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Hypertension and obesity are the most important modifiable risk factors for cardiovascular diseases, but their association is not well characterized in Africa. We investigated regional patterns and association of obesity with hypertension among 30 044 continental Africans. We harmonized data on hypertension (defined as previous diagnosis/use of antihypertensive drugs or blood pressure [BP]≥140/90 mmHg/BP≥130/80 mmHg) and obesity from 30 044 individuals in the Cardiovascular H3Africa Innovation Resource across 13 African countries. We analyzed data from population-based controls and the Entire Harmonized Dataset. Age-adjusted and crude proportions of hypertension were compared regionally, across sex, and between hypertension definitions. Logit generalized estimating equation was used to determine the independent association of obesity with hypertension ( P value

INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic/Latinos and rates of NAFLD vary among Hispanics from different background groups. Genetic variants and continental ancestry contribute to NAFLD disparities among Hispanics. We evaluated two newly identified NAFLD-associated single nucleotide polymorphisms of HSD17B13, rs72613567:TA and rs62305723:A in Hispanics/Latinos. METHODS Clinical data, genotypes of variants of interest and estimates of continental ancestry were extracted from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) database, which includes a cohort of 16 415 US Hispanic/Latinos. Surrogate endpoints for NAFLD were suspected NAFLD based on unexplained aminotransferase elevation, continuous ALT levels and FIB-4 scores to estimate hepatic fibrosis. RESULTS In all, 9342 participants were included for analysis. The rs72613567:TA allele was found in 15.3% and the rs62305723:A allele was identified in 4.5% of HCHS/SOL participants. rs72613567:TA was less frequent in persons with vs without suspected NAFLD (12.4% vs 15.7%, P

Background In regions with weak healthcare systems, critical shortages of the healthcare workforce, and increasing prevalence of dual disease burdens, there is an urgent need for the implementation of proven effective interventions and strategies to address these challenges. Our mixed-methods hybrid type II effectiveness-implementation study is designed to fill this evidence-to-practice gap. This study protocol describes a cluster randomized controlled trial which evaluates the effectiveness of an implementation strategy, practice facilitation (PF), on the integration, adoption, and sustainability of a task-strengthening strategy for hypertension control (TASSH) intervention within primary healthcare centers (PHCs) in Lagos State, Nigeria. Design Guided by the Consolidated Framework for Implementation Research (CFIR) and the Reach Effectiveness Adoption Implementation and Maintenance (RE-AIM), this study tests the impact of a proven effective implementation strategy to integrate hypertension management into the HIV care cascade, across 30 PHCs. The study will be conducted in three phases: (1) a pre-implementation phase that will use CFIR to develop a tailored PF intervention for integrating TASSH into HIV clinics; (2) an implementation phase that will use RE-AIM to compare the clinical effectiveness of PF vs. a self-directed condition (receipt of information on TASSH without PF) on BP reduction; and (3) a post-implementation phase that will use RE-AIM to evaluate the effect of PF vs. self-directed condition on adoption and sustainability of TASSH. The PF intervention components comprise (a) an advisory board to provide leadership support for implementing TASSH in PHCs; (b) training of the HIV nurses on TASSH protocol; and (c) training of practice facilitators, who will serve as coaches, provide support, and performance feedback to the HIV nurses. Discussion This study is one of few, if any trials, to evaluate the impact of an implementation strategy for integrating hypertension management into HIV care, on clinical and implementation outcomes. Findings from this study will advance implementation science research on the effectiveness of tailoring an implementation strategy for the integration of an evidence-based, system-level hypertension control intervention into HIV care and treatment. Trial registration ClinicalTrials.gov (NCT04704336). Registered on 11 January 2021.

Nonalcoholic fatty liver disease (NAFLD) disproportionally affects Hispanic/Latino populations. However, the magnitude varies among Hispanic/Latino ethnic groups. We investigated the mechanisms of these disparities.We examined associations of NAFLD-associated genetic variants and continental ancestry with suspected NAFLD, levels of alanine aminotransferase (ALT), and liver fibrosis using data from the Hispanic Community Health Study/Study of Latinos-a population-based study of Hispanic/Latino adults in the United States. We evaluated data from 16,415 Hispanic/Latino adults in 4 cities from 2008 through 2011. Subjects suspected of having NAFLD or liver fibrosis were identified based on unexplained increases in levels of aminotransferases and FIB-4 score, respectively.Among the 9342 participants with available genetic and aminotransferase data, the PNPLA3 G allele (odds ratio [OR], 1.53; 95% CI, 1.41-1.66), TM6SF2 T allele (OR, 1.41; 95% CI, 1.20-1.67), and PPP1R3B G allele (OR, 1.16; 95% CI, 1.06-1.28) were associated with suspected NAFLD. PNPLA3 G was also associated with increased levels of ALT, except in participants with Dominican and South American backgrounds, and with liver fibrosis. The frequency of PNPLA3 G was high (41%) and TM6SF2 T (5%) was low in Hispanic/Latinos. PNPLA3 G frequency differed among Hispanic background groups with the highest proportion in Mexicans (52%) and the lowest proportion in Dominicans (23%). After adjustment for demographic, clinical, and behavioral factors, as well as PNPLA3 G, TM6SF2 T, and PPP1R3B G, American ancestry had a positive association with level of ALT (r = 6.61%; P.001), whereas African (r = -3.84%; P.001) and European (r = -4.31%; P.001) ancestry were inversely associated with level of ALT.American ancestry and PNPLA3 G are independent predictors of ALT levels in US Hispanic/Latinos and may in part explain NAFLD disparities in US Hispanic/Latinos.

Introduction While blunted nocturnal blood pressure is a major risk factor for cardiovascular events, limited information exist on the association between indoor particulate and circadian blood pressure variation. We report the association of short-time exposure to PM2.5 and PM10 with blunted nocturnal blood pressure among hypertensive adults in Ibadan. Purpose This study was to determine the association between short time exposure to air particulates and blunted nocturnal blood pressure among people of African descent. Methods We conducted a cross-sectional study among fifty hypertensive cases attending our University College Hospital. A 24-hours blood pressure (BP) monitoring was carried out at the same time as indoor particulate matter monitoring in their homes. Exposure to indoor fine particles (PM2.5) and thoracic particles (PM10) was estimated using a real-time particle counter and compared to the World Health Organization (WHO) 24-hours threshold of 25 μg/m3 and 50 μg/m3 for PM2.5 and PM10 respectively. All monitoring was carried out over a 24-hours period during the wet season. Linear regression model was fitted to determine predictors of non-dipping hypertension. Results Of the 50 hypertensive patients studied, 5 (10.0%), 39 (78.0%), 6 (12.0%) were reverse dippers, non-dippers and dippers respectively. The mean indoor PM2.5 (44.17±19.18 μg/m3) and PM10 (60.10±27.13 μg/m3) among the non-dippers were significantly higher than values obtained among dippers (PM2.5 = 22.97±10.19 μg/m3; PM10 = 29.51±12.74 μg/m3); p Conclusion Short-term exposure to indoor PM air pollution was associated with blunted nocturnal blood pressure. Therefore air pollution reduction strategies through improved cooking pattern is advocated in order to prevent future cardiovascular events. Funding Acknowledgement Type of funding source: None

Background APOL1 high‐risk genotypes are associated with increased risk for hypertension‐attributed kidney disease among Black adults in the United States. Biopsy studies show differences in kidney vasculature by APOL1 status; less is known about the variants' associations with systemic vascular and endothelial function. Whether APOL1 risk variants are associated with blood pressure (BP) is also uncertain. Methods and Results Using linear regression, we examined cross‐sectional associations of APOL1 risk genotypes (high=2 risk alleles, low=0 or 1 risk allele) with subclinical measures of vascular function (small arterial elasticity, n=1586; large arterial elasticity, n=1586; ascending aortic distensibility, n=985) and endothelial function (flow‐mediated dilation, n=777). Using linear mixed‐effects models, we studied longitudinal associations of APOL1 risk genotypes with BP (n=1619), adjusting for age, sex, and African ancestry. Among 1619 (12% APOL1 high‐risk) Black participants in MESA (Multi‐Ethnic Study of Atherosclerosis), mean age was 62 years old, 58% had hypertension, and mean systolic BP was 131 mm Hg at baseline. At examination 1 (2000–2002), there was no significant difference in small arterial elasticity, large arterial elasticity, ascending aortic distensibility, or flow‐mediated dilation in participants with APOL1 high‐ versus low‐risk genotypes ( P >0.05 for all). Over a mean follow‐up of 7.8 years, relative annual changes in systolic and diastolic BP and pulse pressure did not differ significantly by APOL1 risk status (between‐group differences of −0.20, −0.14, and −0.25, respectively; P >0.05 for all). Conclusions Among Black participants in MESA, APOL1 high‐risk genotypes were not associated with subclinical vascular and endothelial function or BP trajectories. The relationship of APOL1 with kidney disease may be intrinsic to the kidney rather than through peripheral effects on systemic vasculature or BP.

