Genetic and dietary determinants of Type 2 diabetes in a black South African population

Abstract

Background: The increasing burden of T2D is a global cause of concern. However in Africa where the countries are ill equipped to manage this pandemic, the prevalence of T2D will increase the most by 2030 compared to other parts of the world. Urgent efforts are thus required to lessen the T2D pandemic. It is postulated that adoption of Westernised lifestyles among people who have a genetic predisposition to T2D is fuelling this epidemic. However, it is not clear which nutrient factors and genetic factors interact to increase T2D risk in the black South African population. We set out to determine 1) the predictive utility of the European and Asian derived variants associated with T2D in a black South African population; 2) the rare and low frequency variants associated with T2D using novel whole genome sequences of people of Setswana descent; 3) the nutrient patterns associated with glycated hemoglobin and fasting glucose in a black South African population. Methods: Four types of genetic risk scores (GRS) were computed using the 66 SNPs that had been associated with T2D in the Europeans and Asians. This comprised of the GRSt which consisted of all the 66 variants; GRSn that comprised of the variants associated with T2D in the black South African population of Sestwana descent; GRSb comprised of variants that had been characterised to be involved in the functioning of β cells and GRStrans which comprised of variants that were associated with T2D amongst varied ethnicities. Receiver operating curves (ROC) were used to evaluate the predictive utility of the GRS that was found to be associated with T2D. Extreme phenotype sampling was used to select 16 T2D cases and 14 controls from the tails of the glycated haemoglobin distribution after the adjustment of age, sex, BMI and fasting glucose for whole genome sequencing. The EPACTS software was used to conduct the single variant and gene-based association test using EMMAX to adjust for population structure using whole genome sequence data. Principal component analysis was applied onto 25 nutrients to determine the nutrient patterns in the study population. The associations of the extracted nutrient patterns with fasting glucose and glycated hemoglobin were evaluated. Results: The GRSn was the only polygenic risk score which was significantly associated with T2D in the study population. It was noted to modestly improve the predictive utility of the known risk factors by 2%. However, it was noted to be more predictive of risk among people who were lean and less than 50 years of age. The variant rs7499753 was observed to be associated with T2D beyond the genome wide significance level. However, replication studies are required to confirm this association. Starch, dietary fibre and B vitamins driven nutrient pattern was significantly associated with fasting glucose (β = -0.224 (-0.446; -0.002); p = 0.048), and glycated hemoglobin levels (β = -0.162 (-0.291; -0.033); p = 0.014) in rural women. Thiamine, zinc and plant protein driven nutrient pattern was associated with significant reductions in fasting glucose and glycated hemoglobin of (β = -0.435(-0.802; -0.067) p = 0.021) and (β = -0.301 (-0.554; -0.049); p = 0.020) in rural men. Conclusion: The GRS comprising of variants associated with T2D risk in the Setswana population improved modestly (by 2%) the prediction of this disease in addition to conventional risk factors. More population specific variants are required to develop a GRS that is more predictive of the T2D risk in the Setswana population. A new association of rs7499753 was documented that still needs to be confirmed through replication studies. More, well powered studies are required to whole genome sequence association studies through collaborative initiatives to elucidate more of the population specific variants associated with T2D among the Setswana population group. The consumption of plant based nutrients was noted to be associated with decreases in fasting and glycated hemoglobin. Clinical trials consisting of iso-caloric diets are required to further explore the nutrient patterns associated with T2D risk