Africa-specific human genetic variation near CHD1L associates with HIV-1 load.

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

Characteristics, management and outcomes of primary hyperparathyroidism from 2009 to 2021: a single centre report from South Africa.

BACKGROUND: There has been a notable shift towards the diagnosis of less severe and asymptomatic primary hyperparathyroidism (PHPT) in developed countries. However, there is a paucity of recent data from sub-Saharan Africa (SSA), and also, no reported data from SSA on the utility of intra-operative parathyroid hormone (IO-PTH) monitoring. In an earlier study from Inkosi Albert Luthuli Central Hospital (IALCH), Durban, South Africa (2003-2009), majority of patients (92.9%) had symptomatic disease. The aim of this study was to evaluate the clinical profile and management outcomes of patients presenting with PHPT at IALCH. METHODS: A retrospective chart review of patients with PHPT attending the Endocrinology clinic at IALCH between July 2009 and December 2021. Clinical presentation, laboratory results, radiologic findings, surgical notes and histology were recorded. RESULTS: Analysis included 110 patients (87% female) with PHPT. Median age at presentation was 57 (44; 67.5) years. Symptomatic disease was present in 62.7% (n:69); 20.9% (n:23) had a history of nephrolithiasis and 7.3% (n:8) presented with previous fragility fractures. Mean serum calcium was 2.87 ± 0.34 mmol/l; median serum-PTH was 23.3 (15.59; 45.38) pmol/l, alkaline phosphatase 117.5 (89; 145.5) U/l and 25-hydroxyvitamin-D 42.9 (33.26; 62.92) nmol/l. Sestamibi scan (n:106 patients) identified an adenoma in 83.02%. Parathyroidectomy was performed on 84 patients with a cure rate of 95.2%. Reasons for conservative management (n:26) included: no current surgical indication (n:7), refusal (n:5) or deferral of surgery (n:5), loss to follow-up (n:5) and assessed as high anaesthetic risk (n:4). IO-PTH measurements performed on 28 patients indicated surgical success in 100%, based on Miami criteria. Histology confirmed adenoma in 88.1%, hyperplasia in 7.1% and carcinoma in 4.8%. Post-operative hypocalcaemia developed in 30 patients (35.7%), of whom, 14 developed hungry bone syndrome (HBS). In multivariate analysis, significant risk factors associated with HBS included male sex (OR 7.01; 95% CI 1.28, 38.39; p 0.025) and elevated pre-operative PTH (OR 1.01; 95% CI 1.00, 1.02; p 0.008). CONCLUSIONS: The proportion of asymptomatic PHPT has increased at this centre over the past decade but symptomatic disease remains the dominant presentation. Parathyroidectomy is curative in the majority of patients. IO-PTH monitoring is valuable in ensuring successful surgery.

Genetic loci implicated in meta-analysis of body shape in Africans.

BACKGROUND AND AIMS: Obesity is one of the leading causes of non-communicable diseases (NCD). Thus, NCD risk varies in obese individuals based on the location of their fat depots; while subcutaneous adiposity is protective, visceral adiposity increases NCD risk. Although, previously anthropometric traits have been used to quantify body shape in low-income settings, there is no consensus on how it should be assessed. Hence, there is a growing interest to evaluate body shape derived from the principal component analysis (PCA) of anthropometric traits; however, this is yet to be explored in individuals of African ancestry whose body shape is different from those of Europeans. We set out to capture body shape in its multidimensional structure and examine the association between genetic variants and body shape in individuals of African ancestry. METHOD AND RESULTS: We performed a genome-wide association study (GWAS) for body shape derived from PCA analysis of anthropometric traits in the Ugandan General Population Cohort (GPC, n = 6407) and the South African Zulu Cohort (SZC, n = 2595), followed by a GWAS meta-analysis to assess the genetic variants associated with body shape. We identified variants in FGF12, GRM8, TLX1NB and TRAP1 to be associated with body shape. These genes were different from the genes been associated with BMI, height, weight, WC and waist-hip ration in continental Africans. Notably, we also observed that a standard deviation change in body shape was associated with an increase in blood pressure and blood lipids. CONCLUSION: Variants associated with body shape, as a composite variable might be different for those of individual anthropometric traits. Larger studies are required to further explore these phenomena.

