Given the strong evidence for a beneficial role of vitamin D in diabetes and CVD pathogenesis, and the prevalence of vitamin D deficiency, vitamin D supplementation has been advocated for the prevention of cardiometabolic disease. To provide information on the effects of 5,000IU (125µg) vitamin D3 on cardiometabolic risk, a double blind, RCT in a cohort of overweight and obese UK adult males with plasma 25(OH)D concentration < 75nmol/L for a duration of 8 weeks was conducted. To the best of my knowledge, this is the first RCT to investigate the effect of 5,000IU (125µg) vitamin D3 on cardiometabolic markers in vitamin D insufficient, non-hypertensive and non-diabetic overweight and obese adult males.

Background: Vitamin D may have beneficial effects on cardiometabolic disease, but the evidence is equivocal. This may be due to unaccounted confounders, such as lifestyle factors and genetic variation. We examined the association between circulating 25-hydroxyvitamin D [25(OH)D] and biomarkers of cardiometabolic disease risk, including biomarkers of inflammation, glycemic dysregulation and lipid metabolism, and a panel of 54 plasma proteomic biomarkers, and determined whether lifestyle variables and genetic variation modified these associations. Methods: Participants were from the Toronto Nutrigenomics and Health Study, an ethnically diverse population of individuals aged 20-29 years. Anthropometric measurements were obtained. Participants answered general health and lifestyle and food frequency questionnaires and provided a fasting blood sample for biochemical measurements and genotyping. Results: Across ethnic groups, women who used hormonal contraceptives (HC) had higher 25(OH)D and C-reactive protein (CRP) than women HC non-users and men. Circulating 25(OH)D was positively associated with CRP in the entire population in models not accounting for HC use. However, there was no association after accounting for HC use. 25(OH)D was also not associated with inflammatory cytokines after adjusting for HC use. 25(OH)D was inversely associated with insulin, HOMA-IR, and HOMA-Beta among Caucasians and East Asians and among men and women HC non-users. No biomarkers were associated with 25(OH)D among South Asians and women HC users, although non-significant inverse trends were observed for markers of glycemic dysregulation. Only two of the 54 plasma proteomic biomarkers were associated with 25(OH)D in women HC non-users, and none were associated in men. Among women HC users, after accounting for hormone dose, only three proteins were associated with 25(OH)D. Finally, 25(OH)D affected the association between rs2239182, a variant in the vitamin D receptor (VDR) and the pro-inflammatory cytokine interferon gamma-induced protein 10 (IP-10). However, the association was suggestive of heterosis and may have been due to chance. Conclusions: We identified a confounding effect of HC use on the association between 25(OH)D, biomarkers of inflammation and plasma proteomic biomarkers. In addition, HC use might also affect the association between 25(OH)D and biomarkers of glycemic dysregulation. Genetic variation in VDR did not modify any associations.

Background: Vitamin D may have beneficial effects on cardiometabolic disease, but the evidence is equivocal. This may be due to unaccounted confounders, such as lifestyle factors and genetic variation. We examined the association between circulating 25-hydroxyvitamin D [25(OH)D] and biomarkers of cardiometabolic disease risk, including biomarkers of inflammation, glycemic dysregulation and lipid metabolism, and a panel of 54 plasma proteomic biomarkers, and determined whether lifestyle variables and genetic variation modified these associations. Methods: Participants were from the Toronto Nutrigenomics and Health Study, an ethnically diverse population of individuals aged 20-29 years. Anthropometric measurements were obtained. Participants answered general health and lifestyle and food frequency questionnaires and provided a fasting blood sample for biochemical measurements and genotyping. Results: Across ethnic groups, women who used hormonal contraceptives (HC) had higher 25(OH)D and C-reactive protein (CRP) than women HC non-users and men. Circulating 25(OH)D was positively associated with CRP in the entire population in models not accounting for HC use. However, there was no association after accounting for HC use. 25(OH)D was also not associated with inflammatory cytokines after adjusting for HC use. 25(OH)D was inversely associated with insulin, HOMA-IR, and HOMA-Beta among Caucasians and East Asians and among men and women HC non-users. No biomarkers were associated with 25(OH)D among South Asians and women HC users, although non-significant inverse trends were observed for markers of glycemic dysregulation. Only two of the 54 plasma proteomic biomarkers were associated with 25(OH)D in women HC non-users, and none were associated in men. Among women HC users, after accounting for hormone dose, only three proteins were associated with 25(OH)D. Finally, 25(OH)D affected the association between rs2239182, a variant in the vitamin D receptor (VDR) and the pro-inflammatory cytokine interferon gamma-induced protein 10 (IP-10). However, the association was suggestive of heterosis and may have been due to chance. Conclusions: We identified a confounding effect of HC use on the association between 25(OH)D, biomarkers of inflammation and plasma proteomic biomarkers. In addition, HC use might also affect the association between 25(OH)D and biomarkers of glycemic dysregulation. Genetic variation in VDR did not modify any associations.

