Affordable Access

deepdyve-link
Publisher Website

Genetic modifiers of long-term survival in sickle cell anemia.

Authors
  • Wonkam, Ambroise1, 2
  • Chimusa, Emile R1, 2
  • Mnika, Khuthala1
  • Pule, Gift Dineo1
  • Ngo Bitoungui, Valentina Josiane1
  • Mulder, Nicola3
  • Shriner, Daniel4
  • Rotimi, Charles N4
  • Adeyemo, Adebowale4
  • 1 Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. , (South Africa)
  • 2 Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. , (South Africa)
  • 3 Computational Biology Division, Department of Integrative Biomedical Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa. , (South Africa)
  • 4 Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
Type
Published Article
Journal
Clinical and translational medicine
Publication Date
Aug 01, 2020
Volume
10
Issue
4
Identifiers
DOI: 10.1002/ctm2.152
PMID: 32898326
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less-than-optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non-availability of specific effective interventions for SCA. Against this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a "long survivor" group (age over 40 years), a "stroke" group (at least one episode of overt stroke), and a "random" group (patients younger than 40 years without overt cerebrovascular disease). Fifty-eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated for each group, and gene-set association tests were conducted to test differences between groups. In the "long survivor" group, deleterious/loss-of-function variants were enriched in genes including CLCN6 (a voltage-dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and OGHDL (important in arginine metabolism, which is a therapeutic target in SCA). In the "stroke" group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, SERPINC1, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in "long survivors" group. Published transcriptomic evidence provides functional support for the role of the identified pathways. This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions. © 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Report this publication

Statistics

Seen <100 times