Association between the MTNR1B, HHEX, SLC30A8, and TCF7L2 single nucleotide polymorphisms and cardiometabolic risk profile in a mixed ancestry South African population.

Single nucleotide polymorphisms of the TCF7L2, HHEX, SLC30A8, MTNR1B, SLC2A2 and GLIS3 genes are well established candidate genes for cardiometabolic diseases (CMDs) across different ethnic populations. We investigated their association with CMDs in a mixed ancestry population of South Africa. rs10830963, rs1111875, rs11920090, rs13266634, rs7034200 and rs7903146 SNPs were genotyped by quantitative real time PCR in 1650 participants and Hardy-Weinberg equilibrium (HWE) analyses performed on the SNPs. Diabetes, obesity, hypertension and cardiometabolic traits were compared across genotypes of SNPs in HWE. Linear and logistic regressions adjusting for age, gender and body mass index were used to determine the risk of T2DM, obesity and hypertension. rs7903146 (p = 0.055), rs1111875 (p = 0.465), rs13266634 (p = 0.828), and rs10830963 (p = 0.158) were in HWE. The rs10830963 recessive genotype was able to predict FPG, insulin and HOMA-IR, while the rs1111875 recessive genotype was able to predict total cholesterol, triglyceride, LDL cholesterol and FPG. The rs7903146 recessive genotype was able to predict SBP and LDL cholesterol. The recessive genotypes of MTNRIB and HHEX SNPs were associated with T2DM traits in the study population and could partially explain the high prevalence of T2DM. Further studies are required to confirm these findings and establish candidate genes in the African population.

The 7-Year Change in the Prevalence of Insulin Resistance, Inflammatory Biomarkers, and Their Determinants in an Urban South African Population.

BACKGROUND: Insulin resistance (IR) and subclinical inflammation are involved in pathological pathways leading to the development of biological cardiovascular risk factors and subsequent cardiovascular events. Therefore, monitoring these processes can provide advanced information on the trajectory of cardiovascular risk profile of a population and inform prevention and control strategies. We investigated changes in IR and subclinical inflammation in a population from Cape Town, South Africa, between 2008/09 and 2014/16. METHODS: In a total of 2503 (n = 797, 2008/09) and (n = 1706, 2014/16) participants, IR was calculated using five indices, i.e., insulin fasting, HOMA-IR, QUICKI, McAuley, and Matsuda while subclinical inflammation was measured using usCRP and gamma GT. Linear and logistic regression analyses and interaction tests were conducted. RESULTS: The mean age of participants was 53.2 (2008/09) and 48.2 (2014/16), respectively. In females, IR prevalence significantly decreased between 2008/09 and 2014/2016 by all indices (p ≤ 0.021), while subclinical inflammation prevalence increased from 54.7% (2008/09) to 57.1% (2014/16) based on usCRP and 29.6% to 33.4% based on gamma GT. In a multivariate analysis adjusted for the year of study, age, and gender, prominent factors associated with increased IR or subclinical inflammation were obesity levels measured using waist circumference, glycated haemoglobin, and fasting insulin levels. CONCLUSIONS: Over the 7-year period, subclinical inflammation increased and this was associated with IR and the metabolic syndrome components, both of which are strong predictors of CVDs. The decrease in IR over the year period reflects in part the much younger age in the second survey.

Gene of the month: APOL1.

Apolipoprotein L1 (APOL1) is a protein encoded by the APOL1 gene, found only in humans and several primates. Two variants encoding two different isoforms exist for APOL1, namely G1 and G2. These variants confer increased protection against trypanosome infection, and subsequent African sleeping sickness, and also increase the likelihood of renal disease in individuals of African ancestry. APOL1 mutations are associated with increased risk of chronic kidney disease, inflammation, and exacerbation of systemic lupus erythematosus-associated renal dysfunction. This review serves to outline the structure and function of APOL1, as well as its role in several disease outcomes.

Changes in Obesity Phenotype Distribution in Mixed-ancestry South Africans in Cape Town Between 2008/09 and 2014/16.

Background: The concept of obesity phenotypes encompasses a different approach to evaluating the relationship between obesity and cardiometabolic diseases. Considering the minimal research on obesity phenotypes in Africa, we investigated these changes from 2008/09 to 2014/16 in the mixed ancestry population in Cape Town, South Africa. Methods: In all, 928 (2008/09) and 1969 (2014/16) ≥20 year old participants were included in two community-based cross-sectional studies. For obesity phenotype classification, a combination of body mass index (BMI) categories and prevalent cardiometabolic disease risk factors were used, with the presence of ≥2 cardiometabolic abnormalities defining abnormal metabolic status. Interaction tests were used to investigate changes in their distribution across the years of study. Results: Distribution of BMI categories differed significantly between the 2 years; normal weight, overweight and obese: 27.4, 27.4, and 45.3% in 2008/09 vs. 34.2, 23.6, and 42.2% in 2014/16 (p = 0.001). There was no differential effect in the distribution of obesity phenotypes pattern across the two time-points (interaction p = 0.126). Across BMI categories, levels of cardiometabolic risk factors linearly deteriorated in both metabolically healthy and abnormal participants (all p ≤ 0.018 for linear trends). Findings were not sensitive to the number of metabolic abnormalities included in the definition of obesity phenotypes. Conclusions: Our study showed negligible differences in obesity phenotypes over time, but a high burden of metabolic abnormalities among normal weight participants, and a significant proportion of metabolically health obese individuals. Further investigation is needed to improve risk stratification and cost-effective identification of individuals at high risk for cardiometabolic diseases.

No evidence for association of insulin receptor substrate-1 Gly972Arg variant with type 2 diabetes mellitus in a mixed-ancestry population of South Africa.

BACKGROUND: The most common single-nucleotide polymorphism in the insulin receptor substrate-1 (IRS1) gene is Gly972Arg, which is associated with a 25% increased risk of developing diabetes. The mixed-ancestry population of South Africa (SA) has one of the highest prevalences of type 2 diabetes mellitus (T2DM) in Africa. OBJECTIVE: To report the frequency of IRS1 Gly972Arg and investigate its associations with cardiometabolic traits. METHODS: DNA from 856 mixed-ancestry adults drawn from an urban community of Bellville South, Cape Town, SA, was genotyped by two independent laboratories. Oral glucose tolerance tests were performed and cardiometabolic risk factors measured. RESULTS: A total of 237 (24.7%) participants had T2DM. The IRS1 Gly972Arg variant was present in 7.9% of the individuals studied and only one participant (non-diabetic) carried the homozygous A/A variant. In linear and logistic regression analyses, Gly972Arg was not associated with obesity, insulin resistance/sensitivity or T2DM. CONCLUSIONS: The prevalence of the Gly972Arg variant in the mixed-ancestry population of SA is comparable to that reported in African Americans, but its presence is not associated with cardiometabolic traits. This suggests that the Gly972Arg variant may not aid diabetes risk evaluation in this setting, nor can such information help explain the high prevalence of diabetes previously reported in this population.

Gamma-glutamyltransferase, insulin resistance and cardiometabolic risk profile in a middle-aged African population.

BACKGROUND: Mechanisms linking liver functions with cardiometabolic risk may involve insulin resistance (IR) and non-alcoholic fatty liver disease. We assessed the associations of gamma-glutamyltransferase (GGT) levels with IR and metabolic syndrome (MetS) in an adult South African urban cohort. METHODS: 1198 participants aged >15 years (297 men) were drawn from the Bellville-South suburb (Cape Town). The homeostatic model assessment of insulin (HOMA-IR), ß-cells function (HOMA-B%), fasting insulin resistance index (FIRI) and the quantitative insulin-sensitivity check index (QUICKI) were calculated, and MetS defined according to the Join Interim Statement 2009 criteria. Associations of GGT levels with covariates were assessed on a continuous scale and across sex-specific quarters of GGT, with adjustment for confounders via generalized linear and logistic regressions. RESULTS: Indicators of IR (HOMA-IR, FIRI and fasting insulin) increased, whereas those for insulin sensitivity (Sib and QUICKI) diminished significantly linearly and across increasing GGT quarters. In multivariable-adjusted models, adjustment for sex, age, BMI, cigarette smoking and alcohol intake yielded the strongest, significant associations between GGT and all markers of IR/IS and glycemia excluding glucose insulin ratio. In a similar level of adjustments, with/without further adjustment for markers of IR/insulin sensitivity, the prevalence of MetS significantly increased across quarters of GGT. CONCLUSIONS: GGT levels were independently associated with insulin sensitivity and MetS in this population. Unaccounted, chronic elevation of GGT may therefore be a cue to screen and monitor individuals for MetS and diabetes, and may warrant consideration as an indicator of high risk for the development of these metabolic disorders.

Associations of MC3R polymorphisms with physical activity in South African adolescents.

