Global Sickle Cell Disease Network
Small Study Group D Report from Benin Workshop
Genetic Factors Involved in Phenotypic Diversity: Global Approach
Co-Chairs: Carolyn Hoppe (USA) and Tom Vulliamy (UK)
To answer this question, several other questions were posed including:
- How do we group patients by phenotype?
- How do we define phenotypic sub-groups?
- Can we develop a severity index for SCD?
Example of phenotypic diversity: in Kuwait, despite a high expression of Hb F in all patients with the Arab/Indian haplotype, a sub-group (10-15%) of patients regularly present with vaso-occlusive pain episodes.
Barriers to defining phenotypes include:
- Difficulty in measuring pain objectively
- Need for objective measures (clinical, laboratory and radiographic) to define SCD phenotypes
- Limited resources for objective measures of phenotype in low-income countries
- Limited access to TCD and MRI
- Some clinical criteria are more easily measured e.g. leg ulcer staging, age of presentation of hand-foot syndrome, acute chest syndrome (assuming uniform availability of X-rays)
- Laboratory biomarkers (e.g. Hb F, LDH) can be assessed from frozen blood samples
- There is a general lack of information about the diversity of the SCD phenotypes in sub-Saharan Africa
- Cost could be a deterrent to acquiring phenotypic data because in some countries patients have to pay for services such as X-ray.
- We need to collect meaningful incidence/prevalence data for specific phenotypes and populations with a focus on clinically relevant phenotypes that can be objectively and feasibly measured in sub-Saharan Africa
- Tools available to define genetic models needed to identify genetic loci that impact on specific clinical and biochemical phenotypes (e.g. Hb F expression) include: single locus genotype or candidate gene analysis (e.g. gG Xmnl, UGT1A, α -thalassemia) and genome-wide association studies (GWAS).
- Genetic studies would also be valuable to address pharmacogenomic questions (e.g. GWAS for studies on the variable metabolism of morphine) and define susceptibility to acute and late end-organ complications of SCD
- We should follow examples of international collaborations that have been successful in the past (e.g. breast cancer). The framework for such collaborations could be thought of as “hub with multiple spokes” contributing to it.
- We should build on existing projects (e.g. malaria and HIV research) that have established laboratory and bioinformatics facilities to extend the network of labs involved.
- A two-tier system could be envisaged, with smaller laboratories, capable of processing samples, referring to a centralized laboratory for storage and genetic analysis (i.e. we do not need a DNA sequencer in every lab
- Efforts should be made to keep technologies for genetic research within the country that is collecting the data, but this should be balanced with what is feasible and cost-effective
- In addressing issues relating to ethics of bio-banking and genotyping, we should follow successful examples for the ethical conduct of human research subjects. Genomic sovereignty is critically important to sustain mutually beneficial global collaboration. Local SCD investigators should be encouraged and supported to draft frameworks to protect genomic sovereignty, and institute procedures to safeguard ethical, legal and social implications of genomic research.
- Establish collaborative international partnerships as well as raising awareness of those that already exist.
- For genomic studies, large populations with well-characterized phenotypes are required; this can only be done through global collaborative efforts.
The global network could:
- provide information about availability of training in different laboratories
- encourage and facilitate communication between collaborative groups
- develop a website for exchange of ideas across the network
- facilitate the distribution of technological developments
- develop partnerships with funding agencies in support of research initiatives
- seek support from and linkage to governments and governmental agencies for the maintenance of long-term research programs