Association of Variants at BCL11A and HBS1L-MYB with Hemoglobin F and Hospitalization Rates among Sickle Cell Patients in Cameroon

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Genetic variation at loci influencing adult levels of HbF have been shown to modify the clinical course of sickle cell disease (SCD). Data on this important aspect of SCD have not yet been reported from West Africa. We investigated the relationship between HbF levels and the relevant genetic loci in 610 patients with SCD (98% HbSS homozygotes) from Cameroon, and compared the results to a well-characterized African-American cohort.

Methods and Findings

Socio-demographic and clinical features were collected and medical records reviewed. Only patients >5 years old, who had not received a blood transfusion or treatment with hydroxyurea were included. Hemoglobin electrophoresis and a full blood count were conducted upon arrival at the hospital. RFLP-PCR was used to describe the HBB gene haplotypes. SNaPshot PCR, Capillary electrophoresis and cycle sequencing were used for the genotyping of 10 selected SNPs. Genetic analysis was performed with PLINK software and statistical models in the statistical package R. Allele frequencies of relevant variants at BCL11A were similar to those detected in African Americans; although the relationships with Hb F were significant (p <.001), they explained substantially less of the variance in HbF than was observed among African Americans (∼ 2% vs 10%). SNPs in HBS1L-MYB region ( HMIP) likewise had a significant impact on HbF, however, we did not find an association between HbF and the variations in HBB cluster and OR51B5/6 locus on chromosome 11p, due in part to the virtual absence of the Senegal and Indian Arab haplotypes. We also found evidence that selected SNPs in HBS1L-MYB region ( HMIP) and BCL11A affect both other hematological indices and rates of hospitalization.

Conclusions

This study has confirmed the associations of SNPs in BCL11A and HBS1L-MYB and fetal haemoglobin in Cameroonian SCA patients; hematological indices and hospitalization rates were also associated with specific allelic variants.

Related collections

Most cited references 21

Record: found
Abstract: found
Article: not found

Pain in sickle cell disease. Rates and risk factors.

O S Platt, B D Thorington, D Brambilla … (1991)

Acute episodes of pain are the principal symptom of sickle cell disease, but little is known about the epidemiologic features of these episodes or risk factors for them, nor is it known whether patients with high rates of such episodes die prematurely. We prospectively studied the natural history of sickle cell disease in 3578 patients ranging from newborns to persons up to 66 years old who were followed at clinical centers across the United States. There were 12,290 episodes of pain in 18,356 patient-years. The average rate was 0.8 episode per patient-year in sickle cell anemia, 1.0 episode per patient-year in sickle beta 0-thalassemia, and 0.4 episode per patient-year in hemoglobin SC disease and sickle beta(+)-thalassemia. The rate varied widely within each of these four groups--e.g., 39 percent of patients with sickle cell anemia had no episodes of pain, and 1 percent had more than six episodes per year. The 5.2 percent of patients with 3 to 10 episodes per year had 32.9 percent of all episodes. Among patients with sickle cell anemia who were more than 20 years old, those with high rates of pain episodes tended to die earlier than those with low rates. High rates were associated with a high hematocrit and low fetal hemoglobin levels. alpha-Thalassemia had no effect on pain apart from its association with an increased hematocrit. The "pain rate" (episodes per year) is a measure of clinical severity and correlates with early death in patients with sickle cell anemia over the age of 20. Even when the fetal hemoglobin level is low, one can predict that small increments in the level may have an ameliorating effect on the pain rate and may ultimately improve survival. This outcome is particularly encouraging to investigators studying hydroxyurea and other treatments designed to increase the fetal hemoglobin level.

0 comments Cited 253 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia.

N Arnheim, K B Mullis, R K Saiki … (1985)

Two new methods were used to establish a rapid and highly sensitive prenatal diagnostic test for sickle cell anemia. The first involves the primer-mediated enzymatic amplification of specific beta-globin target sequences in genomic DNA, resulting in the exponential increase (220,000 times) of target DNA copies. In the second technique, the presence of the beta A and beta S alleles is determined by restriction endonuclease digestion of an end-labeled oligonucleotide probe hybridized in solution to the amplified beta-globin sequences. The beta-globin genotype can be determined in less than 1 day on samples containing significantly less than 1 microgram of genomic DNA.

0 comments Cited 249 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.

Daniel E Bauer, Sophia C Kamran, Samuel Lessard … (2013)

Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that common genetic variation at BCL11A associated with fetal hemoglobin (HbF) level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine-mapping uncovers a motif-disrupting common variant associated with reduced transcription factor (TF) binding, modestly diminished BCL11A expression, and elevated HbF. The surrounding sequences function in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the enhancer is required in erythroid but not B-lymphoid cells for BCL11A expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential for appropriate gene expression. We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the β-hemoglobinopathies.

0 comments Cited 218 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Ana Paula Arez: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 25 March 2014

Volume: 9

Issue: 3

Electronic Location Identifier: e92506

Affiliations

[1 ]Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, Republic of South Africa

[2 ]Department of Microbiology, Parasitology and Haematology, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon

[3 ]UCT/MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, Republic of South Africa

[4 ]Department of Public Health Sciences, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, United States of America

[5 ]Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada

Instituto de Higiene e Medicina Tropical, Portugal

Author notes

* E-mail: ambroise.wonkam@ 123456uct.ac.za

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: AW AAV JN. Performed the experiments: VJNB AAV RR AW JN. Analyzed the data: AW VJNB AAV BT RSC GL. Contributed reagents/materials/analysis tools: AW RR JN BT RSC GL. Wrote the paper: AW RR BT RSC GL. Revised and approved the manuscript: AW VJNB AAV RR RSC BT GL JN.

Article

Publisher ID: PONE-D-14-01562

DOI: 10.1371/journal.pone.0092506

PMC ID: 3965431

PubMed ID: 24667352

SO-VID: 72d2075b-c15a-405f-9b50-282a57aa3699

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 12 January 2014

Date accepted : 21 February 2014

Page count

Pages: 9

Funding

The molecular experiments of the study were funded by the National Health Laboratory Services (NHLS), South Africa; the University of Cape Town (UCT) Research Committee and Carnegie Research Development Grant, South Africa. The students' bursaries were supported by the Third World Academy of Sciences (TWAS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Association of Variants at BCL11A and HBS1L-MYB with Hemoglobin F and Hospitalization Rates among Sickle Cell Patients in Cameroon

Read this article at

Abstract

Background

Methods and Findings

Conclusions

Related collections

PLOS Climate

Most cited references 21

Pain in sickle cell disease. Rates and risk factors.

Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia.

An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 295

Cited by 31

Most referenced authors 713