Pancreatic ductal adenocarcinoma: Prognostic indicators of advanced disease.

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with high metastatic risk. Prognosis remains poor even after resection. Previously our group identified biomarkers that improved diagnostic accuracy in PDAC beyond the established diagnostic tumour marker, CA19-9. Risk factors, symptoms and circulating biomarkers associated with a PDAC diagnosis may differ from those that alter disease progression and metastasis. This study aimed at assessing the risk factors, presenting symptoms and potential prognostic biomarkers in PDAC and determine their relationship with PDAC stage and/or metastatic status. METHODS: Seventy-two PDAC patients with imaging available for TNM staging at presentation were enrolled following informed consent. Demographic and clinical data were captured. Blood was collected and 38 cytokines/angiogenic factors measured. Nonparametric association tests, univariate and multivariate logistic regression were performed using STATA version 14.2. A p-value≤0.05 was considered significant and odds ratios reported for effect size. RESULTS: Most risk factors and symptoms did not differ across the stages of cancer. Although male gender and smoking are risk factors for PDAC, the majority of study patients with metastatic PDAC were non-smoking females. In addition to CA19-9, the platelet count (p<0.01), IL-15 (p = 0.02) and GM-CSF (p<0.01) were significant, independent negative predictors of metastatic PDAC. Moreover, using specific cut-off values in a combined panel, the odds in a patient with all three biomarker levels below the cut-offs is 21 times more likely to have metastatic PDAC (p<0.0001). CONCLUSIONS: Platelet count, IL-15 and GM-CSF are potential prognostic indicators of metastatic disease in PDAC patients from our local South African population.

Inflammatory cytokines and combined biomarker panels in pancreatic ductal adenocarcinoma: Enhancing diagnostic accuracy.

BACKGROUND: Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenged by the absence of accurate early diagnostic and prognostic biomarkers. CA19-9 is the established, diagnostic tumour marker in PDAC, despite its limitations. Effective primary screening using circulating biomarker panels have only been considered in a handful of studies and we investigated whether combinations of inflammatory cytokines and angiogenic factors in multivariate logistic models could facilitate earlier diagnosis in our South African setting. METHODS: Plasma levels of 38 cytokines and angiogenic factors were measured in 131 Black South African patients, 85 with PDAC, 25 with benign biliary pathology (BBP) and 21 benign non-HPB controls (BC), by use of human magnetic multiplex screening assays. Multivariate biomarker panels were developed by identifying the top performing biomolecules from univariate logistic regression. Receiver-operator characteristic (ROC) curves and area under the ROC curve (AUC) are reported. RESULTS: Classification modelling to distinguish PDAC patients from BC showed that a panel of CA19-9 and CXCL10 (IP-10) demonstrated improved diagnostic power over CA19-9 alone (AUC = 0.977 vs. AUC = 0.807, p-value = 0.001). A combined panel including age, BMI and IL-15 showed significant diagnostic power in discriminating PDAC from BBP (AUC = 0.952, p < 0.0001). Finally, a combined panel of IL-8, IL-15 and gender demonstrated diagnostic accuracy (AUC = 0.830, p < 0.0001) in distinguishing PDAC in the presence of jaundice from benign controls with either jaundice, choledocholithiasis or common bile duct injury. CONCLUSIONS: Combined biomarker panels improve diagnostic accuracy in PDAC. In addition to CA19-9, cytokines CXCL10, IL-8 and IL-15 are strong additions to diagnostic biomarker panels in PDAC in Black South Africans.

An African perspective on the genetic risk of chronic kidney disease: a systematic review.

BACKGROUND: Individuals of African ethnicity are disproportionately burdened with chronic kidney disease (CKD). However, despite the genetic link, genetic association studies of CKD in African populations are lacking. METHODS: We conducted a systematic review to critically evaluate the existing studies on CKD genetic risk inferred by polymorphism(s) amongst African populations in Africa. The study followed the HuGE handbook and PRISMA protocol. We included studies reporting on the association of polymorphism(s) with prevalent CKD, end-stage renaldisease (ESRD) or CKD-associated traits. Given the very few studies investigating the effects of the same single nucleotide polymorphisms (SNPs) on CKD risk, a narrative synthesis of the evidence was conducted. RESULTS: A total of 30 polymorphisms in 11 genes were investigated for their association with CKD, ESRD or related traits, all using the candidate-gene approach. Of all the included genes, MYH9, AT1R and MTHFR genes failed to predict CKD or related traits, while variants in the APOL1, apoE, eNOS, XPD, XRCC1, renalase, ADIPOQ, and CCR2 genes were associated with CKD or other related traits. Two SNPs (rs73885319, rs60910145) and haplotypes (G-A-G; G1; G2) of the apolipoprotein L1 (APOL1) gene were studied in more than one population group, with similar association with prevalent CKD observed. The remaining polymorphisms were investigated in single studies. CONCLUSION: According to this systematic review, there is currently insufficient evidence of the specific polymorphisms that poses African populations at an increased risk of CKD. Large-scale genetic studies are warranted to better understand susceptibility polymorphisms, specific to African populations.