Introduction Among the risk factors for venous thromboembolism (VTE) are inheritance of the sickle cell gene and antiphospholipid syndrome. Antiphospholipid antibodies are elevated in sickle cell disease but there is little information on its levels in sickle cell trait. The prevalence of anticardiolipin antibodies and association with VTE is equally not known in the Nigerian population. Methods A case control study involving 50 consecutive patients with Doppler confirmed venous thromboembolism at the University College Hospital Ibadan and 50 apparently healthy individuals. Haemoglobin electrophoresis was carried out using cellulose acetate membrane. IgG and IgM anticardiolipin antibodies were assayed by ELISA. Results The mean age of the patients was 58.7±18.5years, range of 21-89 years, there were 21 males (42%). Majority of the patients (42 (84%)) had deep venous thrombosis while five (10%) patients presented with pulmonary embolism, one had both deep venous thrombosis and pulmonary embolism. A patient had portal vein thrombosis and another, an intracardiac clot. Sedentary lifestyles, hypertension and concomitant malignancy were the most prevalent risk factors (34% each) (figure I). Both sedentary lifestyle and cancer were significantly associated with VTE (p Conclusion The prevalence of sickle cell trait and anticardiolipin levels did not differ between VTE patients and healthy controls. Age, hypertension, sedentary lifestyle and malignancies were identified risk factors in our cohort of patients. Larger prospective studies may be helpful in determining the influence of sickle cell trait and antiphospholipid antibodies in venous thromboembolism. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background There is no reliable marker for detecting early renal disease in early children with sickle cell disease (SCD). Estimation of glomerular filtration rate (eGFR) as derived from the height/plasma creatinine formula is dependent on the accuracy of the creatinine analytical method used. The aim of this study was to evaluate different equations for eGFR. Methods Children aged 5–16 years recruited. mGFR was obtained using plasma disappearance of Inutest/Iohexol, serum creatinine (SCr) was measured either by standard laboratory method or by tandem mass spectrometry (MSMS). Estimated GFR was then calculated either by “Bedside Schwartz method” or by the full-age spectrum (FAS) equation. Findings A total of 79 patients (mean age 9.8 ± 4.0 years). A revised eGFR constant was calculated for Schwartz equation from the slope of the plot of height/plasma creatinine versus mGFR. Mean values for mGFR (132.7 ± 32.1 ml/min/1.73m2) and eGFR methods compared: eGFR from standard SCr was significantly higher (144.2 ± 37.3 ml/min/1.73m2, p = 0.008). The MSMS eGFR showed the lowest SD (SD = 27.5), while both FAS eGFR and FAS-height eGFR showed the highest correlation coefficient (r = 0.67). Interpretation eGFR calculation based on height and SCr determined with MSMS traceable creatinine is more reliable than Schwartz formula using jaffe/enzymatic methods in SCD children.

Sickle cell disease (SCD) is one of the most common monogenic diseases in humans with multiple phenotypic expressions that can manifest as both acute and chronic complications. Although described more than a century ago, challenges in comprehensive disease management and collaborative research on this disease are compounded by the complex molecular and clinical phenotypes of SCD, environmental and psychosocial factors, limited therapeutic options and ambiguous terminology. This ambiguous terminology has hampered the integration and interoperability of existing SCD knowledge, and SCD research translation. The SCD Ontology (SCDO), which is a community-driven integrative and universal knowledge representation system for SCD, overcomes this issue by providing a controlled vocabulary developed by a group of experts in both SCD and ontology design. SCDO is the first and most comprehensive standardized human- and machine-readable resource that unambiguously represents terminology and concepts about SCD for researchers, patients and clinicians. It is built around the central concept ‘hemoglobinopathy’, allowing inclusion of non-SCD haemoglobinopathies, such as thalassaemias, which may interfere with or influence SCD phenotypic manifestations. This collaboratively developed ontology constitutes a comprehensive knowledge management system and standardized terminology of various SCD-related factors. The SCDO will promote interoperability of different research datasets, facilitate seamless data sharing and collaborations, including meta-analyses within the SCD community, and support the development and curation of data-basing and clinical informatics in SCD.

International audience; Sickle cell disease (SCD) is a debilitating single gene disorder caused by a single point mutation that results in physical deformation (i.e. sickling) of erythrocytes at reduced oxygen tensions. Up to 75% of SCD in newborns world-wide occurs in sub-Saharan Africa, where neonatal and childhood mortality from sickle cell related complications is high. While SCD research across the globe is tackling the disease on multiple fronts, advances have yet to significantly impact on the health and quality of life of SCD patients, due to lack of coordination of these disparate efforts. Ensuring data across studies is directly comparable through standardization is a necessary step towards realizing this goal. Such a standardization requires the development and implementation of a disease-specific ontology for SCD that is applicable globally. Ontology development is best achieved by bringing together experts in the domain to contribute their knowledge.The SCD community and H3ABioNet members joined forces at a recent SCD Ontology workshop to develop an ontology covering aspects of SCD under the classes: phenotype, diagnostics, therapeutics, quality of life, disease modifiers and disease stage. The aim of the workshop was for participants to contribute their expertise to development of the structure and contents of the SCD ontology. Here we describe the proceedings of the Sickle Cell Disease Ontology Workshop held in Cape Town South Africa in February 2016 and its outcomes. The objective of the workshop was to bring together experts in SCD from around the world to contribute their expertise to the development of various aspects of the SCD ontology.

Background. Breast cancer is the leading cause of cancer-related mortality among women in Ghana. Data are limited on the predictors of poor outcomes in breast cancer patients in low-income countries; however, prolonged waiting time has been implicated. Among breast cancer patients who received treatment at Korle Bu Teaching Hospital, this study evaluated duration and factors that influenced waiting time from first presentation to start of definitive treatment. Method. We conducted a hospital-based retrospective study of 205 breast cancer patients starting definitive treatment at Korle Bu Teaching Hospital between May and December 2013. We used descriptive statistics to summarize patient characteristics. Mann–Whitney U and Kruskal–Wallis tests and Spearman rank correlation were performed to examine the patients, health system, and health worker factors associated with median waiting time. Poisson regression was used to examine the determinants of waiting time. Results. The mean age of the patients was 51.1 ± 11.8 years. The median waiting time was 5 weeks. The determinants of waiting time were level of education, age, income, marital status, ethnicity, disease stage, health insurance status, study sites, time interval between when biopsy was requested and when results were received and receipt of adequate information from health workers. Conclusion. A prolonged waiting time to treatment occurs for breast cancer patients in Ghana, particularly for older patients, those with minimal or no education, with lower income, single patients, those with late disease, those who are insured, and who did not receive adequate information from the health workers. Time to obtain biopsy reports should be shortened. Patients and providers need education on timely treatment to improve prognosis.

Air pollution has been associated with elevated blood pressure in adults. Data on this association in Nigeria, with the highest level of pollution in Africa, is sparse. The present study investigated the association between short-term exposure to particulate matter air pollution and hypertension.

Background Chronic kidney disease (CKD) is a burgeoning epidemic in sub-Saharan Africa. Abnormal blood pressure variations are prevalent in CKD and potentiate the risk of cardiovascular morbidity and mortality. Certain genetic variants (angiotensin II receptor type 1 1166 A>C and angiotensin-converting enzyme insertion and deletion polymorphisms) and biomarkers such as interleukin–6, tumor necrosis factor, soluble (s) E-selectin, homocysteine, and highly sensitive C-reactive protein have been shown to affect blood pressure variability among non-African CKD, hypertensive. and nonhypertensive CKD population. However, the contributions of the pattern, genetic, and environmental determinants of ambulatory blood pressure in African CKD have not been characterized. Understanding these interactions may help to develop interventions to prevent major cardiovascular events among people with CKD. Objective The overarching objective of this study is to identify, document, and develop approaches to address related phenomic, genetic, and environmental determinants of ambulatory blood pressure patterns in African CKD and non-CKD hypertensive patients compared with normotensive controls. Methods This is a longitudinal short-term follow-up study of 200 adult subjects with CKD and 200 each of age-matched hypertensives without CKD and apparently healthy controls. Demographic information, detailed clinical profile, electrocardiography, echocardiography, and 24-hr ambulatory blood pressure measurements will be obtained. Blood samples will be collected to determine albumin-creatinine ratio, fasting plasma glucose, lipid profile, electrolytes, urea and creatinine, C-reactive protein, serum homocysteine, fibroblast growth factor–23, and complete blood count, while 2 mL blood aliquot will be collected in EDTA (ethylenediaminetetraacetic acid) tubes and mixed using an electronic rolling system to prevent blood clots and subsequently used for DNA extraction and genetic analysis. Results A total of 239 participants have been recruited so far, and it is expected that the recruitment phase will be complete in June 2020. The follow-up phase will continue with data analysis and publications of results. Conclusions This study will help stratify Nigerian CKD patients phenotypically and genotypically in terms of their blood pressure variations with implications for targeted interventions and timing of medications to improve prognosis. International Registered Report Identifier (IRRID) DERR1-10.2196/14820

Air pollution has been associated with elevated blood pressure in adults. Data on this association in Nigeria, with the highest level of pollution in Africa is sparsse. The present study investigated the association between short-term exposure to particulate matter air pollution and hypertension. We conducted a case-control study comprising of 25 adults with hypertension and 25 age-, sex- and geographical location-matched normotensive controls. All participants had 24-hr ambulatory blood pressure (BP) monitoring at the same time as indoor particulate matter monitoring using a real-time particle counter and compared with the WHO guideline limit (25μg/m3). All monitoring was carried out over 24 hours during the wet season. Adjusted odds ratio with 95% confidence interval for the relationship between hypertension and particulate matter exposure was assessed at P 5 persons (aOR: 9.37; CI: 1.37 – 63.95) and PM2.5 > 25µg/m3 (aOR: 5.76; CI: 1.08 – 30.88) significantly increased the odds of hypertension. Short-term exposure to ambient PM air pollution was associated with a higher risk of hypertension. Air pollution reduction strategies may as well help in the prevention and control of hypertension. A large longitudinal study is needed to confirm these findings.

