Globally, cardiovascular disease (CVD) is a major cause for morbidity and mortality. Exaggerated postprandial lipaemia has been implicated in the development of atherosclerosis, and by lowering postprandial triacylglycerol (TAG) concentrations, atherogenic progression may be delayed. Many studies have revealed that exercise, in particular acute exercise, can attenuate postprandial TAG concentration. Most of this evidence relates to studies conducted in Western participants. South Asians are a population predisposed to CVD, and their adverse lipid profiles and physical inactivity may be among the underlying reasons. Hence, the studies described in this thesis examined the potential of acute bouts of exercise to favourably modify postprandial lipaemia and other CVD risk markers in young, healthy, South Asian men. The first experimental study described in this thesis compared the effect of 60 minutes of brisk walking on postprandial TAG concentration in 15 South Asian and 14 White European men. Trials were conducted over two days with exercise (or rest) taking place on day 1 and postprandial testing on day 2. A key finding from this study was that postprandial TAG, glucose and interleuklin-6 (IL-6) concentrations were elevated in South Asian compared with White European participants after consumption of high fat meals. This study also revealed a non-significant trend for brisk walking to reduce postprandial TAG concentrations in response to high fat meals in both groups. The second experimental study reported here examined the effect of 60 minutes of treadmill running at 70% of max on postprandial lipaemia and other CVD risk makers on the next day in 10 South Asian and 10 White European men. A significant main effect of trial was shown for postprandial TAG, IL-6 and soluble intercellular adhesion molecule-1 (sICAM-1), showing that TAG and IL-6 concentrations were lower on the exercise trial while sICAM-1 concentrations were higher on the exercise trial. In addition, ethnic group differences were observed for postprandial TAG, glucose and insulin concentrations indicating higher values in South Asians than White Europeans. A significant trial by group interaction effect was also observed for TAG, indicating a greater decrease after exercise in the South Asian men than the European men. In the third experimental study in this thesis the effect of 30 minutes of treadmill running on one day was compared with running for 30 minutes on three consecutive days in 11 South Asian men with regards to postprandial lipaemia. Neither a single bout of running nor three consecutive days of running influenced postprandial TAG in response to high fat meals when compared with the response on a control trial. It is not clear why exercise was ineffective in reducing postprandial lipaemia in this study but possibly the energy expenditure of exercise was insufficient to elicit change. The final experimental chapter described in this thesis combined the data from the first three studies. The objective of this chapter was to enhance the sample size in an effort to clarify the effects of acute exercise and to clarify the effects of ethnic group with respect to several fasting and postprandial CVD risk markers. The key findings were: 1) fasting and postprandial TAG and postprandial glucose concentrations were significantly reduced by exercise; 2) There were significant main effects of ethnic group for fasting high density lipoprotein cholesterol (HDL-C), total cholesterol/ HDL-C, IL-6 and systolic blood pressure (SBP), indicating lower values of HDL-C and SBP and higher values of total cholesterol/HDL-C and IL-6 in South Asian participants. Additionally, there were significant main effects of ethnic group for postprandial TAG and IL-6 indicating higher values in South Asian participants. Taken together, these data indicate that South Asians have an adverse CVD risk factor profile in comparison with White Europeans and this may explain, at least in part, their elevated risk of CVD. Importantly, the data produced within this thesis show for the first time that acute bouts of exercise can be effective for lowering postprandial plasma TAG concentrations in South Asians, at least transiently. Thus, exercise has the potential to serve as a non-pharmacological medicine in South Asians.

