Dataset Information

The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil.

ABSTRACT: High levels of fetal hemoglobin (HbF) reduce sickle cell anemia (SCA) morbidity and mortality. HbF levels vary considerably and there is a strong genetic component that influences HbF production. Genetic polymorphisms at three quantitative trait loci (QTL): Xmn1-HBG2, HMIP-2 and BCL11A, have been shown to influence HbF levels and disease severity in SCA. Hydroxyurea (HU) is a drug that increases HbF. We investigated the influence of single nucleotide polymorphisms (SNPs) at the Xmn1-HBG2 (rs7482144); BCL11A (rs1427407, rs4671393 and rs11886868); and HMIP-2 (rs9399137 and rs9402686) loci on baseline and HU-induced HbF levels in 111 HbSS patients. We found that both BCL11A and HMIP-2 were associated with increased endogenous levels of HbF. Interestingly, we also found that BCL11A was associated with higher induction of HbF with HU. This effect was independent of the effect of BCL11A on baseline HbF levels. Additional studies will be needed to validate these findings and explain the ample inter-individual variations in HbF levels at baseline and HU-induced in patients with SCA.

SUBMITTER: Friedrisch JR

PROVIDER: S-EPMC5972079 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil.

Friedrisch João Ricardo JR Sheehan Vivien V Flanagan Jonathan M JM Baldan Alessandro A Summarell Carly C Ginter CC Bittar Christina Matzembacher CM Friedrisch Bruno Kras BK Wilke Ianaê Indiara II Ribeiro Camila Blos CB Daudt Liane Esteves LE da Rocha Silla Lucia Mariano LM

Blood cells, molecules & diseases 20161109

High levels of fetal hemoglobin (HbF) reduce sickle cell anemia (SCA) morbidity and mortality. HbF levels vary considerably and there is a strong genetic component that influences HbF production. Genetic polymorphisms at three quantitative trait loci (QTL): Xmn1-HBG2, HMIP-2 and BCL11A, have been shown to influence HbF levels and disease severity in SCA. Hydroxyurea (HU) is a drug that increases HbF. We investigated the influence of single nucleotide polymorphisms (SNPs) at the Xmn1-HBG2 (rs7482 ...[more]

PMID: 27838552

Similar Datasets

Project description: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).

Project description:BACKGROUND:Adults with sickle cell anemia (HbSS) are inconsistently treated with hydroxyurea. OBJECTIVES:We retrospectively evaluated the effects of elevating fetal hemoglobin with hydroxyurea on organ damage and survival in patients enrolled in our screening study between 2001 and 2010. METHODS:An electronic medical record facilitated development of a database for comparison of study parameters based on hydroxyurea exposure and dose. This study is registered with ClinicalTrials.gov, number NCT00011648. RESULTS:Three hundred eighty-three adults with homozygous sickle cell disease were analyzed with 59 deaths during study follow-up. Cox regression analysis revealed deceased subjects had more hepatic dysfunction (elevated alkaline phosphatase, Hazard Ratio = 1.005, 95% CI 1.003-1.006, p<0.0.0001), kidney dysfunction (elevated creatinine, Hazard Ratio = 1.13, 95% CI 1.00-1.27, p = 0.043), and cardiopulmonary dysfunction (elevated tricuspid jet velocity on echocardiogram, Hazard Ratio = 2.22, 1.23-4.02, p = 0.0082). Sixty-six percent of subjects were treated with hydroxyurea, although only 66% of those received a dose within the recommended therapeutic range. Hydroxyurea use was associated with improved survival (Hazard Ratio = 0.58, 95% CI 0.34-0.97, p = 0.040). This effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day (Hazard Ratio 0.36, 95% CI 0.17-0.73, p = 0.0050). Hydroxyurea use was not associated with changes in organ function over time. Further, subjects with higher fetal hemoglobin responses to hydroxyurea were more likely to survive (p = 0.0004). While alkaline phosphatase was lowest in patients with the best fetal hemoglobin response (95.4 versus 123.6, p = 0.0065 and 96.1 versus 113.6U/L, p = 0.041 at first and last visits, respectively), other markers of organ damage were not consistently improved over time in patients with the highest fetal hemoglobin levels. CONCLUSIONS:Our data suggest that adults should be treated with the maximum tolerated hydroxyurea dose, ideally before organ damage occurs. Prospective studies are indicated to validate these findings.

Dataset Information

The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil.

Publications

The role of BCL11A and HMIP-2 polymorphisms on endogenous and hydroxyurea induced levels of fetal hemoglobin in sickle cell anemia patients from southern Brazil.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets