Regulation of genomic and biobanking research in Africa: a content analysis of ethics guidelines, policies and procedures from 22 African countries

Background: The introduction of genomics and biobanking methodologies to the African research context has also introduced novel ways of doing science, based on values of sharing and reuse of data and samples. This shift raises ethical challenges that need to be considered when research is reviewed by ethics committees, relating for instance to broad consent, the feedback of individual genetic findings, and regulation of secondary sample access and use. Yet existing ethics guidelines and regulations in Africa do not successfully regulate research based on sharing, causing confusion about what is allowed, where and when. Methods: In order to understand better the ethics regulatory landscape around genomic research and biobanking, we conducted a comprehensive analysis of existing ethics guidelines, policies and other similar sources. We sourced 30 ethics regulatory documents from 22 African countries. We used software that assists with qualitative data analysis to conduct a thematic analysis of these documents. Results: Surprisingly considering how contentious broad consent is in Africa, we found that most countries allow the use of this consent model, with its use banned in only three of the countries we investigated. In a likely response to fears about exploitation, the export of samples outside of the continent is strictly regulated, sometimes in conjunction with regulations around international collaboration. We also found that whilst an essential and critical component of ensuring ethical best practice in genomics research relates to the governance framework that accompanies sample and data sharing, this was most sparingly covered in the guidelines. Conclusions: There is a need for ethics guidelines in African countries to be adapted to the changing science policy landscape, which increasingly supports principles of openness, storage, sharing and secondary use. Current guidelines are not pertinent to the ethical challenges that such a new orientation raises, and therefore fail to provide accurate guidance to ethics committees and researchers

Ethical issues in human genomics research in developing countries

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies (GWAS) provide a powerful means of identifying genetic variants that play a role in common diseases. Such studies present important ethical challenges. An increasing number of GWAS is taking place in lower income countries and there is a pressing need to identify the particular ethical challenges arising in such contexts. In this paper, we draw upon the experiences of the MalariaGEN Consortium to identify specific ethical issues raised by such research in Africa, Asia and Oceania.</p> <p>Discussion</p> <p>We explore ethical issues in three key areas: protecting the interests of research participants, regulation of international collaborative genomics research and protecting the interests of scientists in low income countries. With regard to participants, important challenges are raised about community consultation and consent. Genomics research raises ethical and governance issues about sample export and ownership, about the use of archived samples and about the complexity of reviewing such large international projects. In the context of protecting the interests of researchers in low income countries, we discuss aspects of data sharing and capacity building that need to be considered for sustainable and mutually beneficial collaborations.</p> <p>Summary</p> <p>Many ethical issues are raised when genomics research is conducted on populations that are characterised by lower average income and literacy levels, such as the populations included in MalariaGEN. It is important that such issues are appropriately addressed in such research. Our experience suggests that the ethical issues in genomics research can best be identified, analysed and addressed where ethics is embedded in the design and implementation of such research projects.</p

Candidate polymorphisms and severe malaria in a Malian population.

Malaria is a major health burden in sub-Saharan African countries, including Mali. The disease is complex, with multiple genetic determinants influencing the observed variation in response to infection, progression, and severity. We assess the influence of sixty-four candidate loci, including the sickle cell polymorphism (HbS), on severe malaria in a case-control study consisting of over 900 individuals from Bamako, Mali. We confirm the known protective effects of the blood group O and the HbS AS genotype on life-threatening malaria. In addition, our analysis revealed a marginal susceptibility effect for the CD40 ligand (CD40L)+220C allele. The lack of statistical evidence for other candidates may demonstrate the need for large-scale genome-wide association studies in malaria to discover new polymorphisms. It also demonstrates the need for establishing the region-specific repertoire of functional variation in important genes, including the glucose-6-phosphatase deficiency gene, before embarking on focused genotyping

Heamoglobin S protects against symptomless Plasmodium falciparum patent parasitaemia in two populations from Burkina Faso

HbS protects against clinical Plasmodium falciparum malaria and is associated with lower parasite densities in symptomatic subjects. Conclusive evidence of a protective role of HbS against symptomless P. falciparum infection has not been obtained so far. Here we show, in a large-scale epidemiological survey involving 2200 subjects studied during five cross-sectional surveys across two consecutive years in Burkina Faso, West Africa, that HbS is associated with a 70% reduction of harbouring a P. falciparum infection (OR=0.26 [0.11-0.60], P=0.002). This observation outlines a scenario made of consistent experimental and epidemiological observations. The abnormal display of parasite adhesive molecules on the surface of the HbS and HbC infected erythrocytes, disrupting the pathogenic process of sequestration, might displace the parasite from the deep to the peripheral circulation hence promoting its elimination at the spleen level