Background: Type 2 diabetes affects approximately 8% of the world’s population. Individuals of South Asian ancestry tend to develop metabolic abnormalities, leading to diabetes, at lower measures of absolute obesity and approximately 10 years earlier than white Caucasians. Current literature is unclear on the source of this ethnic heterogeneity; the variation in risk cannot be explained by lifestyle factors alone. The overarching aim of this thesis is to explore the role of genetic variants and epigenetic differences to explain the greater risk for type 2 diabetes among South Asians. Methods: We first conducted a systematic review of the literature to ascertain the genetic risk from known single nucleotide polymorphisms (SNPs) among South Asians. We then compared these risk estimates to those from white Caucasians in a cohort of 69,033 individuals. Second, using the EpiDREAM prospective cohort study of individuals at high-risk for diabetes, we assessed the impact of genetic burden for impaired pancreatic beta-cell function alone and together with abdominal obesity on glucose traits. Ethnic heterogeneity in this interaction was also studied. Lastly, using data from two Canadian birth cohorts of South Asian and white Caucasian ancestry, we investigated ethnic differences in the epigenetic architecture for genes known to be implicated birth weight and length, as both are associated with the future risk of adult diabetes. Results: The systematic review identified 15 SNPs robustly associated with type 2 diabetes in both South Asians and white Caucasians. The magnitude of risk and allele frequency of these genetic variants did not differ between the ethnic groups. Additionally, we identified 8 novel polymorphisms implicated in diabetes only among South Asians. Second, using data from the EpiDREAM study, we identified an interaction between cumulative genetic burden of beta-cell impairment, measured using an un-weighted genotype score, and abdominal obesity on glucose traits in South Asians, but not white Caucasians. Third, our investigation of differential DNA methylation between the ethnic groups revealed seven CpG sites for which changes in methylation corresponded to alterations in birth weight among white Caucasians, but not South Asians. An independent agnostic genome-wide search identified methylation levels at three CpG sites that appear to uniquely modulate birth weight in South Asians. Conclusions: Overall, our results indicate that the greater risk for metabolic traits in South Asians likely does not result from common genetic variants shared by both South Asians and white Caucasians. Rather, differences in risk may be additionally influenced by unique risk variants in South Asians. Furthermore, it appears that the risk from a genetic impairment in South Asians may be magnified by abdominal obesity. / Thesis / Doctor of Philosophy (PhD)

Background: Folate and vitamin B12 have interdependent metabolic functions that are essential for neonate growth outcomes (i.e. birth weight) based on studies from India. The objective of this research was to evaluate the association of maternal folate and vitamin B12 concentrations with neonate birth weight in South Asian (SA) and white European (WE) populations. Methods: In this cross-sectional analysis of prospective cohort studies, maternal and neonatal data were collected during the second trimester from 3758 mother-child dyads living in Canada. Maternal diet and supplement use were assessed using a validated food frequency questionnaire. Biochemical indicators were analyzed in a subset of SA mothers. Birth weight was measured within 72 hours of delivery. All regression analyses were performed unadjusted and with adjustment for identified covariates. Results: Maternal folate and vitamin B12 (dietary, supplemental and total) were not associated with neonate birth weight in SA and WE pregnant women. Higher consumption of milk products by SA women was associated with higher birth weight (β=0.06; p=0.01), whereas higher consumption of egg by WE women was associated with lower birth weight (β=-0.19; p<0.01). Folate and vitamin B12 deficiency in the SA subgroup was 13.7% and 17.8%, respectively. Maternal serum vitamin B12 status was inversely associated with birth weight (β=-0.16; p=0.03). Conclusions: Folate and vitamin B12 may be proxies for poor nutritional status. Therefore, folate and vitamin B12 may have an association with neonate birth weight in a less developed area (i.e. India) rather than in a highly developed area (i.e. Canada). Highly developed countries have an adequate intake of folate and vitamin B12 and thus a higher nutritional baseline status. These findings complement current research on folate and vitamin B12 concentrations with birth weight in well-nourished populations. / Thesis / Master of Science (MSc) / Infant birth weight is an indicator of health and disease risk in adult life. The mother’s vitamin intake can influence the weight of the infant. This research aimed to study whether the mother’s folate and vitamin B12 status is related to infant birth weight. Dietary and supplemental data along with blood samples from South Asian and white European pregnant women living in Canada were collected during the second trimester. The mother’s dietary, supplemental and total folate and vitamin B12 intakes were not related to infant birth weight. In South Asian mothers, higher milk intake was related to higher birth weight and in white Europeans, higher egg intake was related to lower infant birth weight. Higher vitamin B12 in the blood was related to lower infant birth weight in South Asians. More research is needed to determine the relationship between folate and vitamin B12 with infant birth weight.