Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia

Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Abstract: Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Effectiveness of cortisone acetate in treating congenital adrenal hyperplasia as monitored by the plasma concentration of 17α-hydroxyprogesterone

The plasma concentration of total corticosteroids, cortisol, and 17α-hydroxyprogesterone in 4 patients with congenital adrenal hyperplasia of the 21-hydroxylase deficiency type, was measured at intervals on one day when cortisone acetate treatment was administered, and on the following day when treatment was withdrawn. On the day of treatment was withdrawn, the major plasma corticosteroid was 17α-hydroxyprogesterone, and it appeared likely that in addition to cortisol other unidentified adrenal steroids may have been present

The relationship among circulating insulin-like growth factor (IGF)-I, IGF-binding proteins-1 and -2, and birth anthropometry: a prospective study

Fetal IGF-I is a determinant of birth weight, but whether maternal IGF-I plays a significant role is controversial. We sought to examine the relationships among maternal IGF-I, IGF-binding protein (IGFBP)-1, and IGFBP-2, with maternal and newborn anthropometry, in a cohort of 325 nondiabetic pregnant women of African origin. Blood was collected for IGF-I, IGFBP-1, and IGFBP-2 at 9, 25, and 35 wk gestation and in cord blood at delivery.In the second and third trimesters, maternal IGF-I was significantly correlated (P &lt; 0.005) with maternal body mass index and triceps skinfold thickness. Maternal IGFBP-1 and -2 had an inverse correlation (P &lt; 0.0001), with maternal anthropometry. Maternal IGF-I at 35 wk, and fetal IGF-I by cord blood were significantly correlated with birth weight (P = 0.001 and 0.048, respectively). IGFBP-1 in the third trimester and cord blood were negatively correlated with birth weight (P = 0.012 and 0.002). In multiple regression analyses, maternal IGF-I at 35 wk, fetal IGF-I, maternal weight at the first antenatal visit, gender, and gestational age were significant independent factors in the determination of birth weight. In conclusion, maternal IGF-I levels, especially during late pregnancy, positively influence birth weight

Impaired glucose regulation in adults in Jamaica: who should have the oral glucose tolerance test?

OBJECTIVE: To compare the 1999 World Health Organization (WHO) fasting plasma glucose (FPG) criteria and the WHO 2-hour post-challenge glucose (2hPG) criteria during an oral glucose tolerance test (OGTT) in identifying adults in Jamaica with hyperglycemia. As the OGTT is not commonly used in clinical practice, factors associated with the failure of the FPG criteria to detect persons with impaired 2hPG were investigated. METHODS: A random sample of 2 096 adults, 25-74 years old, living in the town of Spanish Town, Jamaica, was evaluated for diabetes. After excluding 215 individuals for reasons such as missing data, the remaining 1 881 persons were composed of 187 who were previously known to have diabetes and 1 694 who were screened for diabetes with both FPG and 2hPG. RESULTS: The FPG criteria detected 83 cases of diabetes, compared to 72 by the 2hPG criteria. The kappa statistic comparing the two criteria was 0.31 (95% confidence interval: 0.28- 0.34), indicating fair agreement. There were 261 cases of impaired glucose tolerance (IGT) and 92 cases of impaired fasting glucose (IFG). In those 92 with IFG, an OGTT would identify 34 cases of IGT and 14 cases of diabetes. Of those classified as normoglycemic by FPG criteria, 14% of them had IGT or diabetes by 2hPG criteria. The factors predicting the likelihood of nondetection of impaired glucose tolerance or diabetes by FPG were age, body mass index, central obesity, systolic blood pressure, and female sex. By receiver operating characteristic curve analysis, an FPG of 5.1 mmol/L would predict a 2hPG > 7.8 mmol/L. CONCLUSIONS: A few individuals classified as normal on FPG will have IGT or diabetes, and an OGTT will be needed to identify them. The yield of IGT detected by screening in Jamaica can be improved by lowering the threshold for IFG or by using clinical information to identify high-risk individuals

Impaired glucose regulation in adults in Jamaica: who should have the oral glucose tolerance test? Alteraciones del control de la glucemia: &iquest;a quiénes se les debe hacer la prueba de tolerancia a una dosis oral de glucosa?

