Chronic disease prevalence in a population with structural hemoglobin disorders undergoing diabetes diagnosis: A bayesian approach.

Background: Structural disorders of hemoglobin are a group of rare and fatal genetic diseases that disrupt the transport and exchange of oxygen in the blood, causing tissue damage and ultimately leading to chronic conditions. The hemoglobin (Hb) S variant predominantly impacts individuals of Afro-descendant heritage. A significant concentration of the Afro-descendant population in Colombia, notably 12.5 %, is found in the city of Cali. Previous research has identified this city's structural hemoglobin disorders prevalence rate of 3.78 %. The aim of this study was to determine the prevalence of HbC, HbS, HbF, and HbA2 variants within a population who underwent HbA1c testing, as well as the prevalence of chronic diseases among patients with these hemoglobin alterations, at a high-complexity hospital in the city of Cali from 2015 to 2019. Methods: A descriptive observational study was conducted, involving a study population that comprised patients with both suspected and monitored diagnoses of diabetes. The cohort was selected from a high-complexity hospital in Cali. A total of 15,608 patients were included in the analysis, all of whom underwent HbA1C measurement through capillary electrophoresis, which also offers an indirect diagnosis of certain structural disorders of hemoglobin. Bayesian methods were employed for frequency analysis. Results: Among the 15,608 patients assessed, 63.6 % (n = 9920) were women. The overall prevalence of structural hemoglobin disorders was 1.98 % (n = 287, 95 % CI = 1.77 %-2.21 %). The co-occurrence of diabetes and kidney disease emerged as the most prevalent combination of pathologies observed in individuals with HbC, for both men and women across various age groups: 18-42 (58.3 % and 50.0 % respectively), 43-55 (50.0 % for both), 56-65 (50.0 % and 37.5 % respectively), and >65 years (66.7 % and 57.1 % respectively). Conclusions: The observed prevalence of the studied variants exceeded 1 %, a threshold underscored by the World Health Organization (WHO) as epidemiologically significant. Among HbC and HbS-positive patients, the elevated prevalence of diabetes and kidney disease is a guiding factor in developing proactive prevention strategies.

The state of the art of fetal hemoglobin-inducing agents.

INTRODUCTION: Sickle cell anemia (SCA) is a hematological genetic disorder caused by a mutation in the gene of the ß-globin. Pharmacological treatments will continue to be an important approach, including the strategy to induce fetal hemoglobin (HbF). AREAS COVERED: Here, we analyzed the articles described in the literature regarding the drug discovery of HbF inducers. The main approaches for such strategy will be discussed, highlighting those most promising. EXPERT OPINION: The comprehension of the mechanisms involved in the ß-globin regulation is the main key to design new drugs to induce HbF. Among the strategies, gamma-globin regulation by epigenetic enzymes seems to be a promising approach to be pursued, although the comprehension of the selectivity role for those new drugs is crucial to reduce adverse effects. The low druggability of transcription factors and their vital role in embryonic human development are critical points that should be taken in account for drug design. The guanylate cyclase and the NO/cGMP signaling pathway seem to be promising not only for HbF induction, but also for the protective effects in the cardiovascular system. The association of drugs acting through different mechanisms to induce HbF seems to be promising for the discovery of new drugs.

Do Genetic Polymorphisms Affect Fetal Hemoglobin (HbF) Levels in Patients With Sickle Cell Anemia Treated With Hydroxyurea? A Systematic Review and Pathway Analysis.

