Proefschrift Universiteit van Amsterdam. / Met lit. opg. - Met samenvatting in het Nederlands.

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Pediatric obesity has reached epidemic proportions. Reducing obesity among children is expected to lower their likelihood of being obese as adults and, therefore, lower their cardiovascular and metabolic risk profile in adulthood including hypertension, dyslipidemia, type II diabetes, heart disease, and stroke. Pediatric obesity among ages 2–19 is defined as a body mass index (BMI) greater than or equal to the 95th percentile for age and gender as defined according to the CDC BMI-for-age growth charts. Risk factors for obesity are present as early as birth, suggesting exposures at different stages of the life cycle are important to study. The primary objective of this thesis was to evaluate exposures throughout childhood and evaluate their association with both weight and metabolic status. Study 1 examined the relationship between physical activity and metabolic syndrome in overweight and obese youth ages 12–19. We found that even modest amounts of moderate to vigorous physical activity were associated with a reduction in risk of metabolic syndrome, with time spent in vigorous physical activity driving the association. Study 2 explored the relationship between environmental tobacco smoke (ETS) exposure and childhood overweight and obesity in 3–6 year old children. We observed that ETS has a positive association with risk of overweight/obesity, with a dose-response effect observed. Study 3 examined the relationship between maternal antibiotic use during pregnancy and infant birthweight. We did not observe any association between maternal antibiotic use and birthweight or BW/GA-z (birthweight adjusted for gestational age z-score), but we did observe a reduction in risk of SGA (small for gestational age) for infants exposed to antibiotics during gestation. This association was most evident among third trimester users. / 2019-06-09T00:00:00Z

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Introduction: Le dalcétrapib est un inhibiteur de la protéine de transfert des esters de cholestérol (CETP) qui augmente le niveau du cholestérol-HDL. Des études d’association pangénomiques ont révélé une association entre les polymorphismes du gène adénylate cyclase de type 9 (ADCY9) et les réponses au dalcétrapib. Le but de cette étude était d’identifier le polymorphisme nucléotidique (SNP) causal, ce qui pourrait mener à comprendre le mécanisme moléculaire modifiant les effets du dalcétrapib sur les bénéfices cardiovasculaires. Méthodes: Des essais d’EMSA (electrophoretic mobility shift assay) ont été réalisés afin d’analyser les effets modificateurs de douze SNPs candidats sur la liaison de protéines nucléaires, provenant de cellules monocytaires THP-1. Ensuite, des essais de transfections avec un gène rapporteur ont été utilisées pour évaluer l’effet transcriptionnel de ces SNPs. La liaison des protéines au SNP rs12920508 a par la suite été étudiée par des chromatographies d’affinité d’ADN suivies par des spectrométries de masse et par MC-EMSA (multiplexed competitor EMSA). Résultats: Sept sur douze SNPs ont démontré une liaison spécifique à un allèle qui n’a pas été influencée par l’exposition des cellules au dalcétrapib. Le résultat des transfections de vecteurs rapporteurs dans les cellules THP-1 a montré que les constructions plasmidiques portant les variants rs1967309 et rs12920508 augmentaient l’activité transcriptionnelle. Onze protéines ont été identifiées comme des candidats potentiels pouvant se lier à la région du SNP rs12920508. De plus, la région contenant les deux variants rs1967309 et rs12920509 a présenté une activité transcriptionnelle accrue et significativement plus élevée pour l’haplotype délétère. Conclusion: Le polymorphisme rs1967309 semble causer la majorité des effets fonctionnels dans la lignée cellulaire THP-1. Cependant, une interaction avec le SNP rs12920508 ou la présence de la région de ce SNP pourrait être nécessaire pour l’activité optimale de rs1967309. Des travaux supplémentaires sont nécessaires pour élucider le lien entre le SNP potentiellement causal et les réponses cardiovasculaires induites par le dalcétrapib. / Introduction: Dalcetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that increases the circulating level of HDL-cholesterol. Genome-wide association studies have revealed an association between polymorphisms found in the adenylate cyclase type 9 (ADCY9) gene and responses to dalcetrapib, including its cardiovascular benefits. The purpose of this study was to identify the causal single nucleotide polymorphisms (SNP) which could lead to understand the molecular mechanisms altering dalcetrapib effects on cardiovascular outcomes. Methods: Electrophoretic mobility shift assays (EMSA) were performed to analyze the allele-specific effects of the best causal SNP candidates on binding with nuclear proteins obtained from a THP-1 monocytic cell line. Afterwards, a dual luciferase reporter assay was used to assess the effect of selected genetic variants on gene transcription. Protein binding to SNP rs12920508 was investigated by DNA-affinity chromatography followed by mass spectrometry and multiplexed competitor EMSA. Results: Seven out of 12 SNPs demonstrated allele-specific protein binding, which was not influenced by dalcetrapib exposure of the cells. Results from dual luciferase reporter assay showed that plasmid constructs bearing variants rs12920508 and rs1967309 increased transcriptional activity when transfected into THP-1 undifferentiated monocytic cells. Eleven proteins were identified as potential candidates binding to region of SNP rs12920508. Additionally, region containing both SNPs rs1967309 and rs12920508 displayed increased transcriptional activity with significantly higher activity for deleterious haplotype. Conclusion: Polymorphism rs1967309 seems to be causing most functional effects in the THP-1 monocytic cell line. However, an interaction with rs12920508 or presence of the DNA region of this SNP may be necessary for optimal activity of rs1967309. Further work is required to elucidate the link between potentially causal SNPs and cardiovascular responses induced by dalcetrapib.

