Sickle cell anemia – Nitric oxide related genetic modifiers of hematological and biochemical parameters

Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β‐globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso‐occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell‐derived microparticle (MP) generation is also involved in the vaso‐occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US‐FDA‐approved therapy to prevent painful vaso‐occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L‐glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.

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“…Aguiar et al suggested that NO and NO precursors should be considered as a possible valid therapy for SCA.…”

Section: Therapiesmentioning

confidence: 99%

Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Piccin

Murphy

Eakins

et al. 2019

European J of Haematology

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“…A comprehensive understanding of the natural history of diseases, including those resulting from mutations in a single (set of) gene(s), such as sickle cell disease or polycystic kidney disease, will benefit from assessing the environmental factors potentially involved. Towards this end, the close collaboration between researchers of this RG and medical doctors allows to examine the association between patient's behavioural data and the development and progression of a given pathology, as well as their role in modelling biochemical markers and genes' impact [121,122]. The consideration of environmental factors is much facilitated by the multidisciplinary nature of ISAMB, which sets the ground for valuable collaborations among researchers with different skills and expertise to be successfully established.…”

Section: Research Group "Ecogenetics and Human Health"mentioning

confidence: 99%

Towards a Global Perspective of Environmental Health: Defining the Research Grounds of an Institute of Environmental Health

et al. 2020

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Environmental health is at the intersection between health and the environment. However, it still has a recent (and narrow) history as a scientific area, mainly addressing human biomonitoring and toxicological issues. Only recently additional environmental ‘layers’, other than the traditional chemical, biological and physical environmental determinants, have been considered. This broader perspective of environmental health also encompasses digital, psychosocial, political, socioeconomic and cultural determinants, all of them relevant when considering human health from a planetary health paradigm. This reflects the progressive adoption of a systemic perspective regarding the impact of gains for human health and well-being towards a sustainable environment. It also implies a multi-method and participatory approach to understand the intertwined relationship between environmental changes and human health. In this paper, the broader approach to environmental health is discussed in order to ‘set the stage’ for introducing the Institute of Environmental Health (ISAMB) of the Lisbon School of Medicine, Portugal. Each of the research groups and labs that compose ISAMB are presented, as well as their main lines of research. Present and planned contributions of ISAMB to advance knowledge on environmental health and for promoting human health gains in an environmentally sustainable way are also discussed.

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“…Nevertheless, these well-documented modifiers cannot explain the clinical diversity observed among haemoglobinopathy patients. Facilitated by the advent of technology, recent studies have identified variants associated with laboratory and clinical markers of disease severity, such as albuminuria and elevated glomerular filtration rate (GFR) for early renal disease [19], serum lactate dehydrogenase (LDH) for haemolysis [20], abnormal transcranial Doppler velocities for stroke [21] and elevated tricuspid regurgitant jet velocities for cardiopulmonary complications [22,23] (for a comprehensive review see [24]). Measurement of such markers would help risk-stratify patients to direct care, assist with early screening and diagnosis of symptoms, adjust dosing regimens for safe and effective drug therapy, and optimise personalised treatment prior to irreversible tissue damage and organ failure [25,26].…”

Section: Introductionmentioning

confidence: 99%

Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies

Stephanou

Tamana

Minaidou

et al. 2019

JCM

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Haemoglobinopathies are common monogenic disorders with diverse clinical manifestations, partly attributed to the influence of modifier genes. Recent years have seen enormous growth in the amount of genetic data, instigating the need for ranking methods to identify candidate genes with strong modifying effects. Here, we present the first evidence-based gene ranking metric (IthaScore) for haemoglobinopathy-specific phenotypes by utilising curated data in the IthaGenes database. IthaScore successfully reflects current knowledge for well-established disease modifiers, while it can be dynamically updated with emerging evidence. Protein–protein interaction (PPI) network analysis and functional enrichment analysis were employed to identify new potential disease modifiers and to evaluate the biological profiles of selected phenotypes. The most relevant gene ontology (GO) and pathway gene annotations for (a) haemoglobin (Hb) F levels/Hb F response to hydroxyurea included urea cycle, arginine metabolism and vascular endothelial growth factor receptor (VEGFR) signalling, (b) response to iron chelators included xenobiotic metabolism and glucuronidation, and (c) stroke included cytokine signalling and inflammatory reactions. Our findings demonstrate the capacity of IthaGenes, together with dynamic gene ranking, to expand knowledge on the genetic and molecular basis of phenotypic variation in haemoglobinopathies and to identify additional candidate genes to potentially inform and improve diagnosis, prognosis and therapeutic management.

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Sickle cell anemia – Nitric oxide related genetic modifiers of hematological and biochemical parameters

Cited by 6 publications

References 24 publications

Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Towards a Global Perspective of Environmental Health: Defining the Research Grounds of an Institute of Environmental Health

Genetic Modifiers at the Crossroads of Personalised Medicine for Haemoglobinopathies

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