HIV infection and anaemia do not affect HbA1c for the detection of diabetes in black South Africans: Evidence from the Durban Diabetes Study.

OBJECTIVE: South Africa has a high burden of HIV infection and anaemia. These conditions may cause HbA1c to over- or underestimate glycaemia; however, this has not been comprehensively investigated in African populations. We assessed the association of anaemia, HIV infection and antiretroviral therapy (ART) with HbA1c , and implications for the detection and diagnosis of diabetes, in a black South African population. RESEARCH DESIGN AND METHODS: In this population-based cross-sectional study in eThekwini municipality (Durban), South Africa, we assessed HbA1c and conducted oral glucose tolerance tests (OGTTs), HIV diagnostic tests and full blood count measurements among 1067 participants without a history of diabetes diagnosis. Linear regression was used to examine differences in HbA1c by anaemia (comparator: no anaemia), or HIV and ART (comparator: no HIV) status. HbA1c -based diabetes prevalence was compared with OGTT-based prevalence among individuals with anaemia and with untreated and ART-treated HIV. RESULTS: In adjusted analyses, normocytic and microcytic anaemia were associated with higher HbA1c compared with no anaemia, whereas macrocytic anaemia and ART-treated HIV were associated with lower HbA1c compared with no anaemia and no HIV, respectively. However, magnitudes of association were small (range: ß  = -3.4 mmol/mol or -0.31%, p < 0.001 [macrocytic anaemia] to ß = 2.1 mmol/mol or 0.19%, p < 0.001 [microcytic anaemia]). There was no significant difference in diabetes prevalence based on HbA1c or OGTT among individuals with anaemia (2.9% vs. 3.3%, p = 0.69), untreated HIV (1.6% vs. 1.6% p = 1.00) or ART-treated HIV (2.9% vs. 1.2%, p = 0.08). CONCLUSIONS: Our results suggest that anaemia and HIV status appear unlikely to materially affect the utility of HbA1c for diabetes detection and diagnosis in this population. Further studies are needed to examine these associations in sub-Saharan African populations.

Clinic-based diabetes screening at the time of HIV testing and associations with poor clinical outcomes in South Africa: a cohort study.

BACKGROUND: HIV clinical care programs in high burden settings are uniquely positioned to facilitate diabetes diagnosis, which is a major challenge. However, in sub-Saharan Africa, data on the burden of diabetes among people living with HIV (PLHIV) and its impact on HIV outcomes is sparse. METHODS: We enrolled adults presenting for HIV testing at an outpatient clinic in Durban. Those who tested positive for HIV-infection were screened for diabetes using a point-of-care hemoglobin A1c (HbA1c) test. We used log-binomial, Poisson, and Cox proportional hazard models adjusting for confounders to estimate the relationship of diabetes (HbA1c ≥ 6.5%) with the outcomes of HIV viral suppression (< 50 copies/mL) 4-8 months after antiretroviral therapy initiation, retention in care, hospitalization, tuberculosis, and death over 12 months. RESULTS: Among 1369 PLHIV, 0.5% (n = 7) reported a prior diabetes diagnosis, 20.6% (95% CI 18.5-22.8%, n = 282) screened positive for pre-diabetes (HbA1c 5.7-6.4%) and 3.5% (95% CI 2.7-4.6%, n = 48) for diabetes. The number needed to screen to identify one new PLHIV with diabetes was 46.5 persons overall and 36.5 restricting to those with BMI ≥ 25 kg/m2. Compared to PLHIV without diabetes, the risk of study outcomes among those with diabetes was not statistically significant, although the adjusted hazard of death was 1.79 (95% CI 0.41-7.87). CONCLUSIONS: Diabetes and pre-diabetes were common among adults testing positive for HIV and associated with death. Clinic-based diabetes screening could be targeted to higher risk groups and may improve HIV treatment outcomes.

The African Genome Variation Project shapes medical genetics in Africa.