Sickle Cell Disease (SCD) is among the most common single-gene diseases in the world but evidence-based comprehensive health care has not been implemented where the highest prevalence of SCD occurs, in sub-Saharan Africa (SSA). It represents an urgent health burden, both in terms of mortality and morbidity with an estimated mortality of 8-16% in children under 5 years in SSA. Addressing the high mortality of SCD in SSA and for effective management of SCD, newborn screening (NBS) should be incorporated with prevention of infections (including pneumococcal septicaemia and malaria), parental education and support at all levels of healthcare provision to enable timely recognition. The NBS working group of the Africa Sickle Cell Research Network (AfroSickleNet) collaboration surveyed current projects in NBS in SSA, and current conditions that hinder more widespread implementation of NBS for SCD. Solutions based on new point-of-care testing technology to disseminate education, and implementation science approaches that leverage existing resources are proposed.

The authors declare no competing financial interests except for the following. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson; O.H.F. received grants from Metagenics (on women’s health and epigenetics) and from Nestle (on child health); L.J.B. is listed as an inventor on Issued U.S. Patent 8,080,371,“Markers for Addiction” covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction; P.S. has received research awards from Pfizer Inc., is a consultant for Mundipharma Co. (Cambridge, UK), is a patent holder with Biocompatibles UK Ltd. (Franham, Surrey, UK) (Title: Treatment of eye diseases using encapsulated cells encoding and secreting neuroprotective factor and/or anti-angiogenic factor; Patent number: 20120263794), and has a patent application with University of Heidelberg (Heidelberg, Germany) (Title: Agents for use in the therapeutic or prophylactic treatment of myopia or hyperopia; Europäische Patentanmeldung 15 000 771.4); P.W.F. has been a paid consultant for Eli Lilly and Sanofi Aventis and has received research support from several pharmaceutical companies as part of a European Union Innovative Medicines Initiative (IMI) project; M.A.N.’s participation is supported by a consulting contract between Data Tecnica Internation and the National Institute on Aging (NIH, Bethesda, MD, USA), and he also consults for Illumina, Inc., the Michael J. Fox Foundation, and University of California Healthcare among others; and M.J.C. is Chief Scientist for Genomics England, a UK government company.; International audience; Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined approximately 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

Publisher's version (útgefin grein)., Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension., The following authors declare commercial private and/or governmental affiliations: Bruce M. Psaty (BMP) serves on the DSMB of a clinical trial funded by Zoll Lifecor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Barbara V. Howard (BVH) has a contract from National Heart, Lung, and Blood Institute (NHLBI). Brenda W.J.H. Penninx (BWJHP) has received research funding (non-related to the work reported here) from Jansen Research and Boehringer Ingelheim. Mike A. Nalls (MAN) is supported by a consulting contract between Data Tecnica International LLC and the National Institute on Aging (NIA), National Institutes of Health (NIH), Bethesda, MD, USA. MAN also consults for Illumina Inc., the Michael J. Fox Foundation, and the University of California Healthcare. MAN also has commercial affiliation with Data Tecnica International, Glen Echo, MD, USA. Mark J. Caulfield (MJC) has commercial affiliation and is Chief Scientist for Genomics England, a UK government company. Oscar H Franco (OHF) is supported by grants from Metagenics (on women's health and epigenetics) and from Nestlé (on child health). Peter S. Sever (PSS) is financial supported from several pharmaceutical companies which manufacture either blood pressure lowering or lipid lowering agents, or both, and consultancy fees. Paul W. Franks (PWF) has been a paid consultant in the design of a personalized nutrition trial (PREDICT) as part of a private-public partnership at Kings College London, UK, and has received research support from several pharmaceutical companies as part of European Union Innovative Medicines Initiative (IMI) projects. Fimlab LTD provided support in the form of salaries for author Terho Lehtimäki (TL) but did not have any additional role in the study design to publish, or preparation of the manuscript. Gen‐info Ltd provided support in the form of salaries for author Ozren Polašek (OP) but did not have any additional role in the study design to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. There are no patents, products in development, or marked products to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

CKD affects an estimated 14% of adults in sub-Saharan Africa, but very little research has been done on the cause, progression, and prevention of CKD there. As part of the Human Heredity and Health in Africa (H3Africa) Consortium, the H3Africa Kidney Disease Research Network was established to study prevalent forms of kidney disease in sub-Saharan Africa and increase the capacity for genetics and genomics research. The study is performing comprehensive phenotypic characterization and analyzing environmental and genetic factors from nine clinical centers in four African countries (Ghana, Nigeria, Ethiopia, and Kenya) over a 5-year period. Approximately 4000 participants with specified kidney disease diagnoses and 4000 control participants will be enrolled in the four African countries. In addition, approximately 50 families with hereditary glomerular disease will be enrolled. The study includes both pediatric and adult participants age

Alpha-thalassemia and the BCL11A rs1427407 T allele are commonly observed in sickle cell anemia (SCA) patients and are associated with reduced hemolysis and higher hemoglobin F levels, respectively. We investigated whether a high-risk genetic profile, defined as SCA patients who did not inherit either α-thalassemia or the BCL11A rs1427407 T allele, had stronger associations with clinical and laboratory variables than the individual genetic components in the University of Ibadan cohort (n=249). We then replicated our findings in SCA cohorts from the University of Illinois at Chicago (UIC)(n=260) and Walk-Treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy (Walk-PHaSST)(n=387). High-risk was associated with higher reticulocytes (15.0% vs. 7.8%, P=0.08) and stroke history (6% vs. 1%, P=0.02) than standard risk patients and these associations were more significant than the individual genetic components in the University of Ibadan cohort. These findings were replicated in high-risk patients from UIC and Walk-PHaSST for reticulocytes (UIC: 13.5% vs. 11.8%, P=0.03; Walk-PHaSST: 9.6% vs. 8.2%, P=0.0003) and stroke history (UIC: 32% vs. 22%, P=0.07; Walk-PHaSST: 14% vs. 7%, P=0.01). On combined analysis, high-risk had strong associations with increased markers of hemolysis (hemoglobin β= -0.29, 95%CI: -0.50 to -0.09; P=0.006; reticulocyte% β=2.29, 95%CI: 1.31 to 3.25; P=1x10-5) and stroke history (OR=2.0, 95%CI: 1.3 to 3.0; P=0.0002), but no association with frequent vaso-occlusive crises (≥3/year). A high-risk genetic profile is associated with increased hemolysis and stroke history in three independent cohorts. This profile may help identify patients to prioritize for hydroxyurea and for closer monitoring strategies for stroke.