OBJECTIVE: To compare the 1999 World Health Organization (WHO) fasting plasma glucose (FPG) criteria and the WHO 2-hour post-challenge glucose (2hPG) criteria during an oral glucose tolerance test (OGTT) in identifying adults in Jamaica with hyperglycemia. As the OGTT is not commonly used in clinical practice, factors associated with the failure of the FPG criteria to detect persons with impaired 2hPG were investigated. METHODS: A random sample of 2 096 adults, 25-74 years old, living in the town of Spanish Town, Jamaica, was evaluated for diabetes. After excluding 215 individuals for reasons such as missing data, the remaining 1 881 persons were composed of 187 who were previously known to have diabetes and 1 694 who were screened for diabetes with both FPG and 2hPG. RESULTS: The FPG criteria detected 83 cases of diabetes, compared to 72 by the 2hPG criteria. The kappa statistic comparing the two criteria was 0.31 (95% confidence interval: 0.28- 0.34), indicating fair agreement. There were 261 cases of impaired glucose tolerance (IGT) and 92 cases of impaired fasting glucose (IFG). In those 92 with IFG, an OGTT would identify 34 cases of IGT and 14 cases of diabetes. Of those classified as normoglycemic by FPG criteria, 14% of them had IGT or diabetes by 2hPG criteria. The factors predicting the likelihood of nondetection of impaired glucose tolerance or diabetes by FPG were age, body mass index, central obesity, systolic blood pressure, and female sex. By receiver operating characteristic curve analysis, an FPG of 5.1 mmol/L would predict a 2hPG > 7.8 mmol/L. CONCLUSIONS: A few individuals classified as normal on FPG will have IGT or diabetes, and an OGTT will be needed to identify them. The yield of IGT detected by screening in Jamaica can be improved by lowering the threshold for IFG or by using clinical information to identify high-risk individuals.OBJETIVO: Comparar los criterios publicados por la Organización Mundial de la Salud (OMS) en 1999 acerca del uso de la prueba de glucemia en ayunas (PGA) y de la prueba de tolerancia a una dosis oral de glucosa con valoración a las dos horas (PTG2h) para identificar a adultos hiperglucémicos en Jamaica. Como la PTG2h no se administra normalmente en un contexto clínico, se investigaron los factores asociados con la inutilidad de la PGA para detectar a personas con hiperglucemia según la PTG2h. MÉTODOS: Se examinó una muestra aleatoria de 2 096 adultos de 25 a 47 años de edad que vivían en la ciudad de Spanish Town, Jamaica, para determinar la presencia de diabetes. Una vez que se eliminó a 215 personas por diversos motivos, entre ellos la ausencia de datos, quedaron 1 881 personas entre las cuales se encontraban 187 que se sabía de antemano que tenían diabetes y otras 1 694 que fueron sometidas tanto a la PGA como a la PTG2h. RESULTADOS: La PGA permitió detectar 83 casos de diabetes, mientras que la PTG2h permitió detectar 72. El estadístico kappa de comparación entre los dos criterios de valoración fue de 0,31 (intervalo de confianza de 95%: 0,28-0,34), valor que revela una concordancia moderada. Se observaron 261 casos de intolerancia a la glucosa tras la PTG2h y 92 casos de hiperglucemia en ayunas. En estas últimas 92 personas, la PTG2h sirvió para identificar 34 casos de intolerancia a la glucosa y 14 casos de diabetes. De las personas que se mostraron normoglucémicas según la PGA, 14% tenían intolerancia a la glucosa o diabetes, según la PTG2h. Algunos factores tuvieron valor pronóstico en relación con la falta de detección de la intolerancia a la glucosa o la diabetes. Estos fueron la edad, el índice de masa corporal, la concentración de la obesidad en el tronco y el abdomen, la tensión sistólica y el sexo femenino. De acuerdo con la curva de eficacia diagnóstica, una glucemia en ayunas de 5,1 mmol/L tendría valor pronóstico con respecto a la presencia de una glucemia de 7,8 mmol/L según la PTG2h. CONCLUSIONES: Algunas personas cuya glucemia en ayunas está dentro de lo normal tienen intolerancia a la glucosa o diabetes; por lo tanto, para identificarlas es necesario hacer la PTG2h. Se puede mejorar la detección de casos de intolerancia a la glucosa en Jamaica si se reduce el umbral de normalidad para la PGA o si se toman en cuenta los datos clínicos para identificar a las personas en alto riesgo