Given the importance of Africa to studies of human origins and disease susceptibility, detailed characterization of African genetic diversity is needed. The African Genome Variation Project provides a resource with which to design, implement and interpret genomic studies in sub-Saharan Africa and worldwide. The African Genome Variation Project represents dense genotypes from 1,481 individuals and whole-genome sequences from 320 individuals across sub-Saharan Africa. Using this resource, we find novel evidence of complex, regionally distinct hunter-gatherer and Eurasian admixture across sub-Saharan Africa. We identify new loci under selection, including loci related to malaria susceptibility and hypertension. We show that modern imputation panels (sets of reference genotypes from which unobserved or missing genotypes in study sets can be inferred) can identify association signals at highly differentiated loci across populations in sub-Saharan Africa. Using whole-genome sequencing, we demonstrate further improvements in imputation accuracy, strengthening the case for large-scale sequencing efforts of diverse African haplotypes. Finally, we present an efficient genotype array design capturing common genetic variation in Africa.

Sociodemographic inequities associated with participation in leisure-time physical activity in sub-Saharan Africa: an individual participant data meta-analysis.

BACKGROUND: Leisure-time physical activity (LTPA) is an important contributor to total physical activity and the focus of many interventions promoting activity in high-income populations. Little is known about LTPA in sub-Saharan Africa (SSA), and with expected declines in physical activity due to rapid urbanisation and lifestyle changes we aimed to assess the sociodemographic differences in the prevalence of LTPA in the adult populations of this region to identify potential barriers for equitable participation. METHODS: A two-step individual participant data meta-analysis was conducted using data collected in SSA through 10 population health surveys that included the Global Physical Activity Questionnaire. For each sociodemographic characteristic, the pooled adjusted prevalence and risk ratios (RRs) for participation in LTPA were calculated using the random effects method. Between-study heterogeneity was explored through meta-regression analyses and tests for interaction. RESULTS: Across the 10 populations (N = 26,022), 18.9% (95%CI: 14.3, 24.1; I2 = 99.0%) of adults (≥ 18 years) participated in LTPA. Men were more likely to participate in LTPA compared with women (RR for women: 0.43; 95%CI: 0.32, 0.60; P < 0.001; I2 = 97.5%), while age was inversely associated with participation. Higher levels of education were associated with increased LTPA participation (RR: 1.30; 95%CI: 1.09, 1.55; P = 0.004; I2 = 98.1%), with those living in rural areas or self-employed less likely to participate in LTPA. These associations remained after adjusting for time spent physically active at work or through active travel. CONCLUSIONS: In these populations, participation in LTPA was low, and strongly associated with sex, age, education, self-employment and urban residence. Identifying the potential barriers that reduce participation in these groups is necessary to enable equitable access to the health and social benefits associated with LTPA.

Genome-wide association study of type 2 diabetes in Africa.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) for type 2 diabetes have uncovered >400 risk loci, primarily in populations of European and Asian ancestry. Here, we aimed to discover additional type 2 diabetes risk loci (including African-specific variants) and fine-map association signals by performing genetic analysis in African populations. METHODS: We conducted two type 2 diabetes genome-wide association studies in 4347 Africans from South Africa, Nigeria, Ghana and Kenya and meta-analysed both studies together. Likely causal variants were identified using fine-mapping approaches. RESULTS: The most significantly associated variants mapped to the widely replicated type 2 diabetes risk locus near TCF7L2 (p = 5.3 × 10-13). Fine-mapping of the TCF7L2 locus suggested one type 2 diabetes association signal shared between Europeans and Africans (indexed by rs7903146) and a distinct African-specific signal (indexed by rs17746147). We also detected one novel signal, rs73284431, near AGMO (p = 5.2 × 10-9, minor allele frequency [MAF] = 0.095; monomorphic in most non-African populations), distinct from previously reported signals in the region. In analyses focused on 100 published type 2 diabetes risk loci, we identified 21 with shared causal variants in African and non-African populations. CONCLUSIONS/INTERPRETATION: These results demonstrate the value of performing GWAS in Africans, provide a resource to larger consortia for further discovery and fine-mapping and indicate that additional large-scale efforts in Africa are warranted to gain further insight in to the genetic architecture of type 2 diabetes.

Prevalence and characteristics of celiac disease in South African patients with type 1 diabetes mellitus: Results from the Durban Diabetes and Celiac Disease Study.