京都大学 / 新制・課程博士 / 博士(ゲノム医学) / 甲第25211号 / 医博JD第3号 / 新制||医JD||1(附属図書館) / 京都大学大学院医学研究科ゲノム医学国際連携専攻 / (主査)教授 村川 泰裕, 教授 平井 豊博, 教授 William Foulkes (ﾏｷﾞﾙ大学), 准教授 George Thanassoulis (ﾏｷﾞﾙ大学), 教授 Krzysztof Kiryluk (ｺﾛﾝﾋﾞｱ大学) / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Exposure to environmental pollutants poses numerous risk factors for human health, including increasing incidence of cardiovascular disease and diabetes. Persistent organic pollutants, such as polychlorinated biphenyls (PCBs) have been strongly linked to the development of these chronic inflammatory diseases and the primary route of exposure is through consumption of contaminated food products. Thus, the gastrointestinal tract is susceptible to the greatest levels of these pollutants and is an important facet to study. The first two hypotheses of this dissertation tested that exposure to PCBs disrupts gut microbiota directly (in vitro) and within a whole body system. PCB exposure disrupted microbial metabolism and production of metabolites (i.e. short chain fatty acids) in vitro. These disruptions in microbial populations were consistent in our mouse model of cardiometabolic disease, where we observed reductions in microbial diversity, an increase in the putative pro-inflammatory ratio of Firmicutes to Bacteroidetes, and reductions in beneficial microbial populations in exposed mice. Furthermore, observed greater inflammation was observed both within the intestines and peripherally in PCB exposed mice as well as disruptions in circulating markers associated with glucose homeostasis. Nutritional interventions high in prebiotic dietary fiber such as inulin may be able to attenuate the toxic effects of pollutant exposure. To test the hypothesis that consumption of the prebiotic inulin can decrease PCB-induced disruption in gut microbial and metabolic homeostasis, LDLr-\- mice were fed a diet containing inulin and exposed to PCB 126. Mice fed an inulin-containing diet and exposed to PCBs exhibited improved glucose tolerance, lower hepatic inflammation and steatosis, and distinct differences in gut microbial populations. Overall, these data suggests that nutritional intervention, specifically prebiotic consumption, may reduce pollutant-induced disease risk.

No description available.

Problématique : Les enfants ayant survécu à un cancer présentent un risque accru de développer des complications cardiométaboliques à long terme par rapport à leurs pairs. Cette étude vise à évaluer la faisabilité et l’impact du volet nutritionnel de l’intervention multidisciplinaire VIE (Valorisation, Implication, Éducation) pendant le traitement du cancer pédiatrique sur les apports alimentaires et la santé cardiométabolique des enfants après la fin de leur traitement. L’aspect multidisciplinaire de cette intervention impliquait également l’activité physique et la psychologie. Méthodologie : La faisabilité de l’étude, évaluée un an après le début de l’intervention, a inclus le taux de rétention, de participation, d’assiduité, d’achèvement des mesures de l’étude et d’engagement des participants. Suite à l’intervention, les participants qui ont été exposés à VIE ont fait l’objet d’une évaluation de fin d’étude, tandis que les participants d’un groupe contrôle ont fait l’objet d’une évaluation unique. Les données ont été recueillies 1,3 ± 0,8 an après la fin du traitement dans le groupe d’intervention et 1,4 ± 0,8 an dans le groupe de contrôle. Des mesures nutritionnelles (journal alimentaire de 3 jours et rappel de 24 heures), anthropométriques (poids, taille, tour de taille, tour brachial, pli cutané), biochimiques (profil lipidique, HbA1c, vitamine D) et de pression artérielle ont été recueillies. Résultats : Après un an d’intervention, le taux de rétention était de 72,6 %, 258 rencontres ont été menées sur 362 planifiées (taux de présence 71,6 %) et la moitié des participants (50,8 %) avaient participé à au moins 4 rencontres de suivi. À l’évaluation de fin d’étude, 45 participants de l’étude VIE (10,2 ± 4,5 ans) ont été comparés à 77 contrôles (12,0 ± 5,6 ans). Par rapport aux contrôles, les participants à l’étude VIE consommaient moins de calories (1997 ± 669 vs. 1759 ± 513, p=0,042) et avaient des apports en calcium ajustés à l’énergie plus élevés (548 ± 240 mg/1000 kcal vs. 432 ± 197 mg/1000 kcal, p=0,005). Les participants à l’étude VIE avaient également tendance à consommer davantage de fibres totales (9,2 ± 3,4 g/1000 kcal contre 8,4 ± 2,8 g/1000 kcal, p=0,188) et de vitamine D (2,6 ± 2,0 g/1000 kcal contre 2,2 ± 2,0 g/1000 kcal, p=0,311) que les contrôles. Aucune différence entre les groupes n’a été constatée en ce qui concerne les résultats anthropométriques ou cardiométaboliques. Conclusion : Cette étude montre que le volet nutritionnel d’une intervention multidisciplinaire, mise en œuvre rapidement après le diagnostic de cancer, est faisable et peut avoir un impact positif sur le régime alimentaire des enfants et des adolescents. Une implantation multicentrique avec le projet VIE-Québec permettra d’augmenter l’étendue des retombées positives. / Background : Children who have survived cancer have an increased risk of developing long-term cardiometabolic complications compared to their peers. The aim of this study is to assess the feasibility and impact of the nutritional component of the multidisciplinary VIE (Valorisation, Implication, Éducation) intervention during pediatric cancer treatment on children's dietary intake and cardiometabolic health after the end of their treatment. The multidisciplinary aspect of this intervention involved also physical activity and psychology. Methods: Study feasibility, assessed one year after the start of the intervention, included retention, participation, attendance, completion of study measures and participant engagement. Following the intervention, participants who had been exposed to VIE underwent an end-of-study assessment, while participants in a control group underwent a one-off assessment. Data were collected 1.3 ± 0.8 years after the end of treatment in the intervention group and 1.4 ± 0.8 years in the control group. Nutritional (3-day food diary and 24-hour recall), anthropometric (weight, height, waist circumference, brachial circumference, skin fold), biochemical (lipid profile, HbA1c, vitamin D) and blood pressure measurements were collected. Results: After one year of intervention, the retention rate was 72.6%, 258 appointments were conducted out of 362 planned (71.6% attendance rate) and half of the participants (50.8%) had attended at least 4 follow-up appointment. At the end-of-study assessment, 45 VIE participants (10.2 ± 4.5 years) were compared with 77 controls (12.0 ± 5.6 years). Compared to controls, VIE participants consumed fewer calories (1997 ± 669 vs. 1759 ± 513, p=0.042) and had higher energy-adjusted calcium intakes (548 ± 240 mg/1000 kcal vs. 432 ± 197 mg/1000 kcal, p=0.005). VIE participants also tended to consume more total fiber (9,2 ± 3,4 g/1000 kcal vs. 8,4 ± 2,8 g/1000 kcal, p=0.188) and vitamin D (2,6 ± 2,0 g/1000 kcal vs. 2,2 ± 2,0 g/1000 kcal, p=0.311) than controls. There were no differences between the groups in terms of anthropometric or cardiometabolic outcomes. Conclusions : This study shows that the nutritional component of a multidisciplinary intervention, implemented rapidly after cancer diagnosis, is feasible and can have a positive impact on the diet of children and adolescents. A multicenter implementation via the VIE-Québec project will increase the extent of the positive impact.