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution., A full list of acknowledgments appears in the Supplementary Note 4. Co-author A.J.M.d.C. recently passed away while this work was in process. This work was performed under the auspices of the Genetic Investigation of ANthropometric Traits (GIANT) consortium. We acknowledge the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium for encouraging CHARGE studies to participate in this effort and for the contributions of CHARGE members to the analyses conducted for this research. Funding for this study was provided by the Aase and Ejner Danielsens Foundation; Academy of Finland (41071, 77299, 102318, 110413, 117787, 121584, 123885, 124243, 124282, 126925, 129378, 134309, 286284); Accare Center for Child and Adolescent Psychiatry; Action on Hearing Loss (G51); Agence Nationale de la 359 Recherche; Agency for Health Care Policy Research (HS06516); ALF/LUA research grant in Gothenburg; ALFEDIAM; ALK-Abelló A/S; Althingi; American Heart Association (13POST16500011); Amgen; Andrea and Charles Bronfman Philanthropies; Ardix Medical; Arthritis Research UK; Association Diabète Risque Vasculaire; Australian National Health and Medical Research Council (241944, 339462, 389875, 389891, 389892, 389927, 389938, 442915, 442981, 496739, 552485, 552498); Avera Institute; Bayer Diagnostics; Becton Dickinson; BHF (RG/14/5/30893); Boston Obesity Nutrition Research Center (DK46200), Bristol-Myers Squibb; British Heart Foundation (RG/10/12/28456, RG2008/08, RG2008/014, SP/04/002); Medical Research Council of Canada; Canadian Institutes for Health Research (FRCN-CCT-83028); Cancer Research UK; Cardionics; Cavadis B.V., Center for Medical Systems Biology; Center of Excellence in Genomics; CFI; CIHR; City of Kuopio; CNAMTS; Cohortes Santé TGIR; Contrat de Projets État-Région; Croatian Science Foundation (8875); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research (DFF-1333-00124, DFF-1331-00730B); County Council of Dalarna; Dalarna University; Danish Council for Strategic Research; Danish Diabetes Academy; Danish Medical Research Council; Department of Health, UK; Development Fund from the University of Tartu (SP1GVARENG); Diabetes Hilfs- und Forschungsfonds Deutschland; Diabetes UK; Diabetes Research and Wellness Foundation Fellowship; Donald W. Reynolds Foundation; Dr Robert Pfleger-Stiftung; Dutch Brain Foundation; Dutch Diabetes Research Foundation; Dutch Inter University Cardiology Institute; Dutch Kidney Foundation (E033); Dutch Ministry of Justice; the DynaHEALTH action No. 633595, Economic Structure Enhancing Fund of the Dutch Government; Else Kröner-Fresenius-Stiftung (2012_A147, P48/08//A11/08); Emil Aaltonen Foundation; Erasmus University Medical Center Rotterdam; Erasmus MC and Erasmus University Rotterdam; the Municipality of Rotterdam; Estonian Government (IUT20-60, IUT24-6); Estonian Research Roadmap through the Estonian Ministry of Education and Research (3.2.0304.11-0312); European Research Council (ERC Starting Grant and 323195:SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC); European Regional Development Fund; European Science Foundation (EU/QLRT-2001-01254); European Commission (018947, 018996, 201668, 223004, 230374, 279143, 284167, 305739, BBMRI-LPC-313010, HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-2011-278913, HEALTH-2011-294713-EPLORE, HEALTH-F2-2008-201865-GEFOS, HEALTH-F2-2013-601456, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550-HYPERGENES, HEALTH-F7-305507 HOMAGE, IMI/115006, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2004-005272, LSHM-CT-2006-037697, LSHM-CT-2007-037273, QLG1-CT-2002-00896, QLG2-CT-2002-01254); Faculty of Biology and Medicine of Lausanne; Federal Ministry of Education and Research (01ZZ0103, 01ZZ0403, 01ZZ9603, 03IS2061A, 03ZIK012); Federal State of Mecklenburg-West Pomerania; Fédération Française de Cardiologie; Finnish Cultural Foundation; Finnish Diabetes Association; Finnish Foundation of Cardiovascular Research; Finnish Heart Association; Fondation Leducq; Food Standards Agency; Foundation for Strategic Research; French Ministry of Research; FRSQ; Genetic Association Information Network (GAIN) of the Foundation for the NIH; German Federal Ministry of Education and Research (BMBF, 01ER1206, 01ER1507); GlaxoSmithKline; Greek General Secretary of Research and Technology; Göteborg Medical Society; Health and Safety Executive; Healthcare NHS Trust; Healthway; Western Australia; Heart Foundation of Northern Sweden; Helmholtz Zentrum München—German Research Center for Environmental Health; Hjartavernd; Ingrid Thurings Foundation; INSERM; InterOmics (PB05 MIUR-CNR); INTERREG IV Oberrhein Program (A28); Interuniversity Cardiology Institute of the Netherlands (ICIN, 09.001); Italian Ministry of Health (ICS110.1/RF97.71); Italian Ministry of Economy and Finance (FaReBio di Qualità); Marianne and Marcus Wallenberg Foundation; the Ministry of Health, Welfare and Sports, the Netherlands; J.D.E. and Catherine T, MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International; KfH Stiftung Präventivmedizin e.V.; King's College London; Knut and Alice Wallenberg Foundation; Kuopio University Hospital; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001); La Fondation de France; Leenaards Foundation; Lilly; LMUinnovativ; Lundberg Foundation; Magnus Bergvall Foundation; MDEIE; Medical Research Council UK (G0000934, G0601966, G0700931, MC_U106179471, MC_UU_12019/1); MEKOS Laboratories; Merck Santé; Ministry for Health, Welfare and Sports, The Netherlands; Ministry of Cultural Affairs of Mecklenburg-West Pomerania; Ministry of Economic Affairs, The Netherlands; Ministry of Education and Culture of Finland (627;2004-2011); Ministry of Education, Culture and Science, The Netherlands; Ministry of Science, Education and Sport in the Republic of Croatia (108-1080315-0302); MRC centre for Causal Analyses in Translational Epidemiology; MRC Human Genetics Unit; MRC-GlaxoSmithKline pilot programme (G0701863); MSD Stipend Diabetes; National Institute for Health Research; Netherlands Brain Foundation (F2013(1)-28); Netherlands CardioVascular Research Initiative (CVON2011-19); Netherlands Genomics Initiative (050-060-810); Netherlands Heart Foundation (2001 D 032, NHS2010B280); Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) (56-464-14192, 60-60600-97-118, 100-001-004, 261-98-710, 400-05-717, 480-04-004, 480-05-003, 481-08-013, 904-61-090, 904-61-193, 911-11-025, 985-10-002, Addiction-31160008, BBMRI–NL 184.021.007, GB-MaGW 452-04-314, GB-MaGW 452-06-004, GB-MaGW 480-01-006, GB-MaGW 480-07-001, GB-MW 940-38-011, Middelgroot-911-09-032, NBIC/BioAssist/RK 2008.024, Spinozapremie 175.010.2003.005, 175.010.2007.006); Neuroscience Campus Amsterdam; NHS Foundation Trust; National Institutes of Health (1RC2MH089951, 1Z01HG000024, 24152, 263MD9164, 263MD821336, 2R01LM010098, 32100-2, 32122, 32108, 5K99HL130580-02, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, AG13196, CA047988, DA12854, DK56350, DK063491, DK078150, DK091718, DK100383, DK078616, ES10126, HG004790, HHSN268200625226C, HHSN268200800007C, HHSN268201200036C, HHSN268201500001I, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C, HL043851, HL45670, HL080467, HL085144, HL087660, HL054457, HL119443, HL118305, HL071981, HL034594, HL126024, HL130114, KL2TR001109, MH66206, MH081802, N01AG12100, N01HC55015, N01HC55016, N01C55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, N01HG65403, N01WH22110, N02HL6‐4278, N01-HC-25195, P01CA33619, R01HD057194, R01HD057194, R01AG023629, R01CA63, R01D004215701A, R01DK075787, R01DK062370, R01DK072193, R01DK075787, R01DK089256, R01HL53353, R01HL59367, R01HL086694, R01HL087641, R01HL087652, R01HL103612, R01HL105756, R01HL117078, R01HL120393, R03 AG046389, R37CA54281, RC2AG036495, RC4AG039029, RPPG040710371, RR20649, TW008288, TW05596, U01AG009740, U01CA98758, U01CA136792, U01DK062418, U01HG004402, U01HG004802, U01HG007376, U01HL080295, UL1RR025005, UL1TR000040, UL1TR000124, UL1TR001079, 2T32HL007055-36, T32GM074905, HG002651, HL084729, N01-HC-25195, UM1CA182913); NIH, National Institute on Aging (Intramural funding, NO1-AG-1-2109); Northern Netherlands Collaboration of Provinces; Novartis Pharma; Novo Nordisk; Novo Nordisk Foundation; Nutricia Research Foundation (2016-T1); ONIVINS; Parnassia Bavo group; Pierre Fabre; Province of Groningen; Päivikki and Sakari Sohlberg Foundation; Påhlssons Foundation; Paavo Nurmi Foundation; Radboud Medical Center Nijmegen; Research Centre for Prevention and Health, the Capital Region of Denmark; the Research Institute for Diseases in the Elderly; Research into Ageing; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Roche; Royal Society; Russian Foundation for Basic Research (NWO-RFBR 047.017.043); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Sanofi-Aventis; Scottish Government Health Directorates, Chief Scientist Office (CZD/16/6); Siemens Healthcare; Social Insurance Institution of Finland (4/26/2010); Social Ministry of the Federal State of Mecklenburg-West Pomerania; Société Francophone du 358 Diabète; State of Bavaria; Stiftelsen för Gamla Tjänarinnor; Stockholm County Council (560183, 592229); Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council; Stroke Association; Swedish Diabetes Association; Swedish Diabetes Foundation (2013-024); Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20120197, 20150711); Swedish Research Council (0593, 8691, 2012-1397, 2012-1727, and 2012-2215); Swedish Society for Medical Research; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 31003A-143914, 33CSCO-122661, 33CS30-139468, 33CS30-148401, 51RTP0_151019); Tampere Tuberculosis Foundation; Technology Foundation STW (11679); The Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community (G.0880.13, G.0881.13); The Great Wine Estates of the Margaret River Region of Western Australia; Timber Merchant Vilhelm Bangs Foundation; Topcon; Tore Nilsson Foundation; Torsten and Ragnar Söderberg's Foundation; United States – Israel Binational Science Foundation (Grant 2011036), Umeå University; University Hospital of Regensburg; University of Groningen; University Medical Center Groningen; University of Michigan; University of Utrecht; Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) (b2011036); Velux Foundation; VU University’s Institute for Health and Care Research; Västra Götaland Foundation; Wellcome Trust (068545, 076113, 079895, 084723, 088869, WT064890, WT086596, WT098017, WT090532, WT098051, 098381); Wissenschaftsoffensive TMO; Yrjö Jahnsson Foundation; and Åke Wiberg Foundation. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute (NHLBI); the National Institutes of Health (NIH); or the U.S. Department of Health and Human Services.

