Alisha N Wade’s research while affiliated with University of Pennsylvania and other places

Introduction Chronic health conditions are the leading causes of morbidity and mortality worldwide, with a disproportionately high burden in low-income and middle-income countries. The burden arising from these conditions presents immense challenges to countries with dysfunctional public healthcare systems, such as South Africa. This necessitates patients to have a good understanding of the conditions and optimal self-management approaches. We explored patients’ understanding of chronic health conditions and self-management practices, including self-monitoring, in the rural South African community of Agincourt in the subdistrict of Bushbuckridge, Mpumalanga Province. Methods We randomly selected patients receiving routine care for chronic health conditions in primary healthcare facilities who were linked to the Agincourt Health and Demographic Surveillance System to participate in focus group discussions. Six focus groups (three with men and three with women) were conducted, with 17 male and 19 female participants (n=35) living with different chronic health conditions. Data were collected using body mapping exercises and semistructured focus group discussions facilitated by two experienced qualitative research assistants. An inclusive thematic approach was used for analysis. Results Participants identified most chronic health conditions and their progression. Participants expressed that some consequences of chronic health conditions were unavoidable and some were attributed to medications. Three themes emerged on the management of chronic health conditions: (1) individual-level management, where participants actively changed or managed lifestyle factors associated with the conditions; (2) clinic-level management and support, where participants believed that following instructions from healthcare providers facilitates better management of their condition(s); and (3) prevention and screening, to prevent disease progression and development of complications. Participants also highlighted the role of religion in the control of chronic disease risk factors and traditional treatments for uncommon conditions such as epilepsy. Costs associated with lifestyle changes and equipment to manage and monitor health were highlighted as barriers to self-management of chronic health conditions. Conclusions Our findings contribute to emerging research on chronic health conditions and self-management approaches. Participants in our study demonstrated a good understanding of various chronic health conditions but lacked knowledge of self-management practices and faced barriers to self-management. There is a need for further studies on self-management of chronic health conditions, including self-monitoring among patients in rural sub-Saharan settings.

Aims/hypothesis Glycaemic traits such as high fasting glucose levels and insulin resistance are positively associated with the risk of type 2 diabetes and other cardiometabolic diseases. Genetic association studies have identified hundreds of associations for each glycaemic trait, yet very few studies have involved continental African populations. We report the results of genome-wide association studies (GWASs) in a pan-African cohort for four glycaemic traits, namely fasting glucose, fasting insulin, insulin resistance (HOMA-IR) and beta cell function (HOMA-B), which are quantitative variables that affect the risk of developing type 2 diabetes. Methods GWASs for the four traits were conducted in approximately 10,000 individuals from the Africa Wits-INDEPTH Partnership for Genomics Studies (AWI-Gen) cohort, with participants from Burkina Faso, Ghana, Kenya and South Africa. Association testing was performed using linear mixed models implemented in BOLT-LMM, with age, sex, BMI and principal components as covariates. Replication, fine mapping and functional annotation were performed using standard approaches. Results We identified a novel signal (rs574173815) in the intron of the ankyrin repeat domain 33B (ANKRD33B) gene associated with fasting glucose, and a novel signal (rs114029796) in the intronic region of the WD repeat domain 7 (WDR7) gene associated with fasting insulin. SNPs in WDR7 have been shown to be associated with type 2 diabetes. A variant (rs74806991) in the intron of ADAM metallopeptidase with thrombospondin type 1 motif 16 (ADAMTS16) and another variant (rs6506934) in the β-1,4-galactosyltransferase 6 gene (B4GALT6) are associated with HOMA-IR. Both ADAMTS16 and B4GALT6 are implicated in the development of type 2 diabetes. In addition, our study replicated several well-established fasting glucose signals in the GCK-YTK6, SLC2A2 and THORLNC gene regions. Conclusions/interpretation Our findings highlight the importance of performing GWASs for glycaemic traits in under-represented populations, especially continental African populations, to discover novel associated variants and broaden our knowledge of the genetic aetiology of glycaemic traits. The limited replication of well-known signals in this study hints at the possibility of a unique genetic architecture of these traits in African populations. Data availability The dataset used in this study is available in the European Genome–Phenome Archive (EGA) database (https://ega-archive.org/) under study accession code EGAS00001002482. The phenotype dataset accession code is EGAD00001006425 and the genotype dataset accession code is EGAD00010001996. The availability of these datasets is subject to controlled access by the Data and Biospecimen Access Committee of the H3Africa Consortium. GWAS summary statistics are accessible through the NHGRI-EBI GWAS Catalog (https://www.ebi.ac.uk/gwas/). Graphical Abstract

