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Genetic Modifiers of Long‐Term Survival in Sickle Cell Anemia

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Genetic Modifiers of Long‐Term Survival in Sickle Cell Anemia Received: 10 July 2020 Revised: 30 July 2020 Accepted: 31 July 2020 Published online: 10 August 2020 DOI: 10.1002/ctm2.152 RESEARCH ARTICLE Genetic modifiers of long-term survival in sickle cell anemia Ambroise Wonkam1,2 Emile R. Chimusa1,2 Khuthala Mnika1 Gift Dineo Pule1 Valentina Josiane Ngo Bitoungui1 Nicola Mulder3 Daniel Shriner4 Charles N. Rotimi4 Adebowale Adeyemo4 1 Division of Human Genetics, Institute of Infectious Disease and Molecular Abstract Medicine (IDM), Faculty of Health Background: Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic Sciences, University of Cape Town, Cape disorder. Medical care has less-than-optimal impact on clinical outcomes in SCA Town, South Africa 2 Institute of Infectious Disease and in Africa due to several factors, including patient accessibility, poor access to Molecular Medicine (IDM), Faculty of resources, and non-availability of specific effective interventions for SCA. Health SciencesUniversity of Cape Town, Methods: Against this background, we investigated 192 African participants Cape Town, South Africa who underwent whole exome sequencing. Participants included 105 SCA 3 Computational Biology Division, Department of Integrative Biomedical patients spanning variable clinical expression: a “long survivor” group (age over Sciences, Institute for Infectious Disease 40 years), a “stroke” group (at least one episode of overt stroke), and a “random” and Molecular Medicine, University of group (patients younger than 40 years without overt cerebrovascular disease). Cape Town, Cape Town, South Africa 4 Center for Research on Genomics and Fifty-eight ethnically matched homozygous hemoglobin A controls were also Global Health, National Human Genome studied. Findings were validated in an independently recruited sample of 29 SCA Research InstituteNational Institutes of patients. Statistical significance of the mutational burden of deleterious and loss- Health, Bethesda, Maryland, USA of-function variants per gene against a null model was estimated for each group, Correspondence and gene-set association tests were conducted to test differences between groups. Ambroise Wonkam, MD, PhD, Divi- Results: In the “long survivor” group, deleterious/loss-of-function variants were sion of Human Genetics, Department of Medicine, Institute of Infectious Disease enriched in genes including CLCN6 (a voltage-dependent chloride channel for and Molecular Medicine, Faculty of Health which rare deleterious variants have been associated with lower blood pres- Sciences, University of Cape Town, Anzio sure) and OGHDL (important in arginine metabolism, which is a therapeutic Road, Observatory, 7925, Cape Town, South Africa. target in SCA). In the “stroke” group, significant genes implicated were asso- Email: [email protected] ciated with increased activity of the blood coagulation cascade and increased Funding information complement activation, for example, SERPINC1, which encodes antithrombin. NIH Clinical Center, Grant/Award Num- Oxidative stress and glutamate biosynthesis pathways were enriched in “long ber: U24-HL-135600; National Human survivors” group. Published transcriptomic evidence provides functional support Genome Research Institute, Grant/Award Number: 1U01HG007459-01; National for the role of the identified pathways. Institutes of Health, Grant/Award Num- Conclusions: This study provides new gene sets that contribute to variability in ber: 1ZIAHG200362 clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics Clin. Transl. Med. 2020;10:e152. wileyonlinelibrary.com/journal/ctm2 1of15 https://doi.org/10.1002/ctm2.152 2of15 WONKAM et al. KEYWORDS Africa, genetic modifiers, sickle cell disease, whole exome sequencing 1 INTRODUCTION lized a whole exome sequence (WES)-based approach to explore the specific hypothesis that rare gene-associated Sickle cell disease (SCD) is a group of blood disorders and function-altering variants with potentially high pen- caused by mutations in HBB that promote polymerization etrance are associated with SCA clinical sub-phenotypes,11 of hemoglobin and sickling of erythrocytes. The most com- and could lead to the identification of modifiable patho- mon and most clinically severe form of SCD is sickle cell physiological pathways. We studied two distinct clinical anemia (SCA [MIM: 603903]) and is caused by homozy- SCA groups, a “long survivor” group and a “stroke” group, gosity of the sickle mutation HbS. While the estimated age which we contrasted with a “random” group to infer criti- of the sickle mutation is ∼7300 years,1 the mutation has cal genes and pathways. We also contrasted the “long sur- persisted in appreciable frequencies because of the protec- vivor” and “stroke” groups as extreme phenotypes that are tion that heterozygotes have against malaria. An estimated likely to come from the relatively benign versus the most 305 800 babies are born each year with SCD worldwide, severe (respectively) ends of the phenotypic spectrum of with nearly 75% of the births occurring in sub-Saharan SCA. Africa (SSA).2 Despite this high incidence, most SSA coun- tries lack effective public health programs focused on SCD.3 2 MATERIALS AND METHODS Clinical expression of SCD often shows considerable variation in features such as the severity of anemia, the fre- 2.1 Ethics statement quency of painful vaso-occlusive crises, stroke, and mor- tality. Both genetic and non-genetic factors are known The study was performed in accordance with the guide- to influence the severity of SCD. For example, high fetal lines of the Helsinki Declaration. Ethical approval was hemoglobin (HbF) levels have long been known to be asso- given by the National Ethical Committee Ministry of Pub- ciated with less severity4; HbF levels are under genetic lic Health, Republic of Cameroon (No 033/CNE/DNM/07); control and are amenable to therapeutic manipulation.5 and the University of Cape Town, Faculty of Health Sci- Similarly, co-inheritance of α-thalassemia is protective ences Human Research Ethics Committee (HREC RE: against some SCD-related complications, such as hemol- 132/2010). ysis, stroke, and kidney disease.6,7 Availability of appro- priate comprehensive medical care for SCD that combines newborn screening, penicillin prophylaxis, screening for 2.2 Patients and methods stroke risk, transfusion program, and the use of hydrox- yurea, in high income countries, usually mitigates mor- Recruitment for the discovery group was conducted in bidity and facilitates longer survival of SCD patients.8 This Cameroon at the Yaoundé Central Hospital and Laquin- is, however, not the case in most of SSA, due to the com- tinie Hospital in Douala, as previously described.12 Socio- bined effect of inappropriate care and often severe clin- demographic and clinical data including blood counts and ical complications,7,9 compounded by other factors such hemoglobin (Hb) electrophoresis were obtained on enrol- as malaria, malnutrition, infectious diseases of childhood, ment. The present study was restricted to SCA (ie, HbSS), and poverty. Thus, up to 90% of infants with SCD in SSA the most prevalent and severe form of SCD. This study are believed to die needlessly by 5 years of age.10 design decision was taken to remove the potential con- Different HBB (MIM: 141900) haplotypes (Cameroon, founding effect of beta-thalassemia and hemoglobin C, Central African Republic, Benin, Senegal, and Ara- both of which are associated with milder forms of SCD. bian/Indian) have also been associated with variable clini- The discovery sample of patients included three groups. cal expression of SCD.2 However, a recent study of sickle (a) A “long survivor group” comprised SCA patients aged HBB haplotypes based on sequence data rather than over 40 years; this cut-off was based on a life expectancy of restriction site data led to a reclassification of the classical 43 years for SCA in the Cooperative Study.4 (b) A “stroke” haplotypes and found sub-structuring of haplotypes that group comprised SCA patients with at least one clini- may have confounded previous associations of the hap- cal episode of overt stroke, a devastating complication of lotypes with clinical severity.1 To search the genome for SCA that is considered to be a proxy of severity4 and is protein coding genes that affect disease severity, we uti- influenced by genetic modifiers.13 (c) A “random group” WONKAM et al. 3of15 comprised patients younger than 40 years with no independent subjects’ group, we filtered each resulting known cerebrovascular disease and randomly selected VCF file using the GATK tool Variant Filtration.16 Variant from among clinically stable patients. No patient was on filtering procedures and quality control assessment are as hydroxyurea, at the time of recruitment. Fifty-eight ethni- described in the Supporting Information Methods. Final cally matched homozygous HbAA controls were randomly call-sets were produced from VariantMetaCaller.17 We selected from apparently healthy blood donors recruited in used ANNOVAR to perform gene-based annotation (Sup- Yaoundé.14 The replication cohort consisted of adult SCA porting Information Methods) on
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