Hypertension is a major risk factor for all cardiovascular diseases, especially among African Americans. This study focuses on identifying specific blood pressure (BP) genes using 15 914 individuals of African ancestry from eight cohorts (Africa America Diabetes Mellitus, Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in young Adults, Genetics Network, Genetic Epidemiology Network of Arteriopathy, Howard University Family Study, Hypertension Genetic Epidemiology Network, and Loyola University Chicago Cohort) to further genetic findings in this population which has generally been underrepresented in BP studies. We genotyped and performed various single variant and gene-based exome-wide analyses on 15 914 individuals on the Illumina HumanExome Beadchip v1.0 or v1.1 to test association with SBP and DBP long-term average residuals that were adjusted for age, age-squared, sex, and BMI. We identified rare variants affecting SBP and DBP in 10 genes: AFF1, GAPDHS, SLC28A3, COL6A1, CRYBA2, KRBA1, SEL1L3, YOD1, CCDC13, and QSOX1. Prior experimental evidence for six of these 10 candidate genes supports their involvement in cardiovascular mechanisms, corroborating their potential roles in BP regulation. Although our results require replication or validation due to their low numbers of carriers, and an ethnicity-specific genotyping array may be more informative, this study, which has identified several candidate genes in this population most susceptible to hypertension, presents one of the largest African-ancestry BP studies to date and the largest including analysis of rare variants.

The Western diet is associated with high consumption of processed foods preserved with phosphate. Higher dietary phosphate consumption stimulates production of fibroblast growth factor 23 (FGF23), which heightens risk for cardiovascular disease and mortality. We hypothesized that adults living in a more westernized society have higher levels of FGF23 due to increased phosphate consumption as measured by urinary phosphate excretion.We measured plasma C-terminal FGF23 levels and urinary phosphate and creatinine levels in timed urine collections among 100 African adults living in the rural area of Igbo-Ora, Nigeria (52 women, 48 men), and 100 African Americans (32 women, 68 men) living in Maywood, IL, an urban suburb of Chicago, IL, USA. Among these 200 participants, urine collections were adequate in 76 and 68 of the Maywood and Igbo-Ora participants, respectively.In the total group, the mean age and body mass index, respectively, were 34.6 ± 8.2 years and 22.1 ± 3.9 kg/m(2) in Igbo-Ora, and 42.8 ± 7.2 years and 25.8 ± 6.5 kg/m(2) in Maywood. Demographic characteristics for each site were very similar after excluding participants without adequate urine collections. Among all 200 participants, the median (interquartile range) FGF23 levels were significantly higher in Maywood versus Igbo-Ora [63.8 (45.0-89.9) versus 12.5 RU/mL (8.5-18.5); P0.0001] and these differences did not change substantially after excluding nine women from Maywood with FGF23 levels400 RU/mL or after excluding participants with inadequate urine collections. Among participants with adequate urine collections, the mean 24-h urinary phosphate excretion was significantly higher in Maywood versus Igbo-Ora (810.6 ± 309.0 versus 347.5 ± 153.1 mg; P0.001) and FGF23 levels correlated significantly with total urinary phosphate excretion (r = 0.62; P0.001) and urinary phosphate-to-creatinine ratios (r = 0.50; P0.001).Living in a more westernized society may be associated with greater net phosphate absorption, as reflected by higher urinary phosphate excretion, and higher FGF23 levels.

Host genetic factors that influence the outcome of Plasmodium falciparum malaria infection are not fully understood. These include alpha-thalassemia, sickle cell disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency and cytochrome b5 reductase 3 (CYB5R3) T117S and ferroportin Q248H polymorphisms. G6PD, an X-linked gene, encodes the sole enzyme in red blood cells that produces NADPH for protection from reactive oxygen species. Hemi- or homozygosity for G6PD A+ (G6PD c. 376G) is an African specific polymorphism with reduced activity (PMID:26633385) but no apparent phenotype; hemi- or homozygosity for G6PD A- (G6PD c 202A/376G) is associated with both decreased activity and increased risk for oxidant-induced hemolysis (PMID:27040960). A Malaria Genomic Epidemiology Network (MalariaGEN) study with almost 30,000 participants reported that G6PD A- increases the risk for severe malarial anemia (PMID:25261933). CYB5R3 in red blood cells transfers electrons from NADH to cytochrome b5, which in turn converts methemoglobin to hemoglobin. The African-specific CYB5R3 T117S variant, is not associated with methemoglobinemia (PMID:9048929) but may afford some protection from malarial anemia in Zambian children. A prevalent African-specific Q248H mutation of the iron exporter, ferroportin, may protect from high malarial parasitemia (PMID: 29599243). We genotyped 212 Nigerian children (age 4 months - 16 years) for these genetic factors: 117 were asymptomatic children who were studied in the community and 95 were children who were studied at the time of admission to hospital with severe malaria (severe anemia and/or cerebral malaria). We isolated DNA from dried blood spots and crude DNA lysate was used for Taqman genotyping to screen for G6PD A+, G6PD A-, FPN Q248H, sickle cell disease and CYB5R3 T117S and multiplex PCR was used to identify the 3.7 kb and 4.2 kb α-globin gene deletions. The clinical characteristics of the two groups of children are shown in Table 1. Children with severe malaria were significantly younger than the children from the community. The gene frequency of CYB5R3 T117S was 0.303, of hemoglobin S was 0.094, and of FPN Q248H was 0.062. The prevalences of hemizygous and homozygous G6PD A+ and A- were 13.9% and 16.0%, respectively. In addition, the prevalences of single and double alpha globin gene deletions were 34.7 % and 11.7%, respectively. Table 2 compares the prevalence of these genotypes in asymptomatic children versus those admitted with severe malaria. Alpha-thalassemia tended to be more prevalent in the asymptomatic children while ferroportin Q248H and G6PD A- were more prevalent in the children with severe malaria. Some genes seemed to have heterogenous associations: sickle trait and homozygous CYB5R3 T117S tended to be more prevalent in the asymptomatic children while hemoglobin SS and heterozygous T117S tended to be more prevalent in the children with severe malaria. In a logistic regression model that adjusted for age, alpha thalassemia (odds ratio 0.6, P=0.038), hemoglobin S trait (odds ratio 0.5, P=0.203), and CYB5R3 T117S homozygous state (odds ratio 0.5, P=0.211) independently decreased the risk of severe malaria, while ferroportin Q248H (odds ratio 5.1, P=0.008) and G6PD deficiency (1.6, P=0.049) independently increased the risk of severe malaria. In conclusion, our results suggest that common genetic factors affect the risk of severe malaria in children. Research to illuminate the mechanisms of these effects may enhance our understanding of the pathogenesis of severe malaria and point to novel preventive and therapeutic measures. Disclosures Gordeuk: Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Pfizer: Research Funding; Inctye: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Imara: Research Funding.

African ancestry alleles may contribute to CKD among Hispanics/Latinos, but whether associations differ by Hispanic/Latino background remains unknown. We examined the association of CKD measures with African ancestry-specific APOL1 alleles that were directly genotyped and sickle cell trait (hemoglobin subunit β gene [HBB] variant) on the basis of imputation in 12,226 adult Hispanics/Latinos grouped according to Caribbean or Mainland background. We also performed an unbiased genome-wide association scan of urine albumin-to-creatinine ratios. Overall, 41.4% of participants were male, 44.6% of participants had a Caribbean background, and the mean age of all participants was 46.1 years. The Caribbean background group, compared with the Mainland background group, had a higher frequency of two APOL1 alleles (1.0% versus 0.1%) and the HBB variant (2.0% versus 0.7%). In the Caribbean background group, presence of APOL1 alleles (2 versus 0/1 copies) or the HBB variant (1 versus 0 copies) were significantly associated with albuminuria (odds ratio [OR], 3.2; 95% confidence interval [95% CI], 1.7 to 6.1; and OR, 2.6; 95% CI, 1.8 to 3.8, respectively) and albuminuria and/or eGFR

Habitual levels of dietary sodium and potassium are correlated with age-related increases in blood pressure (BP) and likely have a role in this phenomenon. Although extensive published evidence exists from randomized trials, relatively few large-scale community surveys with multiple 24-h urine collections have been reported. We obtained three 24-h samples from 2704 individuals from Nigeria, Jamaica and the United States to evaluate patterns of intake and within-person relationships with BP. The average (±s.d.) age and weight of the participants across all the three sites were 39.9±8.6 years and 76.1±21.2 kg, respectively, and 55% of the total participants were females. Sodium excretion increased across the East-West gradient (for example, 123.9±54.6, 134.1±48.8, 176.6±71.0 (±s.d.) mmol, Nigeria, Jamaica and US, respectively), whereas potassium was essentially unchanged (for example, 46.3±22.9, 40.7±16.1, 44.7±16.4 (±s.d.) mmol, respectively). In multivariate analyses both sodium (positively) and potassium (negatively) were strongly correlated with BP (P0.001); quantitatively the association was stronger, and more consistent in each site individually, for potassium. The within-population day-to-day variation was also greater for sodium than for potassium. Among each population group, a significant correlation was observed between sodium and urine volume, supporting the prior finding of sodium as a determinant of fluid intake in free-living individuals. These data confirm the consistency with the possible role of dietary electrolytes as hypertension risk factors, reinforcing the relevance of potassium in these populations.