Importance Reductions in dietary salt are associated with blood pressure reductions; however, national governments that have passed laws to reduce sodium intake have not measured these laws’ impact. Objective To determine if South African regulations restricting sodium content in processed foods were associated with reductions in sodium consumption and blood pressure. Design, Setting, and Participants The HAALSI (Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) study is a population-based cohort study among adults aged 40 years or older randomly selected from individuals living in rural Mpumalanga Province in South Africa. This study incorporated 3 waves of data (2014/2015, 2018/2019, and 2021/2022) from the HAALSI study to examine how 24-hour urine sodium (24HrNa) excretion changed among a population-based cohort following mandatory sodium regulations. Spot urine samples were collected across 3 waves, and data analysis was performed from 2023 to 2024. Exposures South African regulations introduced in 2013 that reduced levels for the maximum amount of sodium in milligrams per 100 mg of food product by 25% to 80% across 13 processed food categories by 2019. Main Outcomes and Measures 24HrNa was estimated using the INTERSALT equation, and generalized estimating equations were used to assess changes in sodium excretion and blood pressure. Results Among 5059 adults 40 years or older, mean (SD) age was 62.43 years (13.01), and 2713 participants (53.6%) were female. Overall mean (SD) estimated 24HrNa excretion at baseline was 3.08 g (0.78). There was an overall reduction in mean 24HrNa excretion of 0.22 g (95% CI, −0.27 to −0.17; P < .001) between the first 2 waves and a mean reduction of 0.23 g (95% CI, −0.28 to −0.18; P < .001) between the first and third waves. The reductions were larger when analysis was restricted to those with samples in all 3 waves (−0.26 g for both waves 2 and 3 compared to wave 1). Every gram of sodium reduction was associated with a −1.30 mm Hg reduction (95% CI, 0.65-1.96; P = .00) in systolic blood pressure. The proportion of the study population that achieved ideal sodium consumption (<2 g per day) increased from 7% to 17%. Conclusion and Relevance In this cohort study, following South African regulations limiting sodium in 13 categories of processed foods, there was a significant reduction in 24HrNa excretion among this rural South African population, which was sustained with reductions in blood pressure consistent with levels of sodium excreted. These results support the potential health effects anticipated by effective implementation of population-based salt reformulation policies.

Introduction The contribution of obesity phenotypes to dyslipidaemia in middle-aged adults from four sub-Saharan African (SSA) countries at different stages of the epidemiological transition has not been reported. We characterized lipid levels and investigated their relation with the growing burden of obesity in SSA countries. Methods A cross-sectional study was conducted in Burkina Faso, Ghana, Kenya and South Africa. Participants were middle aged adults, 40–60 years old residing in the study sites for the past 10 years. Age-standardized prevalence and adjusted mean cholesterol, LDL-C, HDL-C, triglycerides and non-HDL-C were estimated using Poisson regression analyses and association of body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WTHR) with abnormal lipid fractions modeled using a random effects meta-analysis. Obesity phenotypes are defined as BMI ≥ 30 kg/m², increased WC and increased waist-to-hip ratio. Results A sample of 10,700 participants, with 54.7% being women was studied. Southern and Eastern African sites recorded higher age-standardized prevalence of five lipid fractions then West African sites. Men had higher LDL-C (19% vs 8%) and lower HDL-C (35% vs 24%) while women had higher total cholesterol (15% vs 19%), triglycerides (9% vs 10%) and non-HDL-cholesterol (20% vs 26%). All lipid fractions were significantly associated with three obesity phenotypes. Approximately 72% of participants in the sample needed screening for dyslipidaemia with more men than women requiring screening. Conclusion Obesity in all forms may drive a dyslipidaemia epidemic in SSA with men and transitioned societies at a higher risk. Targeted interventions to control the epidemic should focus on health promoting and improved access to screening services.