MicroRNA profiling and their pathways in South African individuals with prediabetes and newly diagnosed type 2 diabetes mellitus.

Early identification of individuals with elevated risk of developing diabetes mellitus, followed by the implementation of effective prevention interventions can delay the onset of the disease and related complications. In this regard, recent studies have shown that miRNAs are useful as early markers of certain disease types, including diabetes. We used high throughput sequencing to assess miRNA expression profiles from whole blood of 12 individuals with screen-detected diabetes, 12 with prediabetes and 12 with normal glucose tolerance, matched for age, blood pressure, smoking and body mass index. We identified a total of 261 (57 novel) differentially expressed miRNA profiles between the study groups. Comparison of the miRNA expression profiles between prediabetess and diabetes revealed 25 common miRNA, but highlighted some interesting differences. For instance, three miRNAs (miR-126-3p, miR-28-3p miR-486-5p) were dysregulated in prediabetes compared to screen-detected diabetes. Target gene analysis showed thousands of potential genes and KEGG pathway analysis revealed 107 significant pathways of which some are involved signal transduction, cell-cell communications, cell growth and death, immune response, endocrine system and metabolic diseases. This first detailed African study has shown both known and novel differentially expressed miRNAs in relation to glucose tolerance.

Genetic factors contributing to hypertension in African-based populations: A systematic review and meta-analysis.

In a systematic review, the authors explored genetic association studies of essential hypertension in African populations. Studies reporting on the association of polymorphism(s) with hypertension in African populations were included. Appropriate studies were pooled using random effects model meta-analysis, under six potential inheritance models. In all, 46 polymorphisms in 33 genes were investigated for their association with hypertension or blood pressure levels. Meta-analysis was possible for three single nucleotide polymorphisms: rs4340, rs699, and rs5186. An association was found between rs5186, rs699, and hypertension under allele contrast and homozygous codominant models (odds ratio, 1.63 [95% confidence interval, 1.04-2.54] and 4.01 [95% confidence interval, 1.17-13.80] for rs5186, respectively; and 1.80 [95% confidence interval, 1.13-2.87] for rs699). Findings were mostly robust in sensitivity analyses. According to the systematic review, there is currently insufficient evidence on the specific polymorphisms that pose the risk of hypertension in African populations. Large-scale genetic studies are warranted to better understand susceptibility polymorphisms that may be specific to African populations.

Inflammatory cytokines and angiogenic factors as potential biomarkers in South African pancreatic ductal adenocarcinoma patients: A preliminary report.

BACKGROUND/OBJECTIVES: Several studies have investigated the association of differentially expressed cytokines with pancreatic ductal adenocarcinoma (PDAC), but none in African countries. This study aimed at investigating T-helper (Th) cell and angiogenic markers as diagnostic or prognostic biomarkers for PDAC in Black South Africans. METHODS: We conducted a prospective, case-control study comprising of 34 PDAC patients and 27 control participants with either critical limb ischemia, abdominal aortic aneurysm or other abdominal pathology from causes other than pancreatic disease. Plasma levels of IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, IL-17A, VEGF, sVEGF-R1, FGF, PIGF, PDGF and P-selectin were measured using commercially available cytometric bead array, ELISA and multi-analyte Luminex kits. RESULTS: Significantly higher levels of IFN-γ (p < 0.001), TNF (p < 0.001), IL-2 (p = 0.001), IL-4 (p < 0.01), IL-10 (p < 0.01), IL-17A (p < 0.01), PlGF (p < 0.0001) and basic FGF (p < 0.0001) were found in cases compared to control participants. PDAC patients with irresectable tumours had higher levels of VEGF (p = 0.02) and IL-6 (p = 0.01). A univariate analysis showed significant associations between IFN-γ, TNF, IL-10, -4, -2, basic FGF, PlGF and PDAC. In a multivariate logistic regression model, basic FGF (p = 0.002) and PlGF (p = 0.007) were independent risk factors for PDAC with a combined sensitivity of 71% and specificity of 100%. CONCLUSION: Our preliminary data suggests a potential role for basic FGF and PlGF as diagnostic, and VEGF and IL-6 as prognostic biomarkers of PDAC in Black South African patients.

