Biology subjects

Vergara, C.

Publications and source records attributed to Vergara, C..

17 recordsLinked to original sources

bioRxiv2026

cis-gamma-Amino-L-proline peptides as chemical probes of amyloidogenic processing in neurons and APP/PS1 mice

Alzheimers disease (AD) is characterized by the accumulation of amyloid-{beta} (A{beta}) peptides, which are a key factor in its pathogenesis. In this study, we present the design and evaluation of {gamma}-amino-L-proline peptides as metabolically stable, cell-penetrating molecules that can modulate amyloidogenic processing. We screened a library of {gamma}-peptides in primary neuronal cultures to determine their effects on endogenous A{beta}1-42 production, cytotoxicity, and {beta}-secretase (BACE1) activity. Comparative analysis of structurally related analogues enabled the identification of molecular features associated with A{beta}-lowering activity, establishing a qualitative structure-activity relationship. Peptide 33 (P33) emerged as a lead candidate, selectively reducing BACE1 activity without significantly inhibiting the homologous enzyme, BACE2. In vitro blood-brain barrier (BBB) assays revealed that P33 exhibits favorable transendothelial permeability. Intraperitoneal administration of P33 in APP/PS1 mice decreased A{beta} levels, reduced amyloid plaque burden, and improved performance in a behavioral recognition task without inducing cytotoxicity or systemic toxicity. These results define cis-{gamma}-amino-L-proline peptides as a bioorganically distinct and modular scaffold for the development of intracellular modulators of A{beta} production. HighlightsO_LI{gamma}LJAminoLJLLJproline peptides as metabolically stable modulators of A{beta} production. C_LIO_LIP33 showed BBB permeability and BACE1 inhibition in primary cortical neurons. C_LIO_LIIn APP/PS1 mice, P33 lowers amyloid burden and improves cognition. C_LIO_LIP33 shows good biocompatibility, supporting its therapeutic potential in AD C_LI

neuroscience↗

bioRxiv2026

Predicting post-TEVAR endoleaks: a pre-operative hemodynamic risk factor from patient-specific Fluid-Structure Interaction simulations

Thoracic Endovascular Aortic Repair (TEVAR) is a minimally invasive procedure for the treatment of thoracic aortic pathologies, such as Thoracic Aortic Aneurysm (TAA). Computational simulations can provide valuable insights into TEVAR outcomes and complications prior to surgery, making them a useful tool in the procedural planning. In this work, Fluid-Structure Interaction (FSI) computational simulations are carried out in ten pre-TEVAR patient-specific TAA cases, for which post-TEVAR outcomes are known, to quantify the hemodynamic drag forces acting on the aortic wall. Based on these results, this study proposes a new risk factor R to predict the occurrence of type I and III endoleaks. The patient cohort is divided in a calibration set, used to associate specific R values with three different risk levels, and a validation set, to test the risk factor efficacy. Based on the risk factor values obtained for the calibration set, R[≤] 0.33 is associated with low risk of endoleak formation, 0.33 < R[≤] 0.67 with moderate risk, and R > 0.67 with high risk. Once it is applied to the validation set,the risk factor is able to predict the formation of a type Ia endoleak. The risk factor proposed in this work is capable of identifying all the endoleak cases analysed, as well as conditions known to increase the risk of TEVAR complications. This study represents a preliminary attempt to determine whether pre-TEVAR hemodynamics can effectively predict post-TEVAR complications and thereby aid clinicians in the pre-operative planning.

bioengineering↗

bioRxiv2025

Personalized computational hemodynamic analysis in transcatheter aortic valve: investigation of long-term degeneration