Background: Epidemiological data suggest the population distribution of thyrotropin (TSH) values is shifted toward lower values in self-identified Black non-Hispanic individuals compared with self-identified White non-Hispanic individuals. It is unknown whether genetic differences between individuals with genetic similarities to African reference populations (GSA) and those with similarities to European reference populations (GSE) contribute to these observed differences. We aimed to compare genome-wide associations with TSH and putative causal TSH-associated variants between GSA and GSE groups. Methods: We performed genome-wide association studies (GWAS) in 9827 GSA individuals and 9827 GSE individuals with TSH values between 0.45 and 4.5 mU/L. We compared effect sizes and allele frequencies of previously reported putative causal TSH-associated variants and our power to detect associations with these variants between the two groups. We additionally focused on variants in PDE8B and PDE10A, loci that have been most strongly associated with TSH in previous GWAS in GSE populations. Results: Four loci attained genome-wide significance in the GSA group compared with seven in the GSE group. PDE8B was not significantly associated with TSH in the GSA group, despite its strong association in the GSE group. Eight putative causal variants had significantly different effect sizes between groups. There was ≥80% power in the GSA group to detect significant associations with variants in PDE8B, PDE10A, NFIA, and LOC105377480, with higher expected power than in the GSE group for variants in PDE8B, NFIA, and LOC105377480 and similar power for other variants in PDE8B and PDE10A. No additional putative causal variants in PDE8B and PDE10A had effect sizes that differed significantly between the groups; power to identify associations with additional putative causal variants in PDE8B and PDE10A was similar between the groups. Conclusions: Patterns of genetic associations with TSH differed between identically sized GSA and GSE groups. Failure to replicate the strongest associations previously reported in GSE individuals in our GSA population was not fully explained by differences in allele frequencies or power, assuming similar effect sizes. Larger GSA population GWAS are necessary to confirm our findings and further investigate the contribution of genetic factors to population differences in the distribution of TSH values.

Background Diabetes can be detected at the primary health-care level, and effective treatments lower the risk of complications. There are insufficient data on the coverage of treatment for diabetes and how it has changed. We estimated trends from 1990 to 2022 in diabetes prevalence and treatment for 200 countries and territories. Methods We used data from 1108 population-representative studies with 141 million participants aged 18 years and older with measurements of fasting glucose and glycated haemoglobin (HbA1c), and information on diabetes treatment. We defined diabetes as having a fasting plasma glucose (FPG) of 7·0 mmol/L or higher, having an HbA1c of 6·5% or higher, or taking medication for diabetes. We defined diabetes treatment as the proportion of people with diabetes who were taking medication for diabetes. We analysed the data in a Bayesian hierarchical meta-regression model to estimate diabetes prevalence and treatment. Findings In 2022, an estimated 828 million (95% credible interval [CrI] 757–908) adults (those aged 18 years and older) had diabetes, an increase of 630 million (554–713) from 1990. From 1990 to 2022, the age-standardised prevalence of diabetes increased in 131 countries for women and in 155 countries for men with a posterior probability of more than 0·80. The largest increases were in low-income and middle-income countries in southeast Asia (eg, Malaysia), south Asia (eg, Pakistan), the Middle East and north Africa (eg, Egypt), and Latin America and the Caribbean (eg, Jamaica, Trinidad and Tobago, and Costa Rica). Age-standardised prevalence neither increased nor decreased with a posterior probability of more than 0·80 in some countries in western and central Europe, sub-Saharan Africa, east Asia and the Pacific, Canada, and some Pacific island nations where prevalence was already high in 1990; it decreased with a posterior probability of more than 0·80 in women in Japan, Spain, and France, and in men in Nauru. The lowest prevalence in the world in 2022 was in western Europe and east Africa for both sexes, and in Japan and Canada for women, and the highest prevalence in the world in 2022 was in countries in Polynesia and Micronesia, some countries in the Caribbean and the Middle East and north Africa, as well as Pakistan and Malaysia. In 2022, 445 million (95% CrI 401–496) adults aged 30 years or older with diabetes did not receive treatment (59% of adults aged 30 years or older with diabetes), 3·5 times the number in 1990. From 1990 to 2022, diabetes treatment coverage increased in 118 countries for women and 98 countries for men with a posterior probability of more than 0·80. The largest improvement in treatment coverage was in some countries from central and western Europe and Latin America (Mexico, Colombia, Chile, and Costa Rica), Canada, South Korea, Russia, Seychelles, and Jordan. There was no increase in treatment coverage in most countries in sub-Saharan Africa; the Caribbean; Pacific island nations; and south, southeast, and central Asia. In 2022, age-standardised treatment coverage was lowest in countries in sub-Saharan Africa and south Asia, and treatment coverage was less than 10% in some African countries. Treatment coverage was 55% or higher in South Korea, many high-income western countries, and some countries in central and eastern Europe (eg, Poland, Czechia, and Russia), Latin America (eg, Costa Rica, Chile, and Mexico), and the Middle East and north Africa (eg, Jordan, Qatar, and Kuwait). Interpretation In most countries, especially in low-income and middle-income countries, diabetes treatment has not increased at all or has not increased sufficiently in comparison with the rise in prevalence. The burden of diabetes and untreated diabetes is increasingly borne by low-income and middle-income countries. The expansion of health insurance and primary health care should be accompanied with diabetes programmes that realign and resource health services to enhance the early detection and effective treatment of diabetes.