Hydroxyurea has long been used for the treatment of sickle cell anemia (SCA), and its clinical effectiveness is related to the induction of fetal hemoglobin (HbF), a major modifier of SCA phenotypes. However, there is substantial variability in response to hydroxyurea among patients with SCA. While some patients show an increase in HbF levels and an ameliorated clinical condition under low doses of hydroxyurea, other patients present a poor effect or even develop toxicity. However, the effects of genetic polymorphisms on increasing HbF levels in response to hydroxyurea in patients with SCA (Hb SS) have been less explored. Therefore, we performed a systematic review to assess whether single-nucleotide polymorphisms (SNPs) affect HbF levels in patients with SCA treated with hydroxyurea. Moreover, we performed pathway analysis using the set of genes with SNPs found to be associated with changes in HbF levels in response to hydroxyurea among the included studies. The systematic literature search was conducted on Medline/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Web of Science. Seven cohort studies were included following our inclusion and exclusion criteria. From the 728 genetic polymorphisms examined in the included studies, 50 different SNPs of 17 genes were found to be associated with HbF changes in patients with SCA treated with hydroxyurea, which are known to affect baseline HbF but are not restricted to them. Enrichment analysis of this gene set revealed reactome pathways with the lowest adjusted p-values and highest combined scores related to VEGF ligand-receptor interactions (R-HSA-194313; R-HSA-195399) and the urea cycle (R-HSA-70635). Pharmacogenetic studies of response to hydroxyurea therapy in patients with SCA are still scarce and markedly heterogeneous regarding candidate genes and SNPs examined for association with HbF changes and outcomes, suggesting that further studies are needed. The reviewed findings highlighted that similar to baseline HbF, changes in HbF levels upon hydroxyurea therapy are likely to be regulated by multiple loci. There is evidence that SNPs in intron 2 of BCL11A affect HbF changes in response to hydroxyurea therapy, a potential application that might improve the clinical management of SCA. Systematic Review Registration: (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=208790).

Reduced rate of sickle-related complications in Brazilian patients carrying HbF-promoting alleles at the BCL11A and HMIP-2 loci.

The presence of high levels of fetal haemoglobin (HbF) provides well-validated clinical benefits to patients with sickle cell anaemia (SCA). Nevertheless it has been difficult to show clear direct effects of the known genetic HbF modifiers, such as the enhancer polymorphisms for haematopoietic transcription factors BCL11A and MYB, on SCA severity. Investigating SCA patients from Brazil, with a high degree of European genetic admixture, we have detected strong effects of these variants on HbF levels. Critically, we have shown, for the first time, that the presence of such HbF-promoting variants leads to a reduced rate of SCA complications, especially stroke.

The XmnI polymorphic site 5' to the gene G(γ) in a Brazilian patient with sickle cell anaemia - fetal haemoglobin concentration, haematology and clinical features.

We report a 20-year-old female with sickle cell anaemia and with an HbF concentration of 15.8%. The patient was not using hydroxyurea and was not receiving regular blood transfusions. The patient never had chronic manifestations of sickle cell anaemia, only pain crises of a mild intensity. After laboratory tests, we found that she was homozygous for HbS with the Bantu/atypical haplotype, and was heterozygous for the XmnI site. The influence of the XmnI site on the expression of HbF can explain the amelioration in clinical features in this haplotype association in a case of sickle cell anaemia.

Agentes indutores da síntese de hemoglobina fetal / Fetal hemoglobin inducing factors

Anemia falciforme é uma doença heterogênea caracterizada por uma grande variabilidade clínica. Desde as primeiras observações desta doença, foi visto que aumento no nível de hemoglobina fetal (HbF) estava associado com manifestações clínicas mais brandas, já que a HbF interfere na polimerização da HbS. A hidroxiuréia é um agente citotóxico que causa vários efeitos nos pacientes com anemia falciforme, tais como: aumento da produção de HbF, aumento do volume corpuscular médio, aumento da hidratação do glóbulo vermelho, melhora da hemoglobina, mielossupressão, produção de óxido nítrico e diminuição de moléculas de adesão. Até o momento, ela é considerada a terapia de maior sucesso para a anemia falciforme e seu uso nesta doença é descrito neste artigo.

Sickle cell anemia is a heterogeneous disorder with variable severity. Initial observations showed that a high level of fetal hemoglobin (HbF) was associated with minor clinical manifestations, as HbF interferes with HbS polymerization. Hydroxyurea, a cytotoxic agent, has several effects on sickle cell patients, such as: increased HbF production, increased mean corpuscular volume, improved red blood cell hydration, improved hemoglobin, myelosuppression, production of nitric oxide and decreases in adhesion molecules. Till now, hydroxyurea is considered the most successful drug therapy for sickle cell anemia and its use is described in this article.