Introduced as an alternative to open-heart surgery for elderly patients, Transcatheter Aortic Valve Implantation (TAVI) has recently been extended to younger patients due to comparable performance with the gold-standard. However, the long-term durability of the bio-prosthetic TAVI valves is limited by Structural Valve Deterioration (SVD), an inevitable degenerative process whose pathogenesis is still unclear. In this study, we aim to computationally investigate a possible relation between aortic hemodynamics and SVD development. To this aim, we collect data from twelve patients with and without SVD at long-term follow-up exams. Starting from pre-operative clinical images, we build early post-operative virtual scenarios and we perform Computational Fluid Dynamics simulations by prescribing a personalized flow rate based on Echo Doppler data. In order to identify a premature onset of SVD, we propose three computational hemodynamic indices: Wall Damage Index (WDI), Leaflet Delamination Index (LDI), and Leaflet Permeability Index (LPI). Additionally, to each index we associate a score and, using the Wilcoxon rank-sum test, we find that each score individually shows a statistically greater median value in the SVD sub-population (WDI: p = 0.008, LDI: p = 0.001, LPI: p = 0.020). Finally, we define a synthetic scoring system that clearly separates between SVD and non-SVD patients. Our results suggest that aortic hemodynamics may drive a premature onset of SVD, and the synthetic score could potentially assist clinicians in a patient-specific planning of follow-up exams to closely monitor those patients at high SVD risk.

bioengineering↗

bioRxiv2025

Identifying myocardial regions perfused by coronary arteriesthrough detailed human microvasculature data

Purposeclinical imaging can resolve the main coronary arteries but not the smaller side branches that penetrate the heartwall. However, precise association between the main coronary branches and the myocardial mass they perfuse is crucial to achieve a correct description of haemodynamics from the large arteries to the cardiac tissue. In this work, we use ex-vivo detailed morphometric data of human coronary microcirculation to build and validate a tool for a personalized coronary-myocardium association, and we use it in a multiscale computational model of cardiac perfusion. Methodsfrom the digitalized dataset of an entire human coronary microcirculation, vascular beds associated to single branches are extracted and analysed to infer patterns in epicardial branching. 3D segmentations of the coronaries with and without this information are used to generate two different myocardial subdivisions, which are compared to the one obtained from the microcirculation data. The impact on haemodynamics is assessed through computational simulations. Resultsepicardial arteries exhibit characteristic patterns of transverse branching, with branching angles [~=] 90{degrees} and rate of branching, with respect to the distance along the vessel, depending on the core diameter. The addition of transverse outflows to the segmentations greatly increases accuracy in the myocardial subdivision, allowing discrimination between mass perfused by the proximal and distal arterial segments. Perfusion simulations including transverse outflows show more homogeneous blood flow across the myocardium, consistently with experimental findings. Conclusionsthe inclusion of transverse outflows in 3D coronary segmentations is essential to correctly capture the coronary-myocardium association and the distribution of myocardial blood flow.

bioengineering↗

bioRxiv2024

Computational analysis to assess hemodynamic forces in descending thoracic aortic aneurysms

Descending Thoracic Aortic Aneurysm (DTAA) is a life-threatening disorder, defined as a localized enlargement of the descending portion of the thoracic aorta. In this context, we develop a Fluid-Structure Interaction (FSI) computational framework, with the inclusion of a turbulence model and different material properties for the healthy and the aneurysmatic portions of the vessel, to study the hemodynamics and its relationship with DTAA. We first provide an analysis on nine ideal scenarios, accounting for different aortic arch types and DTAA ubications, to study changes in blood pressure, flow patterns, turbulence, wall shear stress, drag forces and internal wall stresses. Our findings demonstrate that the hemodynamics in DTAA is profoundly disturbed, with the presence of flow recirculation, formation of vortices and transition to turbulence. In particular, configurations with a more steep aortic arch exhibit a more chaotic hemodynamics. We notice also an increase of pressure values for configurations with less steep aortic arch and of drag forces for configurations with distal DTAA. Secondly, we replicate our analysis for three patient-specific cases (one for type of arch) obtaining conforting results in terms of accordance with the ideal scenarios. Finally, in a very preliminary way, we try to relate our findings to possible stent-graft migrations after TEVAR procedure to provide predictions on the post-operative state. KEY POINTSO_LIThis study employs computational methods to assess hemodynamic forces in descending thoracic aortic aneurysms; C_LIO_LIWe consider ideal cases by varying aortic arch type and aneurysm location; C_LIO_LIOur results show: chaotic hemodynamics for steep aortic arches; increase of pressure values for less steep aortic arches; high risk of plaque in the sac for proximal aneurysms and in the neck for distal aneurysms; C_LIO_LIWe analyse also 3 patient-specific cases, confirming the major outcomes found for the ideal cases; C_LIO_LIWe try to suggest how our pre-operative findings may be put in relation to assess the risk of stent-graft migration of a possible TEVAR procedure. C_LI

bioengineering↗

bioRxiv2024

Investigating the right heart hemodynamics in the Tetralogy of Fallot: a computational study