BACKGROUND: There is evidence demonstrating that the contribution of sedentary behavior and effect of physical activity on metabolic phenotypes is mediated by polymorphisms in genes. METHODS: The type and frequency of physical activity was assessed by means of structured questionnaires in 1555 South African school learners. Anthropometric measurements, blood pressure, fasting blood glucose and lipids were measured using standard procedures. The effect of different types and frequency of physical activity on obesity-related traits was assessed in relation to MC3R T6K and V81I genotypes in 430 of the learners. RESULTS: Levels of total cholesterol were significantly lower in learners carrying the MC3R T6K and V81I minor alleles, after adjusting for age, race, gender, and each specific physical activity category. An activity-by-genotype interaction was also detected: learners heterozygous for the V81I polymorphism and performed house chores often had reduced total cholesterol. Though no association was observed between frequency of physical activity and BMI, television viewing was significantly associated with an increase in height, weight and marginally with waist circumference. CONCLUSION: Our findings suggest that physical activity even in the form of house chores has a positive effect on metabolic traits and this effect is further enhanced in the presence of MC3R polymorphisms.

High prevalence of diabetes mellitus and metabolic syndrome in a South African coloured population: baseline data of a study in Bellville, Cape Town.

OBJECTIVE: The coloured population has the second-highest prevalence of diabetes in South Africa. However, the data were based on a study conducted almost 20 years ago in a peri-urban coloured population of the Western Cape. We aimed to determine the prevalence of diabetes mellitus and metabolic syndrome in an urban coloured population in South Africa. DESIGN: In a cross-sectional survey, 642 participants aged ≥31 years were drawn from an urban community of Bellville South, Cape Town, from mid-January 2008 to March 2009. Type 2 diabetes was assessed according to the WHO criteria, and metabolic syndrome was based on the International Diabetes Federation (IDF), ATP III and 2009 Joint Interim Statement (JIS) definition. RESULTS: The crude prevalence of 28.2% (age-adjusted 26.3%, 95% confidence interval (CI) 22.0 - 30.3) for type 2 diabetes was: 4.4% (age-adjusted 3.2%, 95% CI 1.6 - 4.9) for impaired fasting glycaemia, and 15.3% (age-adjusted 15.0%, 95% CI 11.4 - 18.6) for impaired glucose tolerance. Undiagnosed type 2 diabetes was present in 18.1% (age-adjusted 16.8%, 95% CI 13.3 - 20.4). The crude prevalence of metabolic syndrome was higher with the JIS definition (62.0%) than the IDF (60.6%), and the National Cholesterol Education Program (NCEP) ATP III (55.4%). There was good overall agreement between the MetS criteria, k=0.89 (95% CI 0.85 - 0.92). CONCLUSION: The prevalence of diabetes has increased hugely in the coloured community, and the high prevalence of undiagnosed diabetes portends that cardiovascular diseases might grow to epidemic proportions in the near future in South Africa.

Polymorphisms in the non-muscle myosin heavy chain gene (MYH9) are associated with lower glomerular filtration rate in mixed ancestry diabetic subjects from South Africa.

OBJECTIVE: Though single nucleotide polymorphisms (SNPs) in the non-muscle myosin gene (MYH9) have been reported to explain most of the excess risk of nondiabetic chronic kidney disease (CKD), in African-Americans, some studies have also shown associations with diabetic end-stage renal disease. We investigated the association of MYH9 SNPs with renal traits in a mixed-ancestry South African population prone to diabetes. RESEARCH DESIGN AND METHODS: Three SNPs known to be associated with CKD (rs4821480, rs5756152 and rs12107) were genotyped using Taqman assay in 716 adults (198 with diabetes) from the Bellville-South community, Cape Town. Glomerular filtration rate was estimated (eGFR) and urinary albumin/creatinine ratio (ACR) assessed. Multivariable regressions were used to relate the SNPs with renal traits. RESULTS: Mean age was 53.6 years, with the expected differences observed in characteristics by diabetic status. Significant associations were found between rs575152 and serum creatinine, and eGFR in the total population, and in diabetic participants (all p≤0.003), but not in non-diabetics (all p≥0.16), with significant interactions by diabetes status (interaction-p≤0.009). The association with ACR was borderline in diabetic participants (p = 0.05) and non-significant in non-diabetics (p = 0.85), with significant interaction (interaction p = 0.02). rs12107 was associated with fasting-, 2-hour glucose and HbA1c in diabetic participants only (interaction-p≤0.003), but not with renal traits. CONCLUSION: MYH9 SNPs were associated with renal traits only in diabetic participants in this population. Our findings and other studies suggest that MYH9 may have a broader genetic risk effect on kidney diseases.