BACKGROUND AND AIM: The aim of this study was to assess the prevalence and characteristics of celiac disease (CD) in all patients with type 1 diabetes mellitus attending a tertiary adult diabetes clinic in Durban, South Africa. METHODS: This was a cross-sectional observational study that screened 202 patients; of these, 56.4% were African (Black), 31.7% Asian Indian, 4.5% White, and 7.4% mixed race. Demographic data, symptoms, and anthropometry were documented. Blood tests included anti-tissue transglutaminase antibody (tTG), anti-endomysial antibody (EMA), and anti-gliadin antibody (AGA). Endoscopy and duodenal biopsy were performed in patients with celiac antibodies. Diagnosis of CD was based on the modified Marsh classification. RESULTS: Mean age and mean duration of diabetes were 26.4 ± 11.4 and 10.7 ± 9.1 years, respectively. Celiac antibodies were found in 65 (32.2%) patients: EMA 7.4%, tTG immunoglobulin A (IgA) 8.4%, tTG immunoglobulin G 1.9%, AGA IgA 18.3%, and AGA immunoglobulin G 21.8%. Histological evidence of CD was found in 5.9% (n = 12/202): 2.5% were classed as definite CD (Marsh 3) and 3.4% as potential CD (Marsh 1). None of the patients with CD were symptomatic. The sensitivity of AGA IgA, EMA, and tTG IgA antibodies for detecting histologically proven CD was 66.7%, 50.0%, and 41.7%, respectively. CONCLUSION: The prevalence of CD was similar to reports from western countries. No ethnic specific differences were noted. CD was silent in all patients in this study. The sensitivity of EMA and tTG antibodies was poor and merits further evaluation as screening tools for CD in South African patients with type 1 diabetes mellitus.

Characteristics and outcome of surgically treated pituitary tumours in South Africa: a single-centre experience.

AIMS: To describe the clinical, biochemical, radiological and histological features and to determine the outcome of all patients with pituitary tumours treated surgically at Inkosi Albert Luthuli Central Hospital (ILACH) in Durban over a 5-year period. RESEARCH DESIGN: Retrospective chart review from 2008 to 2012. Clinical, biochemical and radiological data were collected before and 1 year after surgery. Histopathology findings and perioperative complications were recorded. RESULTS: Seventy patients were included (age 44·8 ± 14·9 years, 55·7% female). Headache (84·1%) and visual disturbances (78·3%) were the predominant presenting symptoms (84·1% and 78·3%). Most tumours were macroadenomas (97·1%). Trans-sphenoidal surgery was employed in the majority (90%). A single procedure was required in 55·7% patients, two procedures in 30% and up to six in others. Complete resection was achieved in only nine patients (12·8%), residual tumour postsurgery was found in 48 (68·6%), and no change in tumour size was found in 13 (18·6%) patients. Additional medical therapy was used in 22 (31·4%) and radiotherapy in 13 (18·6%). On biopsy, the most common pathology was nonfunctional adenoma in 33 (47·1%); 29 (41·4%) were secretory tumours, and 8 (11·4%) were craniopharyngiomas. Overall mortality was 4·3%. The commonest surgical complication was cerebrospinal fluid (CSF) leak (10%; n = 7). New postsurgical pituitary hypofunction occurred in 50 (71·4%) patients. The outcome at 1 year was similar to that on discharge. CONCLUSIONS: Patients presenting to IALCH had large tumours, and complete resection was achieved in a minority. There was a low overall mortality but high rate of postsurgical pituitary hypofunction.

High prevalence of antithyroid peroxidase and antiparietal cell antibodies among patients with type 1 diabetes mellitus attending a tertiary diabetes centre in South Africa.