Characterizing flow within the right heart (RH) is particularly challenging due to its complex geometries. However, gaining insight into RH fluid dynamics is of extreme diagnostic importance given the high prevalence of acquired and congenital heart diseases with impaired RH functionality. In this study, we present a comprehensive, patient-specific, image-based computational analysis of the hemodynamics of the RH in healthy and repaired-ToF (ToF) cases. From multi-series cine-MTRI, we reconstruct the geometry and motion of the patients right atrium, ventricle, and pulmonary and tricuspid valves. For this purpose, we develop a novel and flexible reconstruction procedure that enables us, for the first time, to integrate fully patient-specific tricuspid valve dynamics into a computational model, enhancing the accuracy of our RH blood flow simulations. This work provides novel insight into the altered hemodynamics of repaired-ToF RH with severe pulmonary regurgitation and into the hemodynamics changes induced by the pulmonary valve replacement intervention. Modelling the whole RH enables us to understand the contribution of the superior and inferior vena cava inflows to the ventricular filling, as well as the impact of the impaired right atrial function on the ventricular diastole. We analyze the turbulent and transitional behaviour by including the Large-Eddies Simulation sigma model in our computational framework. This highlights how the contribution of the smallest scales in the dissipation of the turbulent energy changes among health and disease.

bioengineering↗

bioRxiv2024

Cardiac hemodynamics computational modeling including chordae tendineae, papillaries, and valves dynamics

In the context of dynamic image-based computational fluid dynamics (DIB-CFD) modeling of cardiac system, the role of sub-valvular apparatus (chordae tendineae and papillary muscles) and the effects of different mitral valve (MV) opening/closure dynamics, have not been systemically determined. To provide a partial filling of this gap, in this study we performed DIB-CFD numerical experiments in the left ventricle, left atrium and aortic root, with the aim of highlighting the influence on the numerical results of two specific modeling scenarios: i) the presence of the sub-valvular apparatus, consisting of chordae tendineae and papillary muscles; ii) different MV dynamics models accounting for different use of leaflet reconstruction from imaging. This is performed for one healthy and one MV regurgitant subjects. Specifically, a systolic wall motion is reconstructed from time-resolved Cine-MRI images and imposed as boundary condition for the CFD numerical simulation. Analyzing the numerical results, we found that sub-valvular apparatus do not affect the global fluid dynamics quantities, although it creates local variations, such as the developing of vortexes or flow disturbances, which lead to different stress distributions on cardiac structures. Moreover, different MV dynamics are considered starting from Cine-MRI MV segmentation at different temporal configurations, and then they are compared and managed numerically through a resistive approach. The obtained results highlight the importance of including a sophisticated diastolic model of MV dynamics, which accounts for MV geometries during diastasis and A-wave, in terms of describing the disturbed flow and ventricular turbulence. Statements and DeclarationsThe authors have no relevant financial or non-financial interests to disclose.

bioengineering↗

bioRxiv2024

Modeling cardiac microcirculation for the simulation of coronary flow and 3D myocardial perfusion

Purposeaccurate modeling of blood dynamics in the coronary microcirculation is a crucial step towards the clinical application of in silico methods for the diagnosis of coronary artery disease (CAD). In this work, we present a new mathematical model of microcirculatory hemodynamics accounting for microvasculature compliance and cardiac contraction; we also present its application to a full simulation of hyperemic coronary blood flow and 3D myocardial perfusion in real clinical cases. Methodsmicrovasculature hemodynamics is modeled with a compliant multi-compartment Darcy formulation, with the new compliance terms depending on the local intramyocardial pressure generated by cardiac contraction. Nonlinear analytical relationships for vessels distensibility are included based on experimental data, and all the parameters of the model are reformulated based on histologically relevant quantities, allowing a deeper model personalization. ResultsPhasic flow patterns of high arterial inflow in diastole and venous outflow in systole are obtained, with flow waveforms morphology and pressure distribution along the microcirculation reproduced in accordance with experimental and in vivo measures. Phasic diameter change for arterioles and capillaries is also obtained with relevant differences depending on the depth location. Coronary blood dynamics exhibits a disturbed flow at the systolic onset, while the obtained 3D perfusion maps reproduce the systolic impediment effect and show relevant regional and transmural heterogeneities in myocardial blood flow (MBF). Conclusionthe proposed model successfully reproduces microvasculature hemodynamics over the whole heartbeat and along the entire intramural vessels. Quantification of phasic flow patterns, diameter changes, regional and transmural heterogeneities in MBF represent key steps ahead in the direction of the predictive simulation of cardiac perfusion.