Background. Despite a large body of evidence that hydroxyurea is effective for sickle cell anemia (SCA), utilization with the "maximum tolerated dose" regimen has been low.1 Hydroxyurea therapy for SCA increases hemoglobin F, reduces pain crises, acute chest syndrome and blood transfusions, and possibly increases survival.2 The increase in hemoglobin F with hydroxyurea is related to the plasma level achieved, which depends on the dose.3 Hydroxyurea is typically initiated at 15 mg/kg/day followed by dose escalations up to 35 mg/kg/day if tolerated - the "maximum tolerated dose" approach used in the seminal Multicenter Study of Hydroxyurea (MSH) in the 1990's.4 With this approach, neutropenia and thrombocytopenia are limitations to achieving maximal dose and frequent blood count monitoring is required.These considerations limit the use of hydroxyurea in areas of the world where frequent blood monitoring is not feasible, and they also cause primary care providers in the US to hesitate to prescribe the medication. Methods. We recently reported a trial of hydroxyurea (500 mg/day orally) in 48 adults with SCA in Ibadan, Nigeria - a "fixed low-dose" approach.5 In the present report, we compare hematologic responses in 38 per protocol patients from the Ibadan study (received at least five of the planned six 4-weekly supplies of hydroxyurea)5 to the responses in 152 patients in the MSH study.6 Results. Baseline hematologic values for the two studies are shown in Table 1. Over the first 12 to 14 weeks of hydroxyurea, responses in hemoglobin, mean corpuscular volume (MCV), and platelets were similar in the two studies (Figure 1). At end-of-study (24 weeks Ibadan and 104 weeks MSH) responses in hemoglobin F and complete blood count were similar, except that the decline in neutrophil count in the Ibadan cohort was significantly less than the decline in MSH after the Bonferroni correction for multiple comparisons (Table 1and Figure 2). At this time the median (range) dose of hydroxyurea per body weight was 10 (7-14) mg/kg per day in the 38 Ibadan patients versus 20 (2.5-35) mg/kg per day in the 119 patients who remained on hydroxyurea in the MSH study.6 We performed a review of the medical records in the Ibadan patients. There were seven acute non-infectious complications in the 38 patients while taking fixed low-dose hydroxyurea for 24 weeks (admission for pain or acute chest syndrome) versus 17 while being observed off hydroxyurea for 24 weeks (pain, acute chest syndrome, need for blood transfusion, heart failure or death) (Table 2). Incidence of infections was similar during 24 weeks of fixed low-dose hydroxyurea and during 24 weeks of observation off hydroxyurea (Table 2). Discussion. These findings suggest that a "fixed low-dose" regimen may have substantial clinical benefit. Such a regimen would have a low chance of inducing cytopenias, would be straightforward for primary care providers to prescribe and would be ideal to test in combination therapy regimens for SCA. It would also be cost-efficient and affordable, especially for patients in low and middle-income countries where access to health insurance is lacking. We propose that the clinical efficacy of "fixed low-dose" hydroxyurea for SCA should be investigated further. We believe that a randomized comparison of the efficacy and safety of the "fixed low-dose" and "maximum tolerated dose" regimens should be a high priority. References Stettler N, McKiernan CM, Melin CQ, Adejoro OO, Walczak NB. Proportion of adults with sickle cell anemia and pain crises receiving hydroxyurea. JAMA 2015;313:1671-2. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med 2008;358:1362-9. Charache S, Dover GJ, Moore RD, et al. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia. Blood 1992;79:2555-65. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995;332:1317-22. Tayo BO, Akingbola TS, Saraf SL, et al. Fixed Low-Dose Hydroxyurea for the Treatment of Adults with Sickle Cell Anemia in Nigeria. Am J Hematol 2018. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75:300-26. Disclosures Hsu: Global Blood Therapeutics: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ironwood: Research Funding; Emmi: Consultancy; Hilton Publishing: Consultancy; Gerson Lehman Group: Consultancy; Guidepoint: Consultancy.

ObjectivesThe purpose of this study is to understand whether naturally occurring genetic variation in the promoter of chromogranin B (CHGB), a major constituent of catecholamine storage vesicles, is functional and confers risk for cardiovascular disease.BackgroundCHGB plays a necessary (catalytic) role in catecholamine storage vesicle biogenesis. Previously, we found that genetic variation at CHGB influenced autonomic function, with association maximal toward the 5′ region.MethodsHere we explored transcriptional mechanisms of such effects, characterizing 2 common variants in the proximal promoter, A-296C and A-261T, using transfection/cotransfection, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP). We then tested the effects of promoter variation on cardiovascular traits.ResultsThe A-296C disrupted a c-FOS motif, exhibiting differential mobility shifting to chromaffin cell nuclear proteins during EMSA, binding of endogenous c-FOS on ChIP, and differential response to exogenous c-FOS. The A-261T disrupted motifs for SRY and YY1, with similar consequences for EMSA, endogenous factor binding, and responses to exogenous factors. The 2-SNP CHGB promoter haplotypes had a profound (p = 3.16E-20) effect on blood pressure (BP) in the European ancestry population, with a rank order of CT

Sex disparity in hypertension prevalence is well established in developed nations; however, there is paucity of data on the distribution of hypertension prevalence between the sexes in developing countries. Therefore, the authors examined sex differences in hypertension prevalence and cardiovascular risk factors in a sample of 352 healthy hospital workers in Nigeria. The mean ages of the men and women were 37.2±7.9 and 44.7±9.1 years, respectively. Thirty-five percent of participants were hypertensive, with 54% on treatment and 70% with controlled blood pressure. Men had a higher prevalence of hypertension (38.4% vs 33.0%) and prehypertension (37.6% vs 29.7%). Women had significantly higher odds of developing hypertension and of being on treatment. Mean blood pressure and fasting plasma glucose values were higher in men, while women were more often older, obese, and dyslipidemic and had a lower mean estimated glomerular filtration rate (P

Metabolic syndrome is associated with higher rates of cardiovascular morbidity and mortality. Although significant disparities in the risks of metabolic syndrome by occupation type and sex are well documented, the factors associated with metabolic syndrome in low- to middle-income countries remain unclear. These gaps in evidence identify the need for patterns of metabolic syndrome among hospital personnel of both sexes in Nigeria. A total of 256 hospital workers comprising 32.8% men were studied. The mean age of the participants was 42.03±9.4 years. Using International Diabetic Federation criteria, the prevalence of metabolic syndrome was 24.2%. Women were substantially and significantly more likely to be identified with metabolic syndrome compared with men (34.9% vs 2.4%, respectively; P=.0001). This study identified metabolic syndrome among health workers with over one third of women with metabolic syndrome compared with

Background.Blood pressure (BP) control is poor among hypertensives in many parts of sub-Saharan Africa. A potentially modifiable factor for control of BP is medication nonadherence (MNA); our study therefore aimed to determine factors associated with MNA among hypertensives in Ghana and Nigeria.Methodology.We conducted a multicenter cross-sectional study. Patients were recruited from Korle-Bu Hospital (n=120), Ghana; and University of Port Harcourt Teaching Hospital, (n=73) Apapa General Hospital Lagos (n=79) and University College Hospital Ibadan (n=85), Nigeria.Results.357 hypertensive patients (42.6% males) participated. MNA was found in 66.7%. Adherence showed correlation with depression (r=-0.208,P<0.001), concern about medications (r=-0.0347,P=0.002), and knowledge of hypertension (r=0.14,P=0.006). MNA was associated with formal education (P=0.001) and use of herbal preparation (P=0.014). MNA was found in 61.7% of uninsured participants versus 73.1% of insured participants (P=0.032). Poor BP control was observed in 69.7% and there was significant association between MNA and poor BP control (P=0.006).Conclusion. MNA is high among hypertensives in Ghana and Nigeria and is associated with depression, concern about hypertensive medications, formal education, and use of herbal preparations. The negative association between health insurance and MNA suggests interplay of other factors and needs further investigation.

Hypertension, once a rare problem in Sub-Saharan Africa (SSA), is predicted to be a major cause of death by 2020 with mortality rates as high as 75%. However, comprehensive knowledge of provider-level factors that influence optimal management is limited. The objective of the current study was to discover physicians’ perceptions of factors influencing optimal management and control of hypertension in SSA. Twelve physicians attending the Cardiovascular Research Training (CaRT) Institute at the University of Ghana, College of Health Sciences, were invited to complete a concept mapping process that included brainstorming the factors influencing optimal management and control of hypertension in patients, sorting and organizing the factors into similar domains, and rating the importance and feasibility of efforts to address these factors. The highest ranked important and feasible factors include helping patients accept their condition and availability of adequate equipment to enable the provision of needed care. The findings suggest that patient self-efficacy and support, physician-related factors, policy factors, and economic factors are important aspects that must be addressed to achieve optimal hypertension management. Given the work demands identified by physicians, future research should investigate cost-effective strategies of shifting physician responsibilities to well-trained no-physician clinicians in order to improve hypertension management.

