An Expert Review of Pharmacogenomics of Sickle Cell Disease Therapeutics: Not Yet Ready for Global Precision Medicine

Abstract

Sickle cell disease (SCD) is a blood disease caused by a single nucleotide substitution (T > A) in the beta globin gene on chromosome 11. The single point mutation (Glu6Val) promotes polymerization of hemoglobin S (HbS) and causes sickling of erythrocytes. Vaso-occlusive painful crises are associated with recurrent and long-term use of analgesics/opioids and hydroxyurea (HU) by people living with SCD. The present analysis offers a stateof-the-art expert review of the effectiveness of pharmacogenomics/genetics of pain management in SCD, with specific focus on HU and opioids. The literature search used the following keywords: SCD, pharmacogenomics, pharmacogenetics, pain, antalgics, opioids, morphine, and HU. The literature was scanned until March 2016, with specific inclusion of targeted landmark and background articles on SCD. Surprisingly, our review identified only a limited number of studies that addressed the genetic/genomic basis of variable responses to pain (e.g., variants in OPRM1, HMOX-1, GCH1, VEGFA COMT genes), and pharmacogenomics of antalgics and opioids (e.g., variants in OPRM1, STAT6, ABCB1, and COMT genes) in SCD. There has been greater progress made toward identifying the key genomic variants, mainly in BCL11A, HBS1L-MYB, or SAR1, which contribute to response to HU treatment. However, the complete picture on pharmacogenomic determinants of the above therapeutic phenotypes remains elusive. Strikingly, no study has been conducted in sub-Saharan Africa where majority of the patients with SCD live. This alerts the broader global life sciences community toward the existing disparities in optimal and ethical targeting of research and innovation investments for SCD specifically and precision medicine and pharmacology research broadly.

Clinical and genetic factors are associated with pain and hospitalisation rates in sickle cell anaemia in Cameroon

“…We initially performed a thorough review of the literature on pharmacogenomics of SCD therapeutics, and identified a list of variants that are potentially associated with pain in SCD (Mnika et al , ). Once the SNPs of interests were identified, we investigated their allele frequencies in African populations present in the 1000 Genomes project (http://www.internationalgenome.org/home), and further narrowed the selection to SNPs that showed high frequency among African populations.…”

Pharmacoproteomics Profiling of Plasma From β‐Thalassemia Patients in Response to Hydroxyurea Treatment

“…Earlier studies on pharmacogenomics mainly dealt with identification of genomic variants in γ‐globin, BCL11A, and HBS1L‐MYB, which might be responsible for the selective response to hydroxyurea treatment . Because so far there is no genomic biomarker on the basis of which hydroxyurea therapy can be adapted for SCD and β‐thalassemia patients, we decided to take a pharmacoproteomics approach. In the past decade rapid technical developments in tandem MS and label‐free quantification have resulted in meaningful understanding of pathological pathways, biomarkers, and drug mechanisms at the proteome level .…”

Development to Enable Precision Medicine in Africa

“…SCD is caused by an SNV in the β-globin gene which results in a Glu6Val substitution. This causes polymerization of hemoglobin S, resulting in erythrocytes with a sickle shape [6].…”

“…More genomics research is needed to better understand the link between genetics and different manifestations of SCD-associated diseases in different African populations [7]. There are also few studies on attempting to understand the link between genetics and variable responses to pain in SCD [6].…”

“…For SCD, for example, some SNVs have been identified in the SAR1, BCL11A and HBS1L-MYB genes that are associated with altered response to hydroxyurea treatment [6]. Efficacy of therapeutics for the key infectious diseases, TB and HIV, has also been found to be impacted by genetics.…”