OBJECTIVE: Data on the prevalence of autoimmune thyroid disease (AITD) and gastric autoimmunity in type 1 diabetes mellitus (T1DM) in Africa are limited. The aim of this study was to assess the prevalence of antithyroid peroxidase (TPO-A) and antiparietal cell antibody (PCA) in patients with T1DM at a tertiary diabetes clinic in Durban, South Africa. RESEARCH DESIGN AND METHODS: This was a cross-sectional observational study among subjects attending the adult T1DM clinic at Inkosi Albert Luthuli Hospital. Information about history and clinical examination was collected. Blood tests included glutamic acid decarboxylase antibody (GADA), TPO-A, PCA, vitamin B12, folate, ferritin, thyroid stimulating hormone (TSH), free thyroxine, lipids and HbA1c. RESULTS: A total of 202 (M:F, 90:112) patients were recruited. The ethnic composition was African (black) (56.4%; n=114), Indian (31.7%; n=64), white (4.5%; n=9) and coloured (mixed race) (7.4%; n=15). Mean age and mean duration of diabetes were 26.4±11.4 and 10.7±9.1 years, respectively. Mean body mass index was 21.6±6.3 kg/m2. GADA was positive in 63.37% (n=128). The prevalence of TPO-A was 18.9% (n=39) and PCA 8.9% (n=17). The prevalence of overt hypothyroidism, subclinical hypothyroidism and Graves' disease was 10.9%, 2.5% and 1.5%, respectively; vitamin B12 deficiency was noted in 3.5% (n=7) and iron deficiency in 19.3% (n=39). CONCLUSIONS: Among patients with T1DM in this study, there was a high prevalence of coexistent AITD and gastric autoimmunity. Screening for hypothyroidism and thyroid autoimmunity should be undertaken in all patients at initial presentation. However, to assess the feasibility and optimal timing of subsequent testing in the African setting with limited resources, more collaborative research with longitudinal studies is required.

Very low rates of screening for metabolic syndrome among patients with severe mental illness in Durban, South Africa.

BACKGROUND: Sub Saharan African is experiencing the largest increase in the prevalence of type 2 diabetes mellitus and cardiovascular disease globally. Metabolic syndrome (MetS) is a cluster of risk factors for these conditions. There is a consistently higher prevalence of cardiometabolic disease among individuals with severe mental illness (SMI) compared to the general population worldwide. However, it is known from research in high income countries that screening for MetS in patients with SMI is low. The objective of this study was to document the extent of the expected low frequency of testing for all the components of the metabolic syndrome (MetS) in patients with SMI in a low middle income country. METHODS: This was a cross sectional study, undertaken from January to June 2012 on out-patients with SMI who were treated with antipsychotic medication for at least 6 months. The study measured the proportion of participants who were tested for MetS in the previous year. RESULTS: The study included 331 (M: F; 167:164) participants with a mean age of 35.2 ± 11.98 years. The majority (78.8%) were black South Africans. Only 2 subjects (0.6%) were screened for all five components of MetS. Regarding the individual components, 99%, 0.6%, 3.9% and 1.8% were screened for raised blood pressure, abdominal obesity, hyperglycaemia, hypertriglyceridaemia and decreased high density lipoprotein cholesterol respectively. CONCLUSION: It is unacceptable that less than one percent of our participants were adequately screened for modifiable risk factors for type 2 diabetes mellitus and cardiovascular disease which are the most common causes of mortality among patients with SMI. These results highlight the need for translating guidelines into action in low and middle income countries.

Precision prognostics for cardiovascular disease in Type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with Type 2 diabetes (T2D). METHODS: We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies. RESULTS: Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort. CONCLUSIONS: Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

People living with type 2 diabetes (T2D) are more likely to develop problems with their heart or blood circulation, known as cardiovascular disease (CVD), than people who do not have T2D. However, it can be difficult to predict which people with T2D are most likely to develop CVD. This is because current approaches, such as blood tests, do not identify all people with T2D who are at an increased risk of CVD. In this study we reviewed published papers that investigated the differences between people with T2D who experienced CVD compared to those who did not. We found some indicators that could potentially be used to determine which people with T2D are most likely to develop CVD. More studies are needed to determine how useful these are. However, they could potentially be used to enable clinicians to provide targeted advice and treatment to those people with T2D at most risk of developing CVD.

Comparative assessment of absolute cardiovascular disease risk characterization from non-laboratory-based risk assessment in South African populations.