Genetic risk of type 2 diabetes in populations of the African continent: A systematic review and meta-analyses.

BACKGROUND: Type 2 diabetes (T2D) is growing faster in Africa than anywhere else, driven by the dual effects of genetic and environmental factors. We conducted a systematic review and meta-analyses of published studies on genetic markers of T2D in populations within Africa. METHODS: Multiple databases were searched for studies of genetic variants associated with T2D in populations living in Africa. Studies reporting on the association of a genetic marker with T2D or indicators of glycaemia were included. Data were extracted on study design and characteristics, genetic determinants, effect estimates of associations with T2D. FINDINGS: Overall, 100 polymorphisms in 57 genes have been investigated in relation with T2D in populations within Africa, in 60 studies. Almost all studies used the candidate gene approach, with >88% published during 2006-2014 and 70% (42/60) originating from Tunisia and Egypt. Polymorphisms in ACE, AGRP, eNOS, GSTP1, HSP70-2, MC4R, MTHFR, PHLPP, POL1, TCF7L2, and TNF-α gene were found to be associated with T2D, with overlapping effect on various cardiometabolic traits. The polymorphisms investigated in multiple studies mostly had consistent effects across studies, with only modest or no statistical heterogeneity. Effect sizes were modestly significant [e.g., odd ratio 1.49 (95%CI 1.33-1.66) for TCF7L2 (rs7903146)]. Underpowered genome-wide studies revealed no diabetes risk loci specific to African populations. INTERPRETATION: Current evidence on the genetic markers of T2D in African populations mostly originate from North African countries, is overall scanty and largely insufficient to reliably inform the genetic architecture of T2D across Africa.

APOL1 genetic variants, chronic kidney diseases and hypertension in mixed ancestry South Africans.

BACKGROUND: The frequencies of apolipoprotein L1 (APOL1) variants and their associations with chronic kidney disease (CKD) vary substantially in populations from Africa. Moreover, available studies have used very small sample sizes to provide reliable estimates of the frequencies of these variants in the general population. We determined the frequency of the two APOL1 risk alleles (G1 and G2) and investigated their association with renal traits in a relatively large sample of mixed-ancestry South Africans. APOL1 risk variants (G1: rs60910145 and rs73885319; G2: rs71785313) were genotyped in 859 African mixed ancestry individuals using allele-specific TaqMan technology. Glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. RESULTS: The frequencies of rs73885319, rs60910145 and rs71785313 risk alleles were respectively, 3.6%, 3.4%, and 5.8%, resulting in a 1.01% frequency of the APOL1 two-risk allele (G1:G1 or G1:G2 or G2:G2). The presence of the two-risk allele increased serum creatinine with a corresponding reduction in eGFR (either MDRD or CKD-EPI based). In dominant and log-additive genetic models, significant associations were found between rs71785313 and systolic blood pressure (both p ≤ 0.025), with a significant statistical interaction by diabetes status, p = 0.022, reflecting a negative non-significant effect in nondiabetics and a positive effect in diabetics. CONCLUSIONS: Although the APOL1 variants are not common in the mixed ancestry population of South Africa, the study does provide an indication that APOL1 variants may play a role in conferring an increased risk for renal and cardiovascular risk in this population.

Genomic medicine and risk prediction across the disease spectrum.