bioengineering↗

bioRxiv2024

Computational hemodynamic indices to identify Transcatheter Aortic Valve Implantation degeneration

PurposeStructural Valve Deterioration (SVD) is the main limiting factor to the long-term durability of bioprosthetic valves, which are used for Transcatheter Aortic Valve Implantation (TAVI). The aim of this study is to perform a patient-specific computational analysis of post-TAVI blood dynamics to identify hemodynamic indices that correlate with a premature onset of SVD. MethodsThe study population comprises two subgroups: patients with and without SVD at long-term follow-up exams. Starting from pre-operative CT images, we created reliable post-TAVI scenarios by virtually inserting the bioprosthetic valve (stent and leaflets), and we performed numerical simulations imposing realistic inlet conditions based on patient-specific data. The numerical results were post-processed to build suitable synthetic scores based on normalized hemodynamic indices. ResultsWe defined three synthetic scores, based on hemodynamic indices evaluated in different contexts: on the leaflets, in the ascending aorta, and in the whole domain. Our proposed synthetic scores are able to clearly isolate the SVD group. Notably, we found that leaflets OSI individually shows statistically significant differences between the two subgroups of patients. ConclusionThe results of this computational study suggest that blood dynamics may play an important role in creating the conditions that lead to SVD. More-over, the proposed synthetic scores could provide further indications for clinicians in assessing and predicting TAVI valves long-term performance.

bioengineering↗

bioRxiv2023

Image-based computational fluid dynamics to compare two mitral valve reparative techniques for the prolapse

ObjectiveNowadays, the treatment of mitral valve prolapse involves two distinct repair techniques: chordal replacement (Neochordae technique) and leaflet resection (Resection technique). However, there is still a debate in the literature about which is the optimal one. In this context, we performed an image-based computational fluid dynamic study to evaluate blood dynamics in the two surgical techniques. MethodsWe considered a healthy subject (H) and two patients (N and R) who underwent surgery for the prolapse of the posterior leaflet and were operated with the Neochordae and Resection technique, respectively. Computational Fluid Dynamics (CFD) was employed with prescribed motion of the entire left heart coming from cine-MRI images, with a Large Eddy Simulation model to describe the transition to turbulence and a resistive method for managing valve dynamics. We created three different virtual scenarios where the operated mitral valves were inserted in the same left heart geometry of the healthy subject to study the differences attributed only to the two techniques. ResultsWe compared the three scenarios by quantitatively analyzing ventricular velocity patterns and pressures, transition to turbulence, and the ventricle ability to prevent thrombi formation. From these results we found that both the operated cases were able to restore almost physiological blood dynamic conditions, with some differences due to the reduced mobility of the Resection posterior leaflet. Conclusions: Our findings suggest that the Neochordae technique developed a slightly more physiological flow with respect to the Resection technique. The latter gave rise to a different direction of the mitral jet during diastole increasing the turbulence that is associated with ventricular effort and hemolysis, with also a larger ability to washout the ventricular apex preventing from thrombi formation.

bioengineering↗

bioRxiv2023

Accurate and Efficient 3D Reconstruction of Right Heart Shape and Motion from Multi-Series Cine-MRI

The accurate reconstruction of the right heart geometry and motion from time-resolved medical images enhances diagnostic tools based on image visualization as well as the analysis of cardiac blood dynamics through computational methods. Due to the peculiarity of the right heart morphology and motion, commonly used segmentation and/or reconstruction techniques, which only employ Short-Axis cine-MRI, lack accuracy in relevant regions of the right heart, like the ventricular base and the outflow tract. Moreover, the reconstruction procedure is time-consuming and, in the case of the generation of computational domains, requires a lot of manual intervention. This paper presents a new method for the accurate and efficient reconstruction of the right heart geometry and motion from time-resolved MRI. In particular, the proposed method makes use of surface morphing to merge information coming from multi-series cine-MRI (such as Short/Long-Axis and 2/3/4 Chambers acquisitions) and to reconstruct important cardiac features. It also automatically provides the complete cardiac contraction and relaxation motion by exploiting a suitable image registration technique. The method is applied both to a healthy and a pathological (tetralogy of Fallot) case, and yelds more accurate results than standard procedures. The proposed method is also employed to provide significant input for computational fluid dynamics. The corresponding numerical results demonstrate the reliability of our approach in the computation of clinically relevant blood dynamics quantities.

