as the criterion measure. The output from the accelerometer explained 24% (p <0.001) of the variation in PAEE in non-pregnant and 11% (p<0.05) in the pregnant women. In Paper IV, 35 pregnant and 73 non-pregnant women underwent a 75g oral glucose tolerance test and habitual energy expenditure and physical activity was assessed objectively. Total physical activity was inversely associated with early insulin response in both pregnant (r=-0.47, p=0.007) and non-pregnant (r=-0.36, p=0.004) women. In, Paper V, 32 women and their offspring (n=33) were studied 4 months post-partum. Body composition was quantified using DXA in the women and air-displacement plethysmography in the infants. Mid-pregnancy weight gain was significantly associated with infant fat mass (r=0.41, p=0.022), whereas late-pregnancy weight gain associated to infant fat-free mass (r=0.37, p=0.04). Conclusion This work describes new methods as well as conventional anthropometric estimates and a questionnaire, that provide relatively strong estimates of body composition and physical activity which could be used in larger studies. Pregnant women were shown to have more sedentary behavior than non-pregnant but physical activity appeared to have equal effect on glucose homeostasis in both groups, which may help guide lifestyle interventions in pregnancy. The impact of weight gain during the different trimesters seems to differentially affect the offspring’s body composition in early infancy, which might give us clues to when different aspects of fetal development and growth occur and how modifiable lifestyle behaviors might be intervened upon to improve long-term health.
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| 9. |
- Pomeroy, Jeremy, et al.
(författare)
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Metabolic risk-factor profiles in infants in relation to those of their mothers during pregnancy
- 2011
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background Maternal characteristics during pregnancy such as BMI, weight gain, and glucose tolerance have been associated with anthropometric traits in their offspring. Here we extend these observations looking at the associations between maternal body composition, weight gain by trimester, and glucose tolerance and anthropometrics in their infants. Materials and methods Participants were 31 (16 female) singleton babies and their mothers (aged 25-35 yrs) in the eastern area of the county of Västerbotten in Sweden. Maternal weight was measured at gestational weeks 10-12, 28-32, and 37-41. Maternal body composition was assessed using isotope dilution and gestational glucose tolerance was assessed with a 2-hour, 75-gram oral glucose challenge at 28-32 weeks gestation. Infant body composition was assessed at 11-19 weeks of age using air- displacement plethysmography. The relationships between maternal and infant variables were assessed with Spearman correlations. Results Mid-pregnancy weight gain was significantly positively related to fat mass (r=0.41, p= 0.022) but not fat-free mass whereas late-pregnancy weight gain was significantly positively related to infant fat-free mass (r=0.37, p=0.04) but not fat mass. Maternal weight, body composition, or glucose tolerance was not significantly related to infant body composition. Early infancy growth (weight-for-length growth z-score) from 0 to 4 months was significantly related to infant percent fat (r=0.48, p=0.006). Gestational weight gain by trimester is differently related to body composition assessed in early infancy. Additionally, greater early infancy growth is associated with higher percent fat at 4 months of age. Both of these findings might identify targets for interventions conducted in pregnancy and during early life.
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