First draft submitted: 17 January 2017; Accepted for publication: 20 January 2017; Published online: 17 February 2017

There is an increasing global burden of sickle cell disease due to migrations and wide implementation of newborn screening and comprehensive care, including the use of hydroxyurea. Fetal hemoglobin, a central disease modifier, is subjected to genetic variants at three principal loci: BCL11A, HBS1L-MYB and HBB cluster. The co-inheritance of α-thalassemia and variants in APOL1 and HMOX1 has been associated with the development of sickle cell disease nephropathies. However, there is the lack of validation of multiple suggestive genetic loci associated to key subphenotypes such as stroke, painful episodes or acute chest syndrome. This highlights the need for global interdisciplinary research on adequately phenotyped large cohorts of patients from different populations and environments, specifically in Africa, the epicenter of the disease.

The increasing burden of sickle cell disease

Sickle cell disease (SCD) is the most common single gene disorder in the world. It is caused by a single point mutation (Glub6Val) that promotes polymerization of hemoglobin (Hb) S and sickling of erythrocytes. Inflammation, hemolysis, microvascular obstruction and organ damage characterize the clinical expression of SCD [1]. There is a strong association between the frequency of the HbS mutation and endemicity of malaria, and it is estimated that 305,800 babies are born each year with SCD worldwide, with nearly 75% of the births occurring in sub-Saharan Africa (SSA) [2]. However, as a result of migration, there is an increasing burden of SCD in countries where it was not initially prevalent. These countries include: South Africa, Ireland, Italy, Germany, England and France [3–8]. In addition, due to the implementation of newborn screening and comprehensive clinical care that includes the use of hydroxyurea (HU) treatment in the west, the SCD-related premature childhood deaths have been reduced by 70% in high-income nations such as the USA. Consequently, there has been a considerable increase in the life expectancy of people living with SCD [9]; and similar trends have been observed in a few African countries [10,11]. However, the death rate in adult SCD patients in the USA has not improved in the last thirty years, due to additional debilitating complications [11–13], and an overall poor quality of life [14,15]. As a result, it is anticipated that the global burden of SCD will continue to increase, as well as dependency of patients on chronic medications. SCD is now an accepted worldwide health problem and comparable to other major global noncommunicable diseases such as diabetes and hypertension [16]. There is a major need for research to help develop effective therapies across the life span of patients living with SCD in all parts of the world, and should incorporate personalized medicine and pharmacogenomics.

Genetic variants associated to specific subphenotypes of SCD

Environmental and multiple genetic factors influence many pathophysiological aspects of SCD that contribute to a highly variable clinical expression in patients. Fetal hemoglobin (HbF) has emerged as a central disease modifier; genetic variants at three principal loci, BCL11A, HBS1L–MYB and HBB cluster, account for 10–20% of HbF variation among SCD patients in USA, Brazil and the UK [17,18] (Table 1); these findings have been replicated in SCD patients living in Tanzania and Cameroon [19–22]. Interestingly, the expression of these modifiers is amenable to therapeutic manipulation, leading to new hope for treatment routes for SCD [23–25]. Moreover, cardiovascular phenotypes of SCD represent a major cause of morbidity and mortality in patients. The vast clinical heterogeneity observed in stroke, kidney disease or hypertension development in SCD, indicates that genetic factors may play a role as substantiated by a few studies [26]. The co-inheritance of α-thalassemia and specific variants in the HbF promoting loci have been proven to delay the clinical progression of kidney disease and stroke in SCD [27–32] (Table 1). In addition, genetic variants in both APOL1 and HMOX1 have been associated with SCD nephropathy among African–American adults and children [33–36] (Table 1). Lastly, there are consistent studies that have shown associations among variants in UGT1A1 and serum bilirubin, and cholelithiasis [37–39]. Nevertheless, there is the lack of validation of multiple studies on suggestive genetic modifiers associated with the development of various subphenotypes of SCD such as stroke, painful episodes, acute chest syndrome, bacteremia/infection, osteonecrosis, priapism, leg ulcers, sickle vasculophathies and hemolysis [40].