bioengineering↗

bioRxiv2023

Kir7.1 is the physiological target for hormones and steroids that regulate uteroplacental function

Preterm birth is a multifactorial syndrome that is detrimental to the well-being of both the mother and the newborn. During normal gestation, the myometrium is maintained in a quiescent state by the action of progesterone. As a steroid hormone, progesterone is thought to modify uterine and placental morphology by altering gene expression, but a nongenomic mode of action has long been suspected. Here we reveal that progesterone activates both human and murine inwardly rectifying potassium channel Kir7.1, which is expressed in mammalian myometrial smooth muscle and placental pericytes during late gestation. Kir7.1 is also activated by compounds used to prevent premature labor, including the progestogens 17-alpha-hydroxyprogesterone caproate and dydrogesterone, revealing an unexpected mode of action for these drugs. Our results reveal that Kir7.1 is the molecular target of a number of endogenous and synthetic steroids that control uterine excitability and placental function, and is therefore a promising therapeutic target to control utero-placental physiology and support healthy pregnancy.

physiology↗

bioRxiv2023

Turbulence and blood washout in presence of mitral regurgitation: a computational fluid-dynamics study in the complete left heart

In this work we performed a computational image-based study of blood dynamics in the whole left heart, both in a healthy subject and in a patient with mitral valve regurgitation (MVR). We elaborated dynamic cine-MRI images with the aim of reconstructing the geometry and the corresponding motion of left ventricle, left atrium, mitral and aortic valves, and aortic root of the subjects. This allowed us to prescribe such motion to computational blood dynamics simulations where, for the first time, the whole left heart motion of the subject is considered, allowing us to obtain reliable subject-specific information. The final aim is to investigate and compare between the subjects the occurrence of turbulence and the risk of hemolysis and of thrombi formation. In particular, we modeled blood with the Navier-Stokes equations in the Arbitrary Lagrangian-Eulerian framework, with a Large Eddy Simulation model to describe the transition to turbulence and a resistive method to manage the valve dynamics, and we used a Finite Elements discretization implemented in an in-house code for the numerical solution. Our results highlighted that the regurgitant jet in the MVR case gave rise to a large amount of transition to turbulence in the left atrium resulting in a higher risk of formation of hemolysis. Moreover, MVR promoted a more complete washout of stagnant fiows in the left atrium during the systolic phase and in the left ventricle apex during diastole. NEW & NOTEWORTHYReconstruction from cine-MRI images of geometries and motion of the left heart (left atrium and ventricle, aortic root, aortic and mitral valve) of a healthy and mitral regurgitant patient. Prescription of such motion to a complete subject-specific computational fluid-dynamic simulation of the left heart. Investigation of turbulence in a regurgitant scenario. Study of the mechanisms of prevention from stagnant flows and hemolysis formation in the atrium.

bioengineering↗

bioRxiv2023

A hepatitis B virus (HBV) sequence variation graph improves sequence alignment and sample-specific consensus sequence construction for genetic analysis of HBV

Hepatitis B virus (HBV) remains a global public health concern, with over 250 million individuals living with chronic HBV infection (CHB) and no curative therapy currently available. Viral diversity is associated with CHB pathogenesis and immunological control of infection. Improved methods to characterize the viral genome at both the population and intra-host level could aid drug development efforts. Conventionally, HBV sequencing data are aligned to a linear reference genome and only sequences capable of aligning to the reference are captured for analysis. Reference selection has additional consequences, including sample-specific consensus sequence construction. It remains unclear how to select a reference from available sequences and whether a single reference is sufficient for genetic analyses. Using simulated short-read sequencing data generated from full-length publicly available HBV genome sequences and HBV sequencing data from a longitudinally sampled individual with CHB, we investigate alternative graph-based alignment approaches. We demonstrate that using a phylogenetically representative genome graph for alignment, rather than linear reference sequences, avoids issues of reference ambiguity, improves alignment, and facilitates the construction of sample-specific consensus sequences genetically similar to an individuals infection. Graph-based methods can therefore improve efforts to characterize the genetics of viral pathogens, including HBV, and may have broad implications in host pathogen research.

