Abstract/Summary

Low vitamin B12 concentrations have been shown to be risk factors for metabolic traits in numerous observational studies; however, the relationship has remained inconsistent. It is possible that certain genotypes might jointly contribute to obesity and vitamin B12 deficiency, and these may be modulated by lifestyle factors (dietary factors and physical activity levels) across different ethnic groups. The implementation of a genetic approach to establish the relationship between vitamin B12 and obesity could be a more desirable option over observational studies, as results are less prone to confounding factors. Hence, the main aims of this thesis were to examine for the first time the association of common vitamin B12-related single nucleotide polymorphisms (SNPs) and metabolic SNPs with vitamin B12 concentrations and metabolic outcomes in multiple ethnic groups. In addition, the interaction between these SNPs and dietary factors (protein, carbohydrate and fat) on vitamin B12 concentrations and metabolic traits was investigated. A total of five studies with different study designs were used. These studies included a case-control study (Chennai Urban Rural Study; CURES, Asian India, n=900), three cross-sectional cohort studies [Genetics of obesity and Diabetes study (GOOD study; Sinhalese Sri Lankan adults, n=109), The Minangkabau Indonesia Study on Nutrition and Genetics (MINANG study; Indonesian women; n=118) and Brazilian adolescents (n=113)] and a 16 week-dietary randomized, single-blind, parallel-group dietary intervention [Dietary Intervention and VAScular function (DIVAS study; British adults, n=119)]. Gene-diet interactions were observed in the Sri Lankan and Indonesian populations between the vitamin B12-related SNPs and protein energy intake (%) on markers of central obesity (waist circumference (P=0.002) and body fat percentage (P= 0.034), respectively). In the Brazilian adolescent population, the metabolic and vitamin B12 related SNPs showed a significant interaction with carbohydrate and protein intakes on oxidised low density lipoprotein cholesterol (P=0.005) and homocysteine concentrations (P = 0.007), respectively, which are well-known independent risk factors for cardiovascular disease. Additionally, in the Indonesian population, an interaction was observed between vitamin B12-related SNPs and dietary fibre intake (g) on glycated haemoglobin levels (P =0.042), a marker of long-term glycaemic status. Furthermore, for the first time, a novel association between two obesity-related SNPs and vitamin B12 concentrations (P = 0.018) was observed in the Indian population. In summary, these studies in multiple ethnic groups show that the relationship between B12 deficiency and metabolic outcomes may be influenced by dietary factors such as protein and fibre intake. However, in the Indian population, we found that vitamin B12 concentrations may be influenced by a genetic predisposition to obesity, but without a dietary influence. Given the limited sample size in some of the cohorts, replication of the study findings is highly warranted.