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- 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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| 2. |
- Shungin, Dmitry, 1982-
(författare)
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Interplay between genetics and environment in obesity
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background. Being one of the largest current global health problems, obesity is a result of interplay between genetic and environmental factors. In this thesis we studied the genetic underpinning of adipose tissue distribution; investigated causality between obesity and periodontitis using instrumental variable analyses in genetic epidemiology settings; studied interactions between obesity-associated loci and physical activity on obesity; and checked if loci identified in genome-wide association studies are good candidates for gene-environment interactions using heterogeneity of variance analyses.Methods. In Paper 1 we performed a meta-analysis of large-scale genetic association studies for waist traits in 224,459 participants followed by a variety of statistical and bioinformatics methods to obtain insights into the biology of the underlying adipose distributions. In Paper 2 we used genetic variants associated with body mass index (BMI) as instruments within a Mendelian randomization framework to study causality between obesity and periodontitis in 49,066 participants. In Paper 3 we studied the interaction between an FTO single nucleotide polymorphism (SNP) rs9939609 and physical activity in obesity outcomes through meta-analysis of 237,434 participants. In Paper 4 we evaluated if SNPs established through main-effects meta-analysis of genome-wide association studies represent strong or weak candidates for gene-environment interactions, inferred by the degree of phenotypic heterogeneity across genotypes at a given SNP locus.Results. In Paper 1 we identified 49 loci (33 novel) associated with waist-to-hip ratio adjusted for BMI (P<5×10-8), 20 of which displayed significant sexual dimorphism, of which 19 displayed a stronger effect in women than in men. We also detected 19 additional loci newly associated with related waist and hip circumference measures. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insights into potential pathophysiological mechanisms. In Paper 2 we confirmed observational associations between BMI and periodontitis with a pooled odds ratio (OR) of 1.13 per standard deviation increase in BMI (95%CI:1.03, 1.24) in all participants and 1.25 (95%CI:1.10, 1.42) in participants with clinical data. The instrumental variable meta-analysis yielded an OR of 1.05 (95%CI:0.80, 1.38) per BMI standard deviation, and 0.90 (95%CI:0.56, 1.46) in participants with clinical data. In Paper 3 we showed that physical activity attenuates the influence of FTO variation in rs9939609 on obesity (Pinteraction=0.001) with the A allele of rs9939609 increasing the odds of obesity less in the physically active group, with a per-allele OR of 1.22 (95%CI:1.19, 1.25), than in the inactive group, with a per-allele OR of 1.30 (95%CI:1.24, 1.36). In Paper 4 we show that rank-ordered distributions of P-values between marginal effects genome-wide association studies (GWAS) and heterogeneity of variance analyses for all SNPs for BMI and lipid traits have very weak correlations for most traits (Spearman rho of 0.0034 for total cholesterol and 0.0044 for BMI for the squared phenotype residuals regression method) indicating that variants with strong marginal effects are in general poor candidates for gene-environment interactions based on heterogeneity of variance analyses, although a small number of variants convey strong marginal and variance effects, such as those at the FTO locus, meaning that they are likely to convey both marginal and interaction effects.Conclusion. The work outlined in this thesis sheds light on the complexity of genetic and environmental factors in obesity. We have identified novel loci associated with waist traits and described pathways implicated in adipose distribution. We have shown that based on Mendelian randomization analyses the association between periodontitis and obesity is unlikely to be causal. We have confirmed interactions between a bona-fide obesity locus (FTO) and physical activity on obesity and have shown that, in contrast to FTO, the majority of genetic variants identified through GWAS are unlikely to be good candidates for gene-environment interactions based on heterogeneity of variance analyses.
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