Background: The vast majority of births with sickle cell anemia occur in Africa 1 and early-life mortality, generally before age five years, is as high as 90% 2,3. Hydroxyurea was approved for sickle cell anemia by the US FDA in 1998 but is not commonly used in Africa due to fear of toxicity, lack of awareness and limited availability. Hemoglobin F is a protective factor that decreases severity of sickle cell anemia, and hydroxyurea treatment leads to an increase in hemoglobin F. In the US, hydroxyurea is typically initiated at a dose of 15 mg/kg followed by dose escalations of up to 35 mg/kg if tolerated with a goal of maximal tolerated dose and maximal response in hemoglobin F. Neutropenia and thrombocytopenia are the usual limitations to achieving maximal dose. In the landmark Multicenter Study of Hydroxyurea, the clinical response to hydroxyurea correlated strongly with a reduction in the neutrophil count as well as an increase in the fetal hemoglobin concentration as reflected in percentage of F cells. A striking decrease in pain crises was observed in the first three months of therapy, before dose escalation and before maximal increase in hemoglobin F levels 4. Furthermore, hydroxyurea in the range of 10-15.9 mg/kg/day was reportedly effective in decreasing the frequency of pain episodes in children and adolescents in Oman 5, and hydroxyurea 10 mg/kg/day decreased pain episodes in children and adults with sickle cell anemia in India 6. From these perspectives, we reasoned that a fixed dose of hydroxyurea 10 mg/kg/day is reasonable to investigate in the African setting where the safety in relationship to the resources and infectious exposures is not known. Methods: We assigned 48 sickle cell anemia patients to hydroxyurea 500 mg/day for 24 weeks to determine safety and efficacy; 28 had high-risk disease based on hemoglobin F Results: The median (interquartile range) age was 25 (22-27) years and the median hydroxyurea dose 9.8 (9.1-10.4) mg/kg per day. The patients complied with treatment for a median of 20 (16-24) weeks. Four (8.3%) developed a pre-specified adverse outcome: clinical malaria (N=2), thrombocytopenia in combination with malaria (N=1), pulmonary tuberculosis (N=1). During therapy the median hemoglobin increased by 9.0 g/L, mean corpuscular volume by 11.2 fL and body weight by 3.0 kg while median white blood cells declined by 2600 per uL and platelets by 127,000 per uL (P Conclusion: Our results suggest that low, fixed-dose dose hydroxyurea for sickle cell anemia in Nigeria is associated with a low adverse outcome rate and with improvements in blood counts, hemoglobin F and body weight. The effects on vaso-occlusive episodes and on the risks of recrudescent tuberculosis and malaria-associated thrombocytopenia should be assessed in further studies. Acknowledgment: Supported by a grant from the Doris Duke Foundation. References 1. Williams TN, Obaro SK. Sickle cell disease and malaria morbidity: a tale with two tails. Trends Parasitol 2011;27:315-20. 2. Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, Williams TN. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med 2011;41:S398-405. 3. Makani J, Cox SE, Soka D, et al. Mortality in sickle cell anemia in Africa: a prospective cohort study in Tanzania. PLoS One 2011;6:e14699. 4. Charache S, Barton FB, Moore RD, et al. Hydroxyurea and sickle cell anemia. Clinical utility of a myelosuppressive "switching" agent. The Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Medicine (Baltimore) 1996;75:300-26. 5. Sharef SW, Al-Hajri M, Beshlawi I, et al. Optimizing Hydroxyurea use in children with sickle cell disease: low dose regimen is effective. Eur J Haematol 2013. 6. Patel DK, Mashon RS, Patel S, Das BS, Purohit P, Bishwal SC. Low dose hydroxyurea is effective in reducing the incidence of painful crisis and frequency of blood transfusion in sickle cell anemia patients from eastern India. Hemoglobin 2012;36:409-20. Disclosures Ezekekwu: American Society of Hematology: Other: The Visitor training program was sponsored by ASH. Hsu: AstraZeneca steering committee for HESTIA trial: Research Funding. Gordeuk: Emmaus Life Sciences: Consultancy.

Background: Circadian variation in blood pressure (BP) has been shown to determine cardiovascular events in people with chronic kidney diseases (CKDs). Studies aimed at elucidating the relationship between diurnal variation in BP and cardiovascular disease have yielded conflicting results, and very few of these studies have been conducted on CKD patients in Sub-Saharan Africa, hence the need for this study. Subjects and Methods: Eighty-five adult participants comprising 54 patients with CKD (36 males and 18 females) and 31 hypertensive patients (16 males and 15 females) free of CKD were recruited for 24 h ambulatory BP monitoring and cardiovascular risk factor assessment. Results: Patients with CKD had a higher mean clinic systolic BP (159.8 ± 28.6 vs. 147.9 ± 19.0 mmHg, P = 0.049) and reduced estimated glomerular filtration rate (19.2 ± 18.6 vs. 106.2 ± 30.6, P < 0.0001) when compared with hypertensives free of CKD. The mean 24 h ambulatory SBP (135.9 ± 28.5 vs. 120.3 ± 11.8 mmHg, P = 0.007), diastolic BP (82.6 ± 18.1 vs. 74.8 ± 9.0 mmHg, P = 0.034) and mean arterial pressure (100.9 ± 21.2 vs. 90.6 ± 10.2 mmHg, P = 0.018) were higher amongst CKD patients. Compared with hypertensive without CKD, daytime hypertension (58.9% vs. 21.4, P = 0.001), nocturnal hypertension (80.4% vs. 50.0%, P = 0.004) and non-dippers (92.0% vs. 73.1%, P = 0.026) were commoner in people with CKD. White coat effect was more common amongst hypertensives without CKD (74.2% vs. 38.0%, P = 0.002). The mean left atrial diameter and left ventricular mass index were higher in CKD group. Conclusion: This study highlights the high prevalence of varied phenotypes in circadian rhythm amongst CKD patients. Ambulatory blood pressure monitoring may be useful for early risk stratification of CKD patients. Large longitudinal study is needed to assess the prognostic implication of the findings.

Background Patients with sickle cell disease in the USA have been noted to have lower levels of vitamin D – measured as 25-hydroxyvitamin D (25(OH)D) – compared to controls. Average serum 25(OH)D levels are also substantially lower in African Americans than whites, while population distributions of 25(OH)D among Jamaicans of African descent and West Africans are the same as among USA whites. The purpose of this study was to examine whether adult patients with sickle cell disease living in tropical regions had reduced 25(OH)D relative to the general population. Methods We analyzed serum 25(OH)D in stored samples collected from studies in Jamaica and West Africa of adult patients with sickle cell disease and adult population controls. Results In samples of 20 Jamaicans and 50 West Africans with sickle cell disease mean values of 25(OH)D were 37% and 39% lower than controls, respectively. Metabolic abnormalities in the absorption and conversion pathways are possible causes for the consistent relative deficiency of 25(OH)D in sickle cell disease. Conclusions Low 25(OH)D levels in tropical Africa where the burden of sickle cell disease is highest, deserve further investigation, and a randomized trial is warranted to address efficacy of supplementation.

Background.Certain hypertension subtypes have been shown to increase the risk for cardiovascular morbidity and mortality and may be related to specific underlying genetic determinants. Inappropriate characterization of subtypes of hypertension makes efforts at elucidating the genetic contributions to the etiology of hypertension largely vapid. We report the hypertension subtypes among patients with hypertension from South-Western Nigeria.Methods.A total of 1858 subjects comprising 76% female, hypertensive, aged 18 and above were recruited into the study from two centers in Ibadan, Nigeria. Hypertension was identified using JNCVII definition and was further grouped into four subtypes: controlled hypertension (CH), isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic-diastolic hypertension (SDH).Results.Systolic-diastolic hypertension was the most prevalent. Whereas SDH (77.6% versus 73.5%) and IDH (4.9% versus 4.7%) were more prevalent among females, ISH (10.1% versus 6.2%) was higher among males(P=0.048). Female subjects were more obese(P<0.0001)and SDH was prevalent among the obese group.Conclusion.Gender and obesity significantly influenced the distribution of the hypertension subtypes. Characterization of hypertension by subtypes in genetic association studies could lead to identification of previously unknown genetic variants involved in the etiology of hypertension. Large-scale studies among various ethnic groups may be needed to confirm these observations.

H3Africa is developing capacity for health-related genomics research in Africa

To identify factors that affect manifestations of sickle cell anemia we compared patients 11-30 years of age from University of Ibadan, Ibadan, Oyo, Nigeria (n = 214) and University of Illinois at Chicago, Chicago, IL, USA (n = 209). Paralleling findings in the general populations of the two countries, the Chicago patients were more often overweight or obese as defined by the Centers for Disease Control and Prevention (Atlanta, GA, USA) guidelines, and more often had elevated blood pressure (BP) as defined by the National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD, USA guidelines. The Ibadan patients did not receive the pneumococcal vaccine or hydroxyurea (HU) therapy as frequently as the Chicago patients. Consistent with lower rates of elevated BP and increased body mass index (BMI), stroke history was less frequent in the Ibadan patients ≥18 years old. Furthermore, in combined analyses, systolic and diastolic BP directly correlated with BMI, and elevated weight status independently associated with history of stroke. Our findings are consistent with the possibility that higher values for BMI and BP in Chicago sickle cell anemia patients may contribute to an increased risk of stroke and highlights the need for measures to reduce these risk factors. On the other hand, lower pneumococcal vaccination and HU therapy rates in Ibadan patients highlights the need for more improved vaccination coverage and for studies to define the role of HU therapy in Africa.

