Research led by Pedro Cruz shows that different genomic inheritances configure specific forms of disease manifestation
The divergence between the genetic inheritances of different groups of patients with sickle cell anemia was the motivation for the study by Pedro Rodrigues Sousa da Cruz, from the Human Genetics Laboratory of the Center for Molecular Biology and Genetic Engineering (CBMEG) at Unicamp, recently published in the journal Scientific Reports. In cooperation with other researchers dedicated to this same line of research, Pedro analyzed patients with sickle cell anemia in Brazil and the United States and verified differences in ancestral origins and the potential impact of demographic history on the manifestation of the disease, demonstrating that genetic findings investigated in a specific population cannot necessarily be extrapolated to patients of a different nationality.
The search results were categorized into genomic and specific. At the genomic level, it was observed that patients of both nationalities presented different proportions of genetic components of African, European and Amerindian origins, as well as representation of African geographic regions in the ancestral composition. At the specific level, that is, in the region where the HbS allele is located, on chromosome 11, this difference in composition remained between populations. In the analysis of the total genome, excluding sex chromosomes, the sample of Brazilian patients presented an average general constitution of 43% of African origin, 45% European and 10% indigenous, compared to 78%, 19% and 1,5%, respectively, of the US population assessed.
Furthermore, origins by African region also differed between the two samples. Brazilians presented a West and South African genetic component, presumably from the Bantu trunk, responsible for two-thirds of the African origin. In American patients, this component accounts for half of the individuals' origin, while a West African component, probably from the Mandé trunk, is responsible for the other half. The findings, as Pedro explains, are in line with records of the slave trade and highlight the importance of analyzing aspects of demography and the origin of the mutation in each population to better understand the ways in which the disease manifests itself. At the local level, restricted to chromosome 11, Brazilian patients presented 44% African, 39,3% European and 16,7% indigenous origins on average, while American patients presented, respectively, 76%, 18,3% and 5,7% , therefore maintaining the difference also locally.
In the region closest to the causative mutation, a point of great divergence in the ancestry of the two populations stands out. Many Brazilian patients there showed an unusual peak of European heritage accompanied by signs of natural selection. “At the point where the gene that causes anemia is located, Brazilians showed an abrupt drop in African heritage and a sharp increase in European heritage. This is an event called introgression and it is relatively rare to happen in such a clear way”, explains Pedro.
The researcher observed, through different indices, that there is evidence of a phenomenon of natural selection that motivated a more in-depth analysis of the location. An association was found between the region analyzed and the production of fetal hemoglobin, which has a positive impact on the life prognosis of patients with sickle cell anemia. This probably happens because this hemoglobin is not affected by the disease and, when at increased levels, improves the quality of life of patients, even being the target of treatment.
“We saw that Brazilian individuals have an important European heritage in this gene region, possibly related to the production of fetal hemoglobin. One hypothesis, which needs to be proven, is that some group of Europeans had a high production of fetal hemoglobin and, when there was miscegenation, it was advantageous for sickle cell patients to have this region that promotes an increase in fetal hemoglobin”, says the researcher.
To carry out the study, the genetic data of Brazilian individuals, from the states of São Paulo, were analyzed, from patients treated at the Hemocentro de Campinas; from Pernambuco, patients treated at the Hematology and Hemotherapy Foundation of Pernambuco (HEMOPE); and the state of Pennsylvania, in the United States, where a partnership was established with the The Children's Hospital of Philadelphia, the place where Pedro carried out an internship when he was a doctoral student in the Postgraduate Program in Genetics and Molecular Biology at Unicamp.
Professor Mônica Barbosa de Melo, a CBMEG researcher, who was Pedro's advisor and also signed the article, points out that the study highlights the need to look more deeply into genomic ancestry, as this, in addition to allowing us to better understand the demographic process that permeates the formation of our population, can reveal unique characteristics that, in the case of this work, are associated with a disease in the Brazilian population. “This is the first study in Brazil, and among the very few worldwide, that addresses the genomic ancestry of these patients.”
Sickle cell anemia
Sickle cell anemia is the most serious among sickle cell diseases. Although there is no precise data, it is estimated that between two and three thousand children with sickle cell disease are born each year in Brazil. The disease is characterized by a change in the shape of red blood cells, red blood cells, which are responsible for transporting oxygen throughout the body. Because they are shaped like a sickle, the disease was called sickle cell. Stroke, leg ulcers, priapism, avascular necrosis of the femoral head, pulmonary hypertension, retinopathy and pain crises are some of the consequences faced by patients with sickle cell anemia, whose life expectancy varies between 40 and 50 years due to the severity of the disease.
At Unicamp, a group of researchers is dedicated to studying sickle cell anemia and other diseases that affect red blood cells. Professor Fernando Ferreira Costa, also author of the article published in Scientific Reports, coordinates the Thematic Project financed by the São Paulo Research Foundation (Fapesp) that gave rise to the research conducted by Pedro. Fernando, together with other researchers, leads the hemoglobin research group at the University's Hematology and Hemotherapy Center, which offers diagnosis, treatment and monitoring of sickle cell patients and those with other genetic diseases that alter hemoglobin, known as hemoglobinopathies.
“There are several researchers working on the same disease from different aspects: cellular, genetic, biochemical, and its association with the clinical characteristics of patients”, observes Mônica. The surveys and research carried out by the team culminate in a better understanding of sickle cell diseases, and both Pedro and Mônica are eager to continue with the studies so that in the future there will be a direct application that impacts the quality of life of these patients.
“We managed to add a little to the understanding of the disease, finding a region that plays an important role in regulating fetal hemoglobin and there is still a lot of work to be done to understand what this region actually does. It ends up being a start for new explorations”, concludes Pedro.
The study, which was also authored by researchers from the Department of Medical Genetics at the Faculty of Medical Sciences at Unicamp, at the Federal University of Pernambuco; of HEMOPE and The Children's Hospital of Philadelphia (USA) can be accessed here
