A Nutrigenetic approach to investigate the effect of genetic and lifestyle factors on cardiometabolic-disease related traits in ethnically diverse populations.

Abstract

Cardiometabolic diseases such as cardiovascular diseases (CVD), obesity, hypertension and type 2 diabetes are a major cause of morbidity, mortality, and healthcare spending worldwide, especially in lower-middle-income countries. While cardiometabolic diseases are strongly affected by changes in environmental factors (such as unhealthy diet, sedentary lifestyle, and urbanization), they also have strong genetic determinants. Thus, understandings the role of gene–lifestyle interactions on cardiometabolic diseases and related traits can improve our understanding of disease pathophysiology and contribute to precision nutrition aiming to prevent and treat these diseases. Genome-wide association studies (GWAS) and candidate gene studies have revealed thousands of single nucleotide polymorphisms (SNPs) that have shown to be associated with cardiometabolic traits. However, these studies have been extensively performed in European populations, inadequately representing other ethnic groups. Genetic association studies of cardiometabolic diseases have great potential in terms of informing personalised and prevention medicine. This potential benefit, however, will only be understood by including populations of diverse ancestral backgrounds in these genetic studies. Hence, the main aims of this PhD work were to investigate the individual and joint effect of several SNPs on cardiometabolic disease-related traits in ethnically diverse populations. The interaction of these SNPs with lifestyle factors such as physical activity and dietary macronutrient intake on cardiometabolic disease-related traits was also assessed. This thesis included five different studies: three cross-sectional cohort studies [The Minangkabau Indonesia Study on Nutrition and Genetics (MINANG study; Indonesian women; n=110), The Genetics of Obesity and Nutrition in Ghana (GONG study; Ghanaian adults; n= 302) and The Obesity, Lifestyle and Diabetes in Brazil (BOLD study; Brazilian young adults; n= 200)] and two case-control studies [study in Turkish adults (n= 400) and Chennai Urban Rural Study (CURES; Asian Indian, n=1062)]. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software (version 24; SPSS Inc., Chicago, IL, USA). We found significant gene-protein interactions on central obesity risk (Pinteraction=0.044) in the Turkish population, on triglyceride levels and waist circumference (WC) (Pinteraction=0.003 and 0.002, respectively) in the Indonesian population, and on fasting blood glucose and glycated haemoglobin (Pinteraction=0.01 and 0.007, respectively) in the Indian population. Furthermore, there were GRS-fat intake interactions on WC in the Ghanaian population and on fasting insulin level (Pinteraction=0.017), insulin-glucose ratio (Pinteraction=0.010), homeostasis model assessment estimate of insulin secretion (HOMA-B) (Pinteraction=0.002) and homeostasis model assessment estimate of insulin resistance (HOMA-IR) (Pinteraction=0.051) in the Brazilian population. Also, a significant interaction between the fat mass and obesity-associated (FTO) SNP rs9939609 and physical activity on adiponectin concentrations was found in the Turkish population. In summary, the findings from this thesis contribute to the science of nutrigenetics by demonstrating the existence of genetic heterogeneity in gene-diet interactions on cardiometabolic disease-related traits across different ethnic groups. However, these findings need to be replicated using larger cohort and dietary intervention studies before they would be considered for personalised dietary recommendations, which are an innovative and promising approach for the prevention and treatment of cardiometabolic diseases