Genomic medicine is based on the knowledge that virtually every medical condition, disease susceptibility or response to treatment is caused, regulated or influenced by genes. Genetic testing may therefore add value across the disease spectrum, ranging from single-gene disorders with a Mendelian inheritance pattern to complex multi-factorial diseases. The critical factors for genomic risk prediction are to determine: (1) where the genomic footprint of a particular susceptibility or dysfunction resides within this continuum, and (2) to what extent the genetic determinants are modified by environmental exposures. Regarding the small subset of highly penetrant monogenic disorders, a positive family history and early disease onset are mostly sufficient to determine the appropriateness of genetic testing in the index case and to inform pre-symptomatic diagnosis in at-risk family members. In more prevalent polygenic non-communicable diseases (NCDs), the use of appropriate eligibility criteria is required to ensure a balance between benefit and risk. An additional screening step may therefore be necessary to identify individuals most likely to benefit from genetic testing. This need provided the stimulus for the development of a pathology-supported genetic testing (PSGT) service as a new model for the translational implementation of genomic medicine in clinical practice. PSGT is linked to the establishment of a research database proven to be an invaluable resource for the validation of novel and previously described gene-disease associations replicated in the South African population for a broad range of NCDs associated with increased cardio-metabolic risk. The clinical importance of inquiry concerning family history in determining eligibility for personalized genotyping was supported beyond its current limited role in diagnosing or screening for monogenic subtypes of NCDs. With the recent introduction of advanced microarray-based breast cancer subtyping, genetic testing has extended beyond the genome of the host to also include tumor gene expression profiling for chemotherapy selection. The decreasing cost of next generation sequencing over recent years, together with improvement of both laboratory and computational protocols, enables the mapping of rare genetic disorders and discovery of shared genetic risk factors as novel therapeutic targets across diagnostic boundaries. This article reviews the challenges, successes, increasing inter-disciplinary integration and evolving strategies for extending PSGT towards exome and whole genome sequencing (WGS) within a dynamic framework. Specific points of overlap are highlighted between the application of PSGT and exome or WGS, as the next logical step in genetically uncharacterized patients for whom a particular disease pattern and/or therapeutic failure are not adequately accounted for during the PSGT pre-screen. Discrepancies between different next generation sequencing platforms and low concordance among variant-calling pipelines caution against offering exome or WGS as a stand-alone diagnostic approach. The public reference human genome sequence (hg19) contains minor alleles at more than 1 million loci and variant calling using an advanced major allele reference genome sequence is crucial to ensure data integrity. Understanding that genomic risk prediction is not deterministic but rather probabilistic provides the opportunity for disease prevention and targeted treatment in a way that is unique to each individual patient.

Contribution of ENPP1, TCF7L2, and FTO polymorphisms to type 2 diabetes in mixed ancestry ethnic population of South Africa.

BACKGROUND: Transcription factor 7-like 2 gene (TCF7L2), fat mass and obesity-associated gene (FTO), and ectonucleotide pyrophosphatase/phosphodiesterase gene (ENPP1) are known risk loci for type 2 diabetes (T2DM) mostly in European populations. OBJECTIVES: To assess the association of these genes with T2DM risk in a South African mixed-ancestry population. METHODS: Five hundred and sixty six participants were genotyped for ENPP1-rs997509 and -rs1044498, FTO-9941349 and -rs3751812, TCF7L2-rs12255372 and -rs7903146 polymorphisms using Taqman genotyping assays and validated by automated sequencing to assess the association of the polymorphisms with cardiometabolic traits. RESULTS: In logistic regression models adjusted for age, sex, body mass index (BMI) and insulin resistance, minor allele of rs997509 was associated with a higher risk of prevalent T2DM under a recessive model [odd ratio 4.60 (95% confidence interval: 1.07 to 19.86); p = 0.040].Under additive model, the rs7903146 [1.43 (1.00 to 2.04); p= 0.053] and rs9941349 [1.43 (1.00 to 2.04); p = 0.052] minor alleles showed marginally significant associations with a high risk of T2DM. However, only the rs7903146 alleles (p=0.011) and genotypes (p=0.025) distributions were statistically significantly different between diabetic and non-diabetic individuals. CONCLUSION: Our findings demonstrate that ENPP1, TCF7L2, and FTO may predispose to T2DM in the mixed-ancestry population.

Air pollution and risk of type 2 diabetes mellitus: a systematic review and meta-analysis.