BACKGROUND: All rigorous primary cardiovascular disease (CVD) prevention guidelines recommend absolute CVD risk scores to identify high- and low-risk patients, but laboratory testing can be impractical in low- and middle-income countries. The purpose of this study was to compare the ranking performance of a simple, non-laboratory-based risk score to laboratory-based scores in various South African populations. METHODS: We calculated and compared 10-year CVD (or coronary heart disease (CHD)) risk for 14,772 adults from thirteen cross-sectional South African populations (data collected from 1987 to 2009). Risk characterization performance for the non-laboratory-based score was assessed by comparing rankings of risk with six laboratory-based scores (three versions of Framingham risk, SCORE for high- and low-risk countries, and CUORE) using Spearman rank correlation and percent of population equivalently characterized as 'high' or 'low' risk. Total 10-year non-laboratory-based risk of CVD death was also calculated for a representative cross-section from the 1998 South African Demographic Health Survey (DHS, n = 9,379) to estimate the national burden of CVD mortality risk. RESULTS: Spearman correlation coefficients for the non-laboratory-based score with the laboratory-based scores ranged from 0.88 to 0.986. Using conventional thresholds for CVD risk (10% to 20% 10-year CVD risk), 90% to 92% of men and 94% to 97% of women were equivalently characterized as 'high' or 'low' risk using the non-laboratory-based and Framingham (2008) CVD risk score. These results were robust across the six risk scores evaluated and the thirteen cross-sectional datasets, with few exceptions (lower agreement between the non-laboratory-based and Framingham (1991) CHD risk scores). Approximately 18% of adults in the DHS population were characterized as 'high CVD risk' (10-year CVD death risk >20%) using the non-laboratory-based score. CONCLUSIONS: We found a high level of correlation between a simple, non-laboratory-based CVD risk score and commonly-used laboratory-based risk scores. The burden of CVD mortality risk was high for men and women in South Africa. The policy and clinical implications are that fast, low-cost screening tools can lead to similar risk assessment results compared to time- and resource-intensive approaches. Until setting-specific cohort studies can derive and validate country-specific risk scores, non-laboratory-based CVD risk assessment could be an effective and efficient primary CVD screening approach in South Africa.

Characteristics, management and outcome of primary hyperparathyroidism in South Africa: a single-centre experience.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterised by hypercalcaemia and elevated parathyroid hormone (PTH) levels. However, it remains a relatively underdiagnosed disease in the developing world primarily due to a lack of routine blood chemistry screening. The aim of this analysis was to evaluate the characteristics, management and outcome of patients with PHPT at a tertiary referral clinic in South Africa. METHODS: A retrospective analysis was undertaken on all patients with a diagnosis of PHPT attending the endocrinology clinic at a tertiary referral hospital in Durban, South Africa, between January 2003 and June 2009. Information on clinical presentation, past medical history, biochemistry, radiology, histology and surgical notes were recorded. Patients with multiple endocrine neoplasia were excluded. RESULTS: A total of 28 case records of PHPT were reviewed. The mean age at presentation was 60±14.5 years with a female preponderance (78.6%). The mode of presentation included referral for investigation of an abnormal serum calcium (n: 23), referral from urologist with nephrolithiasis (n: 3) and for investigation of bone disease (n: 2). Symptomatic disease was found in 26 patients (92.9%), including bone pain (75%), fatigue (46.4%) and abdominal pain (32.1%). Mean serum calcium was 3.0+0.39 (normal 2.08-2.65) mmol/L, serum intact PTH 34.7±41.5 (normal 1.2-8.5) pmol/L and serum alkaline phosphatase 206.3±340.2 (normal 53-141) mIU/L. Sestamibi scan was performed on 24 patients and an adenoma was identified in 83.3%. Of the 19 (68%) patients who had parathyroidectomy, an adenoma was identified as the cause in all cases where histology was available (n:18). Surgery was successful in 18 patients with only one patient requiring repeat parathyroidectomy for persistent hypercalcaemia. Postoperative hypocalcaemia developed in eight patients (42.1%) including four patients who required intravenous calcium infusion for symptomatic hypocalcaemia. CONCLUSIONS: PHPT is a treatable disorder with good surgical success. Asymptomatic disease was uncommon in this group of patients. This is compatible with the symptomatic pattern of presentation reported in other developing countries.

Multivariate GWAS analysis reveals loci associated with liver functions in continental African populations.

