Dataset Information

Profiling system-wide variations and similarities between Rheumatic Heart Disease and Acute Rheumatic Fever-A pilot analysis.

ABSTRACT: Rheumatic heart disease (RHD) continues to affect developing countries with low income due to the lack of resources and effective diagnostic techniques. Understanding the genetic basis common to both the diseases and that of progression from its prequel disease state, Acute Rheumatic Fever (ARF), would aid in developing predictive biomarkers and improving patient care. To gain system-wide molecular insights into possible causes for progression, in this pilot study, we collected blood transcriptomes from ARF (5) and RHD (5) patients. Using an integrated transcriptome and network analysis approach, we identified a subnetwork comprising the most significantly differentially expressed genes and most perturbed pathways in RHD compared to ARF. For example, the chemokine signaling pathway was seen to be upregulated, while tryptophan metabolism was found to be downregulated in RHD. The subnetworks of variation between the two conditions provide unbiased molecular-level insights into the host processes that may be linked with the progression of ARF to RHD, which has the potential to inform future diagnostics and therapeutic strategies. We also found a significantly raised neutrophil/lymphocyte ratio in both ARF and RHD cohorts. Activated neutrophils and inhibited Natural Killer cell gene signatures reflected the drivers of the inflammatory process typical to both disease conditions.

SUBMITTER: Guttapadu R

PROVIDER: S-EPMC10109489 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Profiling system-wide variations and similarities between Rheumatic Heart Disease and Acute Rheumatic Fever-A pilot analysis.

Guttapadu Ranjitha R Prakash Nandini N M Alka A Chatterjee Ritika R S Mahantesh M M Jayranganath J Sastry Usha Mk UM Subramanyam Jayshree Rudrapatna JR Chakravortty Dipshikha D R Kalpana S KS Chandra Nagasuma N

PLoS neglected tropical diseases 20230405 4

Rheumatic heart disease (RHD) continues to affect developing countries with low income due to the lack of resources and effective diagnostic techniques. Understanding the genetic basis common to both the diseases and that of progression from its prequel disease state, Acute Rheumatic Fever (ARF), would aid in developing predictive biomarkers and improving patient care. To gain system-wide molecular insights into possible causes for progression, in this pilot study, we collected blood transcripto ...[more]

PMID: 37018379

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Project description:BackgroundRheumatic heart disease (RHD) disproportionately affects low-income and middle-income countries. Latin America and the Caribbean (LAC) have been less represented in scientific literature. We aimed to describe the epidemiology, burden and implemented screening and prevention strategies of RHD in LAC.MethodsWe systematically searched PubMed, Embase, LILACS, and SciELO from 1990 to April 2021. Observational and experimental studies that described data on the epidemiology, burden, or prevention/screening strategies of RHD, regardless of age or language, were included. The risk of bias was assessed by previously published tools depending on their study design. Pre-specified data were independently extracted and presented by each topic (epidemiology, burden, prevention/screening). PROSPERO registration number: CRD42021250043.ResultsForty-eight studies out of 1692 non-duplicate records met the eligibility criteria. They were mainly from Brazil, observational in design, and hospital-based. Data on the epidemiology of acute rheumatic fever (ARF) was not recent (most before 2000) with studies describing decreasing incidence through the years. The prevalence of RHD was described in six studies, ranging from 0.24 to 48 per 1,000 among studies evaluating schoolchildren. Nine studies described data based on admissions, ranging from 0.04% to 7.1% in single-center studies. Twenty-four studies assessed the burden of RHD with most of them reporting mortality rates/proportions and complications such as the need for intervention, atrial fibrillation, or embolism. Six preventive strategies were identified that included educational, register-based, and/or secondary prophylaxis strategies. Three well-established echocardiographic screening studies in Brazil and Peru were identified.ConclusionsMost ARF/RHD research in LAC comes from a single country, Brazil where preventive/screening efforts have been conducted. There was a paucity of data from several countries in the region, reflecting the need for epidemiological studies from more countries in LAC which will provide a better picture of the current situation of ARF/RHD and guide the implementation of preventive strategies.

Project description:BackgroundAcute rheumatic fever (ARF) is a serious sequela of Group A Streptococcus (GAS) infection associated with significant global mortality. Pathogenesis remains poorly understood, with the current prevailing hypothesis based on molecular mimicry and the notion that antibodies generated in response to GAS infection cross-react with cardiac proteins such as myosin. Contemporary investigations of the broader autoantibody response in ARF are needed to both inform pathogenesis models and identify new biomarkers for the disease.MethodsThis study has utilised a multi-platform approach to profile circulating autoantibodies in ARF. Sera from patients with ARF, matched healthy controls and patients with uncomplicated GAS pharyngitis were initially analysed for autoreactivity using high content protein arrays (Protoarray, 9000 autoantigens), and further explored using a second protein array platform (HuProt Array, 16,000 autoantigens) and 2-D gel electrophoresis of heart tissue combined with mass spectrometry. Selected autoantigens were orthogonally validated using conventional immunoassays with sera from an ARF case-control study (n=79 cases and n=89 matched healthy controls) and a related study of GAS pharyngitis (n=39) conducted in New Zealand.ResultsGlobal analysis of the protein array data showed an increase in total autoantigen reactivity in ARF patients compared with controls, as well as marked heterogeneity in the autoantibody profiles between ARF patients. Autoantigens previously implicated in ARF pathogenesis, such as myosin and collagens were detected, as were novel candidates. Disease pathway analysis revealed several autoantigens within pathways linked to arthritic and myocardial disease. Orthogonal validation of three novel autoantigens (PTPN2, DMD and ANXA6) showed significant elevation of serum antibodies in ARF (p < 0.05), and further highlighted heterogeneity with patients reactive to different combinations of the three antigens.ConclusionsThe broad yet heterogenous elevation of autoantibodies observed suggests epitope spreading, and an expansion of the autoantibody repertoire, likely plays a key role in ARF pathogenesis and disease progression. Multiple autoantigens may be needed as diagnostic biomarkers to capture this heterogeneity.

Dataset Information

Profiling system-wide variations and similarities between Rheumatic Heart Disease and Acute Rheumatic Fever-A pilot analysis.

Publications

Profiling system-wide variations and similarities between Rheumatic Heart Disease and Acute Rheumatic Fever-A pilot analysis.

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