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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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- Chikowore, Tinashe, et al.
(författare)
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GWAS transethnic meta-analysis of BMI in similar to 700k individuals reveals novel gene-smoking interaction in African populations
- 2020
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Ingår i: Genetic Epidemiology. - : John Wiley & Sons. - 0741-0395 .- 1098-2272. ; 44:5, s. 475-476
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Sixty two percent of the 1.12 billion obese people globally reside in low‐middle income countries, 77% of which are in Africa. There is paucity of data on gene‐lifestyle interactions associated with the increasing prevalence of obesity among Africans. We hypothesised that gene‐environment interacting (GEI) variants exhibit heterogenous effects on obesity in transethnic meta‐analysis of marginal SNP associations as a result of modification by an unknown exposure that varies across populations.Body mass index (BMI) genome‐wide association study (GWAS) summary statistics for 678,671 individuals representative of the major global ancestries were aggregated at 21,338,816 SNPs via fixed‐effects meta‐analysis. Lead SNPs attaining genome‐wide significance (P < 5 × 10−8) were tested for heterogeneity in effects between GWAS. Lead SNPs with significant evidence of heterogeneity after Bonferroni correction were then selected for interaction analysis with selected lifestyle factors in an independent AWI‐Gen study of 10,500 African participants. Significant interaction findings were then replicated in 3,177 individuals of African ancestry in the UK Biobank.Of 881 lead SNPs, five had significant heterogenous effects on BMI (P < 5.7 × 10−5). Rs471094, at the CDKAL1 locus had significant interaction with smoking status, which reduced the effect of the BMI raising allele in current smokers (Betaint = −0.949 kg/m2; P int = .002) compared with non‐smokers in AWI‐Gen. This finding was validated in the UK Biobank (Betaint = −1.471 kg/m2, P int = .020; meta‐analysis Betaint = −1.050 kg/m2, P int = .0002). Our results highlight the first gene‐lifestyle interaction on BMI in Africans and demonstrate the utility of transethnic meta‐analysis of GWAS for identifying GEI effects.
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- 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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- 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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