No description available.

Peripheral blood biomarkers can inform clinical care and drug development. Establishing causality between biomarker and disease is often critical for such applications, but epidemiological studies are limited due to biases from confounding and reverse causation. Mendelian randomization analysis leverages random inheritance of genetic variants at conception to mimic properties of randomized studies and estimate unconfounded effects between biomarker and disease, or vice-versa. This thesis demonstrates the utility of Mendelian randomization as a complementary tool to elucidate observational studies, predict drug safety and repurposing opportunities, and improve diagnostic biomarkers for cardiometabolic diseases. First, we characterized the hypothesized relationship between lipoprotein(a) and atrial fibrillation. We demonstrated both observed and genetically predicted lipoprotein(a) levels were associated with higher risk of atrial fibrillation across multiple independent cohorts. Importantly, risk was partly mediated independent of atherosclerotic cardiovascular disease, a known consequence of elevated lipoprotein(a) and itself a risk factor for atrial fibrillation. Next, we explored the lifelong effects of endogenous testosterone across a comprehensive set of 461 health outcomes in 161,268 males from the UK Biobank cohort. Using Mendelian randomization analysis, we found higher testosterone had beneficial effects on body composition and bone mineral density but adverse effects on prostate cancer, androgenic alopecia, spinal stenosis, and hypertension. Finally, we applied Mendelian randomization with the intention of discovering biomarkers caused by disease, which are expected to represent markers of early disease. As a proof-of-concept, we applied this framework to identify biomarkers associated with genetic predisposition to kidney function among 238 biomarkers measured in the ORIGIN trial. We discovered reduced kidney function caused increased trefoil factor 3 and showed its addition to models with known risk factors improved discrimination of incident early-stage chronic kidney disease. Taken together, Mendelian randomization identified biomarkers that warrant further study, with promising implications for screening, prevention, and treatment of different cardiometabolic diseases. / Thesis / Doctor of Philosophy (PhD) / Biological markers associated with disease can inform novel therapeutics or diagnostics but distinguishing causation from correlation is challenging. Mendelian randomization – a technique that leverages random inheritance of genetic variation to infer causality – was used to examine the role of biomarkers in cardiometabolic diseases. First, we implicated lipoprotein(a) as a risk factor for atrial fibrillation that acts independent of atherosclerotic cardiovascular disease. Second, we comprehensively characterized the lifelong effects of testosterone on health outcomes in males, where we found evidence of both beneficial and adverse effects on disease. Finally, we discovered trefoil factor 3 as a diagnostic marker for early-stage chronic kidney disease. Altogether, this thesis demonstrated different applications of Mendelian randomization that showcase its utility as a complementary tool to reveal causal biomarkers, and served to identify biomarkers for cardiometabolic diseases that merit further studies to evaluate their potential benefit on patient care.