genomics↗

bioRxiv2020

Modeling the effect of COVID-19 disease on the cardiac function: a computational study

BackgroundThe effect of COVID-19 on the cardiac function and on the vascular system increases the morbidity and mortality of infected subjects with cardiovascular diseases. ObjectivesTo provide preliminary results on cardiac global outcomes (such as cardiac output, ventricular pressures) obtained by means of computational models in plausible scenarios characterized by COVID-19. MethodsWe considered a lumped parameters computational model of the cardiovascular system, which models, from the mechanical point of view, the systemic and pulmonary circulations, the four cardiac valves and the four heart chambers, through mathematical equations of the underlying physical processes. To study the effect of COVID-19, we varied the heart rate, the contractility and the pulmonary resistances in suitable ranges. ResultsOur computations on individuals with both otherwise normal and impaired cardiac functions revealed that COVID-19 worsen cardiac function, as shown by a decrease of some cardiac biomarkers values such as cardiac output and ejection fraction. In the case of existing impaired cardiac function, the presence of COVID-19 lead to values outside the normal ranges. ConclusionsComputational models revealed to be an effective tool to study the effect of COVID-19 on the cardiovascular system. Such effect could be significant for patients with impaired cardiac function. This is especially useful to perform a sensitivity analysis of the hemodynamics for different conditions. CONDENSED ABSTRACTEmerging studies address how COVID-19 infection might impact the cardiovascular system. This relates particularly to the development of myocardial injury, acute coronary syndrome, myocarditis, arrhythmia, and heart failure. Prospective treatment approach is advised for these patients. By the assessment of conventional important biomarkers obtained with new sources as a 0-dimentional computational model, we propose a new study protocol as an effective method to evaluate short-term prognosis. The clinical protocol proposed will help to rapidly identify which patients require intensive monitoring, diagnostic strategy and most adequate therapy.

pathology↗

bioRxiv2018

Genotype Imputation Performance of Three Reference Panels Using African Ancestry Individuals

Genotype imputation is used to estimate unobserved genotypes from genome-wide maker data, to increase genome coverage and power for genome-wide association studies. Imputation has been most successful for European ancestry populations in which very large reference panels are available. Smaller subsets of African descent populations are available in 1000 Genomes (1000G), the Consortium on Asthma among African-Ancestry Populations in the Americas (CAAPA) and the Haplotype Reference Consortium (HRC). We aimed to compare the performance of these reference panels when imputing variation in 3,747 African Americans (AA) from 2 cohorts (HCV and COPDGene) genotyped using the Illumina Omni family of microarrays. The haplotypes of 2,504 individuals (from 1000G), 883 (from CAAPA) and 32,611 (from HRC) were used as reference. We compared the performance of these panels based on number of variants, imputation quality, imputation accuracy and coverage. In both cohorts, 1000G imputed 1.5-1.6x more variants compared to CAAPA and 1.2x more variants than HRC. Similar findings were observed for variants with higher imputation quality (R2>0.5) and for rare, low frequency, and common variants. When merging the results of the three panels the total number of imputed variants was 62M-63M with 20M overlapping variants imputed by all three panels, and a range of 5 to 15M unique variants imputed exclusively with one of the three panels. For overlapping variants, imputation quality was highest for HRC, followed by 1000G, then CAAPA, and improved as the minor allele frequency increased. The 1000G, HRC and CAAPA participants of African ancestry provided high performance and accuracy for imputation of African American admixed individuals, increasing the total number of variants with high quality available for subsequent analyses. These three panels are complementary and would benefit from the development of an integrated African reference panel, including data from multiple sources and populations.

genetics↗

bioRxiv2017

Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci

BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.\n\nMETHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.\n\nRESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 x 10-9 and 2.97 x 10-8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the \"atopic march\" and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 x10-6 [≤] p [≤] 3.06 x10-6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.\n\nCONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

bioinformatics↗