AIM: Whether exposure to relatively high levels of air pollution is associated with diabetes occurrence remains unclear. We sought to assess and quantify the association between exposure to major air pollutants and risk of type 2 diabetes. METHODS: PubMed and EMBASE databases (through September 2013) were searched using a combination of terms related to exposure to gaseous (NO2 and NOx) or particulate matter pollutants (PM2.5, PM10 and PM10-2.5) and type 2 diabetes. Descriptive and quantitative information were extracted from selected studies. We used random-effects models meta-analysis to derive overall risk estimates per type of pollutant. RESULTS: We included ten studies (five cross-sectional and five prospective), assessing the effects of air pollutants on the occurrence of diabetes. In prospective investigations, the overall effect on diabetes occurrence was significant for both NO2 (adjusted hazard ratio [HR], 1.13; 95% confidence interval [95%CI], 1.01-1.22; p < 0.001; I(2) = 36.4%, pheterogeneity = 0.208) and PM2.5 (HR, 1.11; 95%CI, 1.03-1.20; p < 0.001; I(2) = 0.0%, pheterogeneity = 0.827). Odds ratios were reported by two cross-sectional studies which revealed similar associations between both NO2 and PM2.5 with type 2 diabetes. Across studies, risk estimates were generally adjusted for age, gender, body mass index and cigarette smoking. CONCLUSIONS: Available evidence supports a prospective association of main air pollutants with an increased risk for type 2 diabetes. This finding may have implications for population-based strategies to reduce diabetes risk.

Proliferator-activated receptor gamma Pro12Ala interacts with the insulin receptor substrate 1 Gly972Arg and increase the risk of insulin resistance and diabetes in the mixed ancestry population from South Africa.

BACKGROUND: The peroxisome proliferator-activated receptor gamma (PPARG), Pro12Ala and the insulin receptor substrate (IRS1), Gly972Arg confer opposite effects on insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the independent and joint effects of PPARG Pro12Ala and IRS1 Gly972Arg on markers of insulin resistance and T2DM in an African population with elevated risk of T2DM. In all 787 (176 men) mixed-ancestry adults from the Bellville-South community in Cape Town were genotyped for PPARG Pro12Ala and IRS1 Gly972Arg by two independent laboratories. Glucose tolerance status and insulin resistance/sensitivity were assessed. RESULTS: Genotype frequencies were 10.4% (PPARG Pro12Ala) and 7.7% (IRS1 Gly972Arg). Alone, none of the polymorphisms predicted prevalent T2DM, but in regression models containing both alleles and their interaction term, PPARG Pro12 conferred a 64% higher risk of T2DM. Furthermore PPARG Pro12 was positively associated in adjusted linear regressions with increased 2-hour post-load insulin in non-diabetic but not in diabetic participants. CONCLUSION: The PPARG Pro12 is associated with insulin resistance and this polymorphism interacts with IRS1 Gly972Arg, to increase the risk of T2DM in the mixed-ancestry population of South Africa. Our findings require replication in a larger study before any generalisation and possible application for risk stratification.

Optimal waist-to-height ratio values for cardiometabolic risk screening in an ethnically diverse sample of South African urban and rural school boys and girls.

BACKGROUND: The proposed waist-to-height ratio (WHtR) cut-off of 0.5 is less optimal for cardiometabolic risk screening in children in many settings. The purpose of this study was to determine the optimal WHtR for children from South Africa, and investigate variations by gender, ethnicity and residence in the achieved value. METHODS: Metabolic syndrome (MetS) components were measured in 1272 randomly selected learners, aged 10-16 years, comprising of 446 black Africans, 696 mixed-ancestry and 130 Caucasians. The Youden's index and the closest-top-left (CTL) point approaches were used to derive WHtR cut-offs for diagnosing any two MetS components, excluding the waist circumference. RESULTS: The two approaches yielded similar cut-off in girls, 0.465 (sensitivity 50.0, specificity 69.5), but two different values in boys, 0.455 (42.9, 88.4) and 0.425 (60.3, 67.7) based on the Youden's index and the CTL point, respectively. Furthermore, WHtR cut-off values derived differed substantially amongst the regions and ethnic groups investigated, whereby the highest cut-off was observed in semi-rural and white children, respectively, Youden's index0.505 (31.6, 87.1) and CTL point 0.475 (44.4, 75.9). CONCLUSION: The WHtR cut-off of 0.5 is less accurate for screening cardiovascular risk in South African children. The optimal value in this setting is likely gender and ethnicity-specific and sensitive to urbanization.

Chronic kidney diseases in mixed ancestry south African populations: prevalence, determinants and concordance between kidney function estimators.

BACKGROUND: Population-based data on the burden of chronic kidney disease (CKD) in sub-Saharan Africa is still very limited. We assessed the prevalence and determinants of CKD, and evaluated the concordance of commonly advocated estimators of glomerular filtration rate (eGFR) in a mixed ancestry population from South Africa. METHODS: Participants were a population-based sample of adults selected from the Bellville-South community in the metropolitan city of Cape Town. eGFR was based on the Cockroft-Gault (CG), Modification of Diet in Kidney Disease (MDRD) and CKD Epidemiology Collaboration (CKD-EPI) equations (with and without adjustment for ethnicity). Kidney function staging used the Kidney Disease Outcome Quality Initiative (KDOQI) classification. Logistic regressions and kappa statistic were used to investigate determinants of CKD and assess the agreement between different estimators. RESULTS: The crude prevalence of CKD stage 3-5 was 14.8% for Cockcroft-Gault, 7.6% and 23.9% respectively for the MDRD with and without ethnicity correction, and 7.4% and 17.3% for the CKD-EPI equations with and without ethnicity correction. The highest agreement between GFR estimators was between MDRD and CKD-EPI equations, both with ethnicity correction, Kappa 0.91 (95% CI: 0.86-0.95), correlation coefficient 0.95 (95% CI: 0.94-0.96). In multivariable logistic regression models, sex, age and known hypertension were consistently associated with CKD stage 3-5 across the 5 estimators. CONCLUSIONS: The prevalence of CKD stages greater than 3 is the highest reported in Africa. This study provides evidence for support of the CKD-EPI equation for eGFR reporting and CKD classification.

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.

CYP2D6 genotyping and use of antidepressants in breast cancer patients: test development for clinical application.

Approximately 25% of clinically important drugs and numerous environmental carcinogens are metabolised by CYP2D6. Variation in the CYP2D6 gene and concomitant use of tamoxifen (TAM) with certain antidepressants may increase recurrence risk in breast cancer patients due to reduced enzyme activity. In this study we determined the appropriateness of adding CYP2D6 genotyping to the breast cancer genetic testing options already available in South Africa, which include BRCA mutation screening and transcriptional profiling to assess estrogen receptor (ER) status. A total of 114 South African breast cancer patients, including 52 Caucasian and 62 Coloured (Mixed ancestry), and 63 Caucasian control individuals were genotyped for the most common inactivating allele (CYP2D6*4, rs3892097) previously identified in the CYP2D6 gene. In the initial validation data set consisting of 25 Caucasian and 62 Coloured patients, the CYP2D6*4 allele frequency was significantly higher in Caucasian compared to Coloured patients (24% vs. 3%, p<0.001), similar to previous findings in the general South African population. Extended CYP2D6 genotyping was subsequently performed in an implementation data set of 27 Caucasian breast cancer patients, to determine the prevalence of depression and use of antidepressants in a clinical setting. A medical history of depression and/or use of antidepressants was reported in 37% (10/27) of these breast cancer patients genotyped for CYP2D6*4. This translational research study has led to increased awareness among clinicians of the potential benefits of CYP2D6 genotyping to facilitate prevention of cumulative risk in a high-risk genetic subgroup of breast cancer patients considered for concomitant treatment of TAM and antidepressants that may reduce enzyme function.

Negative association of MC3R variants with weight and blood pressure in Cape Town pupils aged 11 - 16 years.

BACKGROUND: Human and animal studies support the role of MC4R and MC3R in human obesity, but limited data are available on the genetic contribution to obesity in South African populations. OBJECTIVE: To screen obese-overweight South African pupils for MC3R and MC4R polymorphisms that may play a role in the development of obesity. DESIGN: A cross-sectional study screened 227 obese-overweight (115 black and 112 coloured) and 204 normal weight (94 black, 110 coloured) school pupils for the presence of MC4R and MC3R polymorphisms using a single strand conformation polymorphism, subsequent sequencing, and allele specific restriction enzyme analysis. RESULTS: Two polymorphisms were detected in the MC3R (T6K and V81I) but none in MC4R. After adjusting for age, gender and case-control status, the frequency distributions of T6K and V81I genotype and allele varied significantly between the ethnic groups. The frequency of the V81I A allele was significantly lower in coloured overweight-obesity than normal pupils. In coloured pupils, both polymorphisms were associated with obesity indices and total cholesterol. The T6K A allele was also associated with lower blood pressure. Likewise, different T6K-V81I haplotypes demonstrated negative associations with obesity indices and blood pressure. CONCLUSION: We demonstrated that the MC3R polymorphisms have a protective effect on metabolic traits; however, further analysis is required to confirm whether this translates to a lower incidence of metabolic syndrome in coloured populations.