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Gene x lifestyle interactions in type 2 diabetes mellitus and related traits
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine. (Genetic Epidemiology and Clinical Research Group)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

 

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.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2010. , 115 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1324
Keyword [en]
Gene x environment interaction, gene x lifestyle interaction, physical activity, type 2 diabetes, European Youth Heart Study, Malmö Preventive Project, Prevalence and Prediction and Prevention of Diabetes in Botnia, PPARGC1A, CDKN2A/B, HNF1B, TCF7L2, FTO
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Epidemiology; Genetics
Identifiers
URN: urn:nbn:se:umu:diva-30523ISBN: 978-91-7264-932-3 (print)OAI: oai:DiVA.org:umu-30523DiVA: diva2:284492
Public defence
2010-01-29, Sal D, Tandläkarhögskolan, Umeå Universitet, 13:00 (English)
Opponent
Supervisors
Available from: 2010-01-18 Created: 2010-01-07 Last updated: 2010-04-10Bibliographically approved
List of papers
1. PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene x environment interactions in children from the European youth heart study
Open this publication in new window or tab >>PPARGC1A sequence variation and cardiovascular risk-factor levels: a study of the main genetic effects and gene x environment interactions in children from the European youth heart study
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2009 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 4, 609-613 p.Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: The PPARGC1A gene coactivates multiple nuclear transcription factors involved in cellular energy metabolism and vascular stasis. In the present study, we genotyped 35 tagging polymorphisms to capture all common PPARGC1A nucleotide sequence variations and tested for association with metabolic and cardiovascular traits in 2,101 Danish and Estonian boys and girls from the European Youth Heart Study, a multicentre school-based cross-sectional cohort study. METHODS: Fasting plasma glucose concentrations, anthropometric variables and blood pressure were measured. Habitual physical activity and aerobic fitness were objectively assessed using uniaxial accelerometry and a maximal aerobic exercise stress test on a bicycle ergometer, respectively. RESULTS: In adjusted models, 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, beta = -0.01 cm per minor allele copy, 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 the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association in the main effect models. None of these tests was statistically significant. CONCLUSIONS/INTERPRETATION: Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health in these children.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-23444 (URN)10.1007/s00125-009-1269-z (DOI)19183932 (PubMedID)
Available from: 2009-06-16 Created: 2009-06-16 Last updated: 2012-04-11Bibliographically approved
2. TCF7L2 gene variants influence growth, insulin secretion and glucose metabolism in children: the European youth heart study
Open this publication in new window or tab >>TCF7L2 gene variants influence growth, insulin secretion and glucose metabolism in children: the European youth heart study
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-30809 (URN)
Available from: 2010-01-18 Created: 2010-01-18 Last updated: 2010-01-18Bibliographically approved
3. Previously associated type 2 diabetes variants may interact with physical activity to modify the risk of impaired glucose regulation and type 2 diabetes: a study of 16,003 Swedish adults
Open this publication in new window or tab >>Previously associated type 2 diabetes variants may interact with physical activity to modify the risk of impaired glucose regulation and type 2 diabetes: a study of 16,003 Swedish adults
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2009 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, no 6, 1411-1418 p.Article in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-30810 (URN)10.2337/db08-1623 (DOI)
Available from: 2010-01-18 Created: 2010-01-18 Last updated: 2017-12-12Bibliographically approved
4. Assessing the effect of interaction between an FTO variant (rs9939609) and physical activity on obesity in 15,925 Swedish and 2,511 Finnish adults.
Open this publication in new window or tab >>Assessing the effect of interaction between an FTO variant (rs9939609) and physical activity on obesity in 15,925 Swedish and 2,511 Finnish adults.
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2009 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 52, no 7, 1334-1338 p.Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: Recent reports have suggested that genotypes at the FTO locus interact with physical activity to modify levels of obesity-related traits. We tested this hypothesis in two non-diabetic population-based cohorts, the first from southern Sweden and the second from the Botnia region of western Finland. METHODS: In total 2,511 Finnish and 15,925 Swedish non-diabetic middle-aged adults were genotyped for the FTO rs9939609 variant. Physical activity was assessed by questionnaires and standard clinical procedures were conducted, including measures of height and weight and glucose regulation. Tests of gene x physical activity interaction were performed using linear interaction effects to determine whether the effect of this variant on BMI is modified by physical activity. RESULTS: The minor A allele at rs9939609 was associated with higher BMI in both cohorts, with the per allele difference in BMI being about 0.13 and 0.43 kg/m(2) in the Swedish and Finnish cohorts, respectively (p < 0.0001). The test of interaction between physical activity and the rs9939609 variant on BMI was not statistically significant after controlling for age and sex in either cohort (Sweden: p = 0.71, Finland: p = 0.18). CONCLUSIONS/INTERPRETATION: The present report does not support the notion that physical activity modifies the effects of the FTO rs9939609 variant on obesity risk in the non-diabetic Swedish or Finnish adults studied here.

Keyword
Gene × environment interaction, gene × lifestyle interaction, genetic, physical activity, obesity, FTO, Swedish, Finnish
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-32407 (URN)10.1007/s00125-009-1355-2 (DOI)19373445 (PubMedID)
Available from: 2010-03-11 Created: 2010-03-11 Last updated: 2017-12-12Bibliographically approved

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