Global obesity is linked to chronic diseases including hypercholesterolemia, a cardiovascular disease risk factor, thus weight reduction in obesity is a key priority for combatting obesity. The cholesterol transporters ABCG5, ABCG8 and NPC1L1 mediate cholesterol trafficking across the intestinal wall, thus are important in regulating cholesterol metabolism and circulating levels. The objective of this study was to examine if single nucleotide polymorphisms (SNP) of cholesterol transporters ABCG5, ABCG8 and NPC1L1 are associated with changes in cholesterol synthesis and absorption and lipid parameters (LP) subsequent to weight loss (WtL) in overweight individuals. Eighty-nine individuals from two WtL trials (Trial A (n = 54) and Trial B (n = 35)) completed a 20-wk WtL period. After 10% WtL, lipid parameters excluding LDL-C were improved in Trial A, while all lipid parameters were ameliorated after 12% of WtL when Trial A and B were combined. Post-WtL, cholesterol synthesis (CS) was reduced; however, cholesterol absorption was not changed in either Trial A or the combined trials. Polymorphisms in ABCG8 V632A were associated with changes in TC and TG levels after WtL in both trial A and the combined data. SNPs in ABCG5 Q604E, ABCG8 T400K, were associated with changes in CS because of WtL in Trial A; however, the association is no longer seen in combined analysis. In conclusion, cardio-protective changes in LP due to weight loss were mediated by reductions in CS. Additionally, polymorphisms in ABCG8 were associated with amelioration in LP after WtL. Thus, the benefits in CVD risk subsequent to weight loss vary across individuals due to genetic factors associated with cholesterol trafficking.

Global obesity is linked to chronic diseases including hypercholesterolemia, a cardiovascular disease risk factor, thus weight reduction in obesity is a key priority for combatting obesity. The cholesterol transporters ABCG5, ABCG8 and NPC1L1 mediate cholesterol trafficking across the intestinal wall, thus are important in regulating cholesterol metabolism and circulating levels. The objective of this study was to examine if single nucleotide polymorphisms (SNP) of cholesterol transporters ABCG5, ABCG8 and NPC1L1 are associated with changes in cholesterol synthesis and absorption and lipid parameters (LP) subsequent to weight loss (WtL) in overweight individuals. Eighty-nine individuals from two WtL trials (Trial A (n = 54) and Trial B (n = 35)) completed a 20-wk WtL period. After 10% WtL, lipid parameters excluding LDL-C were improved in Trial A, while all lipid parameters were ameliorated after 12% of WtL when Trial A and B were combined. Post-WtL, cholesterol synthesis (CS) was reduced; however, cholesterol absorption was not changed in either Trial A or the combined trials. Polymorphisms in ABCG8 V632A were associated with changes in TC and TG levels after WtL in both trial A and the combined data. SNPs in ABCG5 Q604E, ABCG8 T400K, were associated with changes in CS because of WtL in Trial A; however, the association is no longer seen in combined analysis. In conclusion, cardio-protective changes in LP due to weight loss were mediated by reductions in CS. Additionally, polymorphisms in ABCG8 were associated with amelioration in LP after WtL. Thus, the benefits in CVD risk subsequent to weight loss vary across individuals due to genetic factors associated with cholesterol trafficking.