Early days of pharmacogenetics & drug metabolism in SCD

HU is the only US FDA approved treatment of SCD in adults and children. HU is a ribonucleotide reductase inhibitor that increases the HbF level. Patients respond differently to HU due to key genomic variants (Table 1), mainly in HbF promoting loci (BCL11A, HBG2 and HBS1L–MYB; [41–43]). However, the complete picture on pharmacogenomic determinants of HU remains elusive [44]. Strikingly, no study has been conducted in SSA where the majority of patients with SCD live. The common medications used by patients living with SCD are analgesics, to manage pain. Genetic differences are also suggested to be the reason for inter-individual variability in pain perception and experience, as well as variable responses to anti-inflammatory and opioid drugs. Surprisingly, our recent review identified only a limited number of studies that addressed the genetic/genomic basis of variable responses to pain, and pharmacogenomics of analgesics and opioids in general, with little focus on SCD. The few available and largely non replicated studies have identified variants in OPRM1, HMOX-1, GCH1, VEGFA, STAT6, ABCB1 and COMT genes [45].

Future research directions: Africa, & large cohort studies & pharmacogenetics

Despite the increasing global burden of SCD and major progress in understanding the genetic modifiers of SCD subphenotypes and response to HU, there are limited data to support pharmacogenetics of SCD therapeutics for precision medicine. It is expected that most patients living with SCD will have access to analgesics, antibiotics and HU treatment worldwide; which could increases the global interest in the field of pharmacogenetics of SCD. As the understanding of pathophysiology of SCD advances and more is known about regulatory mechanisms, associated pathways and associated gene expressions, it is likely that more medications that are outside HbF induction will be developed. For example to induce stress hematopoiesis or endothelial nitric oxide release, to reduce leukocytes counts or red blood cells adhesion to the endothelium or inflammation processes [45].

Understanding the genetic basis of severity of SCD and it pharmacogenetics is a major endeavor, given the pathophysiological complexity and interlocking nature of the biological processes culminating in SCD subphenotypes. Longitudinal cohort studies are the most scientifically rigorous methods in understanding both environmental and genetics risk factors, health and disease outcomes. While high regional disease prevalence in SSA would be expected to facilitate epidemiologic, translational and clinical research studies on SCD; there is still a lack of integration and coordination of the emerging efforts from a few African countries that are implementing newborn screening and comprehensive care, or initiating genetic studies. This highlights the need for global interdisciplinary research on adequately phenotyped large cohorts of patients with SCD from different populations and environments, to help develop effective therapies across the life course for SCD; which clearly could be best established in Africa, the epicenter of SCD. Developing large research activities on a large cohort of SCD patients in Africa, will only be successful with establishing appropriate public health comprehensive care infrastructures, in order to improve childhood mortality, and serious coordination of SCD patients follow-up plans. An adequately well phenotyped large multicentre cohort of SCD individuals from variable populations and environments in Africa could allow a careful exploration and validation of multiple genetic variants that modulate some of the common subphenotypes of SCD, using high-throughput genotyping methods, whole exome and whole genome sequencing, coupled with innovative bioinformatics, and biostatics and geocoding analytical techniques. The aim will be to possibly generate genetic and environmental markers that could be used in an integrated model, to anticipate guidance in order to improve the care, quality of life and ultimately survival of patients living with SCD.

Table 1. Selected replicated genomic modifiers in sickle cell disease. Gene SNPs Chromosome: locus Phenotypes Effect Ref. HBS1L–MYB rs28384513 6:135417902 HbF and hydroxyurea induced HbF Protective

Protective [17–22]

[41–43] rs9399137 6:135460711 Protective rs4895441 6:135468266 BCL11A rs4671393 2:60574475 HbF and hydroxyurea induced HbF Protective [17–22]

[41–43] HBG2 rs7482144 11:5254939 HbF and hydroxyurea induced HbF Protective [17,42–43] HBA (3.7 or 4.2kb α-globin gene deletion) 16 Hematological indices and stroke Protective [27,28] Hematological indices and nephropathy Protective [29–32] APOL1 rs73885319 22:36265860 Nephropathy Risk [33–36] rs60910145 22:36265988 rs71785313 22:36266000–36266005 HMOX1 rs3074372 22:35380894–35380895 Nephropathy Risk [35,36] rs743811 22:35396981 Nephropathy Protective/risk [35,36] UGT1A1 rs887829 2:234333309 Serum bilirubin and cholelithiasis Protective [37–39]