Insulin secretion increases progressively during pregnancy to maintain normal maternal blood glucose levels. The placenta plays a crucial role in this process by releasing hormones and extracellular vesicles into the maternal circulation, which drive significant changes in pregnancy physiology. Placental extracellular vesicles, which are detectable in the plasma of pregnant women, have been shown to signal peripheral tissues and contribute to pregnancy-related conditions. While studies using murine models have demonstrated that extracellular vesicles can modulate insulin secretion in pancreatic islets, it remains unclear whether these effects translate to human biology. Understanding how placental signals enhance insulin synthesis and secretion from β cells could be pivotal in developing new therapies for diabetes. In our study, we isolated placental small extracellular vesicles from human placentae and utilised the human β cell line, EndoC-βH3, to investigate their effects on β-cell function in vitro. Our results indicate that human β cells internalise placental small extracellular vesicles, leading to enhanced insulin gene expression and increased insulin content within the β cells. Moreover, these vesicles upregulated the expression of Annexin A1, a protein known to increase insulin content. This upregulation of Annexin A1 holds promise as a potential mechanism by which placental small extracellular vesicles enhance insulin biosynthesis.

Background Adiposity can be measured using BMI (which is based on weight and height) as well as indices of abdominal adiposity. We examined the association between BMI and waist-to-height ratio (WHtR) within and across populations of different world regions and quantified how well these two metrics discriminate between people with and without hypertension. Methods We used data from studies carried out from 1990 to 2023 on BMI, WHtR and hypertension in people aged 20–64 years in representative samples of the general population in eight world regions. We graphically compared the regional distributions of BMI and WHtR, and calculated Pearson’s correlation coefficients between BMI and WHtR within each region. We used mixed-effects linear regression to estimate the extent to which WHtR varies across regions at the same BMI. We graphically examined the prevalence of hypertension and the distribution of people who have hypertension both in relation to BMI and WHtR, and we assessed how closely BMI and WHtR discriminate between participants with and without hypertension using C-statistic and net reclassification improvement (NRI). Findings The correlation between BMI and WHtR ranged from 0·76 to 0·89 within different regions. After adjusting for age and BMI, mean WHtR was highest in south Asia for both sexes, followed by Latin America and the Caribbean and the region of central Asia, Middle East and north Africa. Mean WHtR was lowest in central and eastern Europe for both sexes, in the high-income western region for women, and in Oceania for men. Conversely, to achieve an equivalent WHtR, the BMI of the population of south Asia would need to be, on average, 2·79 kg/m² (95% CI 2·31–3·28) lower for women and 1·28 kg/m² (1·02–1·54) lower for men than in the high-income western region. In every region, hypertension prevalence increased with both BMI and WHtR. Models with either of these two adiposity metrics had virtually identical C-statistics and NRIs for every region and sex, with C-statistics ranging from 0·72 to 0·81 and NRIs ranging from 0·34 to 0·57 in different region and sex combinations. When both BMI and WHtR were used, performance improved only slightly compared with using either adiposity measure alone. Interpretation BMI can distinguish young and middle-aged adults with higher versus lower amounts of abdominal adiposity with moderate-to-high accuracy, and both BMI and WHtR distinguish people with or without hypertension. However, at the same BMI level, people in south Asia, Latin America and the Caribbean, and the region of central Asia, Middle East and north Africa, have higher WHtR than in the other regions. Funding UK Medical Research Council and UK Research and Innovation (Innovate UK).