Camila Rodrigues

Red blood cell alloimmunization in patients with sickle cell disease: correlation with HLA and cytokine gene polymorphisms.

The reason for the difference in susceptibility to red blood cell (RBC) alloimmunization among patients with sickle cell disease (SCD) is not clearly understood and is probably the result of multiple factors. Our hypothesis is that genetic polymorphisms are associated with RBC alloimmunization.

New associations: INFG and TGFB1 genes and the inhibitor development in severe haemophilia A

The development of factor VIII (FVIII) inhibitor is the main complication of replacement therapy in patients with haemophilia A (HA). A ratio of 5–7% of individuals HA develops antibodies (inhibitors) against the FVIII infused during the treatment, thereby reducing their pro‐coagulant activity. The immunomodulatory cytokine genes have been related to the risk of development of alloantibodies in several studies, mainly in HA with severe form.

Genetics factors associated with myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a clinically and cytogenetically heterogeneous group of clonal diseases. Clonal chromosomal abnormalities are observed in 30-50% of patients with MDS. The deletions are among the most common alterations, and often involve the long arms of chromosomes 5, 7, 8, 13, and 20 and the short arms of chromosomes 12 and 17. The advent of new technologies for the detection of genetic abnormalities led to the description of a new set of recurrent mutations, leading to new insights into the pathophysiology of MDS. The recent recognition that genes involved in the regulation of histone function (EZH2, ASXL1, and UTX) and DNA methylation (DNMT3A, IDH1/IDH2, and TET2) are frequently mutated in MDS, has led to the proposal that there is an important link between genetic and epigenetic alterations in this disease. In fact, regulatory factors have also been considered as miR-143/miR-145, miR-146a, miR-125a and MiR-21. Somatic mutations may influence the clinical phenotype but are not included in current prognostic scoring systems. In recent years research has brought new insights into these diseases, but few of the findings are sufficiently robust to be incorporated into the clinical routine at this time. Thus, the aim of this study was to review the role of genetic factors involved in the diagnosis and development of the different phenotypes of MDS.

Importance of immune response genes in hemophilia A

Hemophilia A is a disease caused by a deficiency of coagulation factor VIII resulting from genetic inheritance linked to chromosome X. One treatment option is the administration of plasma or recombinant FVIII. However, some patients develop inhibitors or antibodies against this factor. Inhibitors are alloantibodies that bind to the epitope of factor VIII causing it to be recognized by the immune system as a foreign peptide. This is the most serious complication in hemophilia patients in respect to replacement therapy. Some studies have suggested that genetic factors influence the development of factor VIII inhibitors such as ethnicity, family history, mutations in the factor VIII gene and in genes of the immune system. The aim of this study was to conduct a literature review to assess the influence of genetic factors of immune response genes, especially genes of the major histocompatibility complex and cytokines, which may be related to the development of factor VIII inhibitors in hemophilia A patients. Understanding these risk factors will help to determine future differential treatment in the control and prevention of the development of inhibitors.

Association of TNF polymorphisms with JAK2 (V617F) myeloproliferative neoplasms in Brazilian patients

The classical chromosome Philadelphia-negative myeloproliferative neoplasms (MPNs) are a group of disorders that share clinical, hematological, and histological features. Proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) are elevated in patients with MPN. The aim of this study was to verify the association between the polymorphisms of TNF gene (-308G/A and -238 G/A) in BCR-ABL-negative MPN in our population. Blood samples obtained from MPN patients were genotyped for the JAK2V617F mutation and both TNF polymorphisms using PCR-RFLP. Thirty three (26.8%) patients with polycythemia vera (PV), 35 (28.7%) essential thrombocythemia (ET), 22 (17.7%) primary myelofibrosis (PMF), and 33 (26.8%) with unclassifiable MPN (MPNu) were included in the study. The JAK2 V617F mutation was detected in 94 (76.42%) patients. Were observed a significant increase on the frequency of the TNF-238 GA genotype in MPN patients compared to controls (OR=2.21, 95% CI=1.02-4.80, P<0.04). The distribution of the genotypes and allelic frequencies of TNF-308 was significantly different among the MPNs, JAK2V617F positive, PV and PMF, and controls. Our data has demonstrated that the polymorphisms on TNF-238 GA, TNF-308 GA were associated to MPN development in this population, triggered by JAK2 V617F mutation.

Allele and haplotype frequencies of HLA-A, B, C, DRB1 and DQB1 genes in polytransfused patients in ethnically diverse populations from Brazil.

The red blood transfusion is a practice often used in patients with haematological and oncological diseases. However, the investigation of human leucocyte antigen (HLA) system frequency in these individuals is of great importance because multiple transfusions may lead to HLA alloimmunization. Brazil is a country that was colonized by many other ethnicities, leading to a mixed ethnicity and regionalized population. In view of the importance of HLA typing in these patients, the aim of this study was to investigate the allele and haplotype frequencies from polytransfused patients from three different regions from Brazil. HLA‐A, HLA‐B, HLA‐C, HLA‐DRB1 and HLA‐DQB1 genotyping of 366 patients was performed by PCR‐SSO, based on the Luminex technology (One Lambda®), and the anti‐HLA class I and class II antibodies were analysed using LabScreen Single Antigen Antibody Detection (One Lambda, Inc.). Allele and haplotype frequencies of polytransfused patients of three regions from Brazil were obtained using the Arlequin program. The most frequent allele frequencies observed were HLA‐A*02, A*03, B*15, B*35, B*51, C*07, C*04, C*03, DRB1*13, DRB1*11, DRB1*07, DRB1*03, DRB1*01, DQB1*03, DQB1*02, DQB1*06 and DQB1*05. There were differences between the groups for allele variants HLA‐B*57 (between Group 1 and Group 2) and HLA‐C*12 (between Group 1 and Group 3). The most frequent haplotypes found in the sample were HLA‐A*01B*08DRB1*03, DRBI*07DQB1*02, DRB1*01DQB1*05, DRB1*13DQB1*06 and A*02B*35. HLA class I and II antibodies were detected in 77.9% and 63.9% patients, respectively, while the both alloantibodies were detected in 62 (50.9%) patients. In conclusion, the HLA typing for polytransfused patients in each region has a great importance, as seen in this study; individuals from different regions from Brazil have HLA distribution not completely homogeneous.

JAK2 46/1 haplotype is associated with JAK2 V617F – positive myeloproliferative neoplasms in Brazilian patients

This study aimed to verify the association between the JAK2 46/1 haplotype (V617F positive) and some hematological parameters in BCR‐ABL‐negative chronic myeloproliferative neoplasms (cMPNs) in our population.