BACKGROUND: Liver disease is any condition that causes liver damage and inflammation and may likely affect the function of the liver. Vital biochemical screening tools that can be used to evaluate the health of the liver and help diagnose, prevent, monitor, and control the development of liver disease are known as liver function tests (LFT). LFTs are performed to estimate the level of liver biomarkers in the blood. Several factors are associated with differences in concentration levels of LFTs in individuals, such as genetic and environmental factors. The aim of our study was to identify genetic loci associated with liver biomarker levels with a shared genetic basis in continental Africans, using a multivariate genome-wide association study (GWAS) approach. METHODS: We used two distinct African populations, the Ugandan Genome Resource (UGR = 6,407) and South African Zulu cohort (SZC = 2,598). The six LFTs used in our analysis were: aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin, and albumin. A multivariate GWAS of LFTs was conducted using the exact linear mixed model (mvLMM) approach implemented in GEMMA and the resulting P-values were presented in Manhattan and quantile-quantile (QQ) plots. First, we attempted to replicate the findings of the UGR cohort in SZC. Secondly, given that the genetic architecture of UGR is different from that of SZC, we further undertook similar analysis in the SZC and discussed the results separately. RESULTS: A total of 59 SNPs reached genome-wide significance (P = 5x10-8) in the UGR cohort and with 13 SNPs successfully replicated in SZC. These included a novel lead SNP near the RHPN1 locus (lead SNP rs374279268, P-value = 4.79x10-9, Effect Allele Frequency (EAF) = 0.989) and a lead SNP at the RGS11 locus (lead SNP rs148110594, P-value = 2.34x10-8, EAF = 0.928). 17 SNPs were significant in the SZC, while all the SNPs fall within a signal on chromosome 2, rs1976391 mapped to UGT1A was identified as the lead SNP within this region. CONCLUSIONS: Using multivariate GWAS method improves the power to detect novel genotype-phenotype associations for liver functions not found with the standard univariate GWAS in the same dataset.

Precision Prognostics for Cardiovascular Disease in Type 2 Diabetes: A Systematic Review and Meta-analysis.

Background Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with type 2 diabetes (T2D). Methods We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies. Results Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination, with lower performance in populations different from the original development cohort. Conclusions Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

Type 2 diabetes mellitus in sub-Saharan Africa: challenges and opportunities.

Type 2 diabetes mellitus (T2DM), which was once thought to be rare in sub-Saharan Africa (SSA), is now well established in this region. The SSA region is undergoing a rapid but variable epidemiological transition fuelled by the pace of urbanization, with disease burden profiles shifting from communicable diseases to non-communicable diseases (NCDs). Information on the epidemiology of T2DM has increased, but wide variations in study methods, diagnostic biomarkers and criteria hamper analytical comparison, and data from high-quality studies are limited. The prevalence of T2DM is still low in some rural populations but moderate or high rates are reported in many countries/regions, with evidence for an increase in some. In addition, the proportion of undiagnosed T2DM is still high. The prevalence of T2DM is highest in African people living in urban areas, and the gradient between African people living in urban areas and people in the African diaspora is rapidly fading. However, data from longitudinal studies are lacking and there is limited information on chronic complications and the genetics of T2DM. The large unmet needs for T2DM care call for greater investment of resources into health systems to manage NCDs in SSA. Proposed health-system paradigms are being developed in some countries/regions. However, national NCD programmes need to be adequately funded and coordinated to stem the tide of T2DM and its complications.

Polygenic Prediction of Type 2 Diabetes in Africa.

OBJECTIVE: Polygenic prediction of type 2 diabetes (T2D) in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of T2D from Africa and the poor transferability of European-derived polygenic risk scores (PRSs) in diverse ethnicities. We set out to evaluate if African American, European, or multiethnic-derived PRSs would improve polygenic prediction in continental Africans. RESEARCH DESIGN AND METHODS: Using the PRSice software, ethnic-specific PRSs were computed with weights from the T2D GWAS multiancestry meta-analysis of 228,499 case and 1,178,783 control subjects. The South African Zulu study (n = 1,602 case and 981 control subjects) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis were conducted in the Africa America Diabetes Mellitus (AADM) study (n = 2,148 case and 2,161 control subjects). RESULTS: The discriminatory ability of the African American and multiethnic PRSs was similar. However, the African American-derived PRS was more transferable in all the countries represented in the AADM cohort and predictive of T2D in the country combined analysis compared with the European and multiethnic-derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (odds ratio 3.63; 95% CI 2.19-4.03; P = 2.79 × 10-17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier than those in the first decile. CONCLUSIONS: African American-derived PRS enhances polygenic prediction of T2D in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in T2D.