The hepatitis C virus (HCV), which was not recognized as an infectious agent until the 1980s, is responsible for a worldwide epidemic. The World Health Organization estimates global prevalence at 2.8%, with 185 million persons infected. In contrast to hepatitis B, where successful vaccine campaigns have reduced the disease burden, much less progress has been made toward the control of HCV. Phylogenetic studies suggest that HCV originated in Africa and has been endemic in some regions for at least 500–600 years. However, little is known about the epidemiology, transmission, and clinical course of HCV in Africa. With the advent of highly effective anti-HCV agents, there exists great potential to at least curb the global epidemic. For regions such as sub-Saharan Africa, however, this will require a thorough understanding of the regional population-level epidemiology, risk factors, and transmission mechanisms. Only then can effective treatment and prevention strategies be introduced.

Introduction: Hypertension is a major cardiovascular disease and is responsible for fatal cardiovascular outcomes such as stroke, myocardial infarction, heart failure and renal failure. In Nigeria, the prevalence of hypertension and its associated complications is increasing at an alarming rate. Whereas excess weight is associated with increased rate of death from cardiovascular diseases, data on association between excess weight and hypertension in Nigerian population are sparse. In the present study we investigated the association between excess body weight and hypertension in a Nigerian semi-urban settlement. Methods: A cross-sectional survey was carried out at the Kumapayi settlement located in the suburb of Ibadan in southwestern Nigeria. A total of 293 subjects, comprising 40% males, aged 18 years and above who consented to the study following a period of publicity and invitations to all residents of the settlement were enrolled into the study. Demographic, anthropometry and blood pressure measurements were carried out on all the subjects by trained health personnel. Results: Mean subject age was 47.3 ± 15.2 years with 28.9% overweight (BMI 25-29 kg/m2) and 21.6% obese (BMI ≥ 30 kg/m2). The prevalence of overweight and obesity increased with age peaking at age 40-64 years and then falling. The prevalence of hypertension (BP ≥ 140/90 mmHg) was 43.3%. There was significant association between increased BMI and both systolic (P

Two common genetic modifiers, α-thalassemia and the BCL11A rs1427407 T allele, are observed in approximately one-third of patients with sickle cell anemia (SCA) and are associated with reduced hemolysis and higher hemoglobin F (HbF) levels, respectively. We investigated the laboratory and clinical effects of α-thalassemia and the BCL11A rs1427407 T allele in the University of Ibadan cohort of SCA patients and replicated our findings in two independent SCA cohorts, University of Illinois at Chicago (UIC) and Walk-Treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy (Walk-PHaSST). Alpha-thalassemia status was determined by PCR in all 3 cohorts while the BCL11A rs1427407 genotype was determined by PCR in the Ibadan and UIC cohorts and imputed in the Walk-PHaSST cohort. Comparisons according to genotype were performed using the linear trend test for continuous variables and Cochran's test of linear trend for categorical variables. Alpha-thalassemia was observed in 43% of 257 SCA patients from Ibadan and was associated with higher body mass index and lower white blood cell count (Table 1). The BCL11A rs1427407 T allele was observed in 46% of SCA patients from Ibadan and was associated with higher hemoglobin concentration. HbF levels by HPLC were available in 25 patients (12 with the BCL11A rs1427407 T allele) enrolled in a study of low-dose hydroxyurea; these levels were higher in patients with at least one rs1427407 T allele at baseline and progressively during therapy with hydroxyurea 10 mg/kg/day (repeated measures P=0.01). We defined a high risk genetic group as the absence of α-thalassemia in combination with absence of the BCL11A rs1427407 T allele. This high risk group was observed in 31% of SCA patients from the Ibadan cohort and was associated with a higher reticulocyte percentage (15.0% vs. 7.8%, P=0.08) and a higher prevalence for a history of stroke (6% vs. 1%, P=0.02). The association with stroke history persisted on logistic regression analysis after adjusting for age, gender, and hydroxyurea therapy (OR 9.4, 95%CI: 1.2-72.8; P=0.03). We then replicated the association of this high risk group with markers of hemolysis and with history of stroke in the UIC and Walk-PHaSST SCA cohorts. In the UIC cohort, the high risk group was observed in 34% (92/271) and was also associated with higher reticulocyte counts (13.5% vs. 11.9%, P=0.10) and higher prevalence for stroke history (33% vs. 22%; age, gender, HU-adjusted OR 1.7, 95%CI: 1.0-3.0; P=0.066). In the Walk-PHaSST cohort, this high risk profile was observed in 38% (149/394) and was associated with a higher reticulocyte percentage (9.7% vs. 8.4%, P=0.0005), lower hemoglobin concentration (8.4 vs. 8.8 g/dL; P=0.017), and higher prevalence for stroke history (15% vs. 6%; age, gender, HU-adjusted OR 2.6, 95%CI: 1.3-5.3; P=0.007). In conclusion, a high risk group of SCA patients, defined by the lack of the protective α-thalassemia and the BCL11A rs1427407 variants, is associated with a higher degree of hemolysis and a higher prevalence of stroke history on cross sectional analysis in three independent cohorts. This high-risk profile may help identify patients to prioritize for hydroxyurea therapy and for closer monitoring strategies for stroke. Disclosures Hsu: Sancilio: Research Funding; Astra Zeneca: Consultancy, Research Funding; Purdue Pharma: Research Funding; Gerson Lehman Group: Consultancy; Eli Lilly: Research Funding; Centers for Medicare and Medicaid Innovation: Research Funding; Hilton Publishing: Consultancy, Research Funding; Mast Therapeutics: Research Funding; EMMI Solutions: Consultancy; Pfizer: Consultancy, Research Funding.

We compare the SNP-based and gene-based association studies using 697 unrelated individuals. The Benjamini-Hochberg procedure was applied to control the false discovery rate for all the multiple comparisons. We use a linear model for the single-nucleotide polymorphism (SNP) based association study. For the gene-based study, we consider three methods. The first one is based on a linear model, the second is similarity based, and the third is a new two-step procedure. The results of power using a subset of SNPs show that the SNP-based association test is more powerful than the gene-based ones. However, in some situations, a gene-based study is able to detect the associated variants that were neglected in a SNP-based study. Finally, we apply these methods to a replicate of the quantitative trait Q1 and the binary trait D (D = 1, affected; D = 0, unaffected) for a genome-wide gene search.

Background The rapid progress currently being made in genomic science has created interest in potential clinical applications; however, formal translational research has been limited thus far. Studies of population genetics have demonstrated substantial variation in allele frequencies and haplotype structure at loci of medical relevance and the genetic background of patient cohorts may often be complex. Methods and Findings To describe the heterogeneity in an unselected clinical sample we used the Affymetrix 6.0 gene array chip to genotype self-identified European Americans (N = 326), African Americans (N = 324) and Hispanics (N = 327) from the medical practice of Mount Sinai Medical Center in Manhattan, NY. Additional data from US minority groups and Brazil were used for external comparison. Substantial variation in ancestral origin was observed for both African Americans and Hispanics; data from the latter group overlapped with both Mexican Americans and Brazilians in the external data sets. A pooled analysis of the African Americans and Hispanics from NY demonstrated a broad continuum of ancestral origin making classification by race/ethnicity uninformative. Selected loci harboring variants associated with medical traits and drug response confirmed substantial within- and between-group heterogeneity. Conclusion As a consequence of these complementary levels of heterogeneity group labels offered no guidance at the individual level. These findings demonstrate the complexity involved in clinical translation of the results from genome-wide association studies and suggest that in the genomic era conventional racial/ethnic labels are of little value.

There are few data describing the relative height and weight patterns of children and adolescents in rural Nigeria, despite a prevalence of stunting of over 38% among children younger than 5 years.The present study documented the height and weight patterns relative to international standards among children and adolescents aged 5-20 years in rural Nigeria.Children 5-20 years of age were enrolled from two rural villages. Height and weight were measured; body composition was estimated using bioelectrical impedance analysis. z-scores and centiles for height and body mass index were calculated; prevalences of low relative height (i.e.2 standard deviations below mean for age and sex) and weight by sex and age were estimated.A total of 623 participants (326 male and 297 female) were enrolled. The mean height-for-age z-score for males younger than 19 years was -2.1 and prevalence of low relative height was 50%. Among females, the mean height-for-age z-score was -1.2 during adolescence; only 15% of adolescent females were of low relative height. Based on BMI-for-age, 37% of the adolescent males and 23% of females were underweight. No children or adolescents were overweight based on BMI-for-age.Low relative height and underweight occur in a large proportion of children and adolescents in rural Nigeria, with the lowest relative heights and weights occurring in mid-adolescence and among males.