HbS protects against symptomless P. falciparum patent parasitaemia in two populations from Burkina Faso

HbS protects against clinical Plasmodium falciparum malaria and is associated with lower parasite densities in symptomatic subjects. Conclusive evidence of a protective role of HbS against symptomless P. falciparum infection has not been obtained so far. Here we show, in a large-scale epidemiological survey involving 2200 subjects studied during five cross-sectional surveys across two consecutive years in Burkina Faso, West Africa, that HbS is associated with a 70% reduction of harbouring a P. falciparum infection (OR=0.26 [0.11-0.60], P=0.002). This observation outlines a scenario made of consistent experimental and epidemiological observations. The abnormal display of parasite adhesive molecules on the surface of the HbS and HbC infected erythrocytes, disrupting the pathogenic process of sequestration, might displace the parasite from the deep to the peripheral circulation hence promoting its elimination at the spleen level

Investigating the evolutionary link between malaria and autoimmunity: a large scale immunogenetic study in two West African populations.

AIM. Despite equivalent exposure to infection and comparable use of protective measures, the Fulani of West Africa have been shown to mount stronger immune responses to Plasmodium falciparum antigens and to be less susceptible to infection and mild disease than sympatric populations (Modiano et al. 1996, PNAS). The Fulani also show a higher response to other pathogens, and both their Th1 and Th2 responses are enhanced, suggesting that their resistance to malaria could result from a generally stronger immune activation. Key genes related to T regulatory cell function are indeed down-regulated in the Fulani (Torcia et al. 2008 PNAS). This disorder of immune homeostasis could be driven by genetic factors positively selected by P. falciparum and may underlie the higher susceptibility of the Fulani to diseases with autoimmune pathogenesis reported in the literature (Fish et al. 1987, Diabetologia; Mahe et al. 1996, Br J Dermatol; Brieger et al. 1997, Trop Med Int Health). The general aim of the proposed investigation is to explore the genetic basis of the lower susceptibility to malaria observed in the Fulani, and in particular to evaluate the role of autoimmunity loci. MATERIALS AND METHODS. To investigate this hypothesis, we conducted a large-scale epidemiological study in rural villages of Burkina Faso inhabited by Fulani, Mossi and Rimaibe communities. The field study lasted 2 years (2007-8) and consisted in a combination of cross sectional and longitudinal surveys. At each survey we collected parasitological (P. falciparum index and parasite density), clinical (fever, anemia, spleen size) and serological data (IgG levels against P. falciparum and self antigens). We genotyped 363 Single Nucleotide Polymorphisms (SNPs) on 2186 samples using the Sequenom System, based on allele-specific primer extension and MALDI-TOF Mass Spectrometry. SNPs included polymorphisms previously shown to be involved in resistance to severe malaria, in resistance to infection and/or in antibody production, as well as polymorphisms at autoimmunity loci. We conducted population genetic analyses and genetic association analysis with parasitological, clinical and serological phenotypes using the free software package R. RESULTS. Principal component analysis revealed that Mossi and Rimaibe (Non-Fulani) are not genetically distinct among themselves, whereas the Fulani are a clearly distinct group, in agreement with data obtained on HLA class I-II alleles (Modiano et al. 2001, Tissue Antigens; Lulli et al. 2009, Hum Immunol). We therefore compared allele frequencies and calculated Fst, a measure of population genetic differentiation, between Fulani and Non-Fulani. We observed that the proportion of autoimmunity SNPs with Fst>0.05 (indicating moderate/high differentiation and corresponding to at least a two-fold difference in allele frequency) is 20%, versus 10% shown by other loci (p=0.03). Genetic association analysis of susceptibility to infection and infection levels showed association signals among genes involved in resistance to severe malaria (TNF, DDC, ABO, IFNG-IL22, GNAS, MECP2, G6PD). Furthermore we observed strong signals of association, both in Fulani and Non-Fulani, in the 5q31 region of the genome, which has been previously linked to P. falciparum infection levels (Rihet et al. 1998, Am J Hum Genet; Mangano et al. 2008, Genes Immun). Finally, association signals were also observed among genes related to T regulatory cell function and/or involved in autoimmunity (TGFBR3, CD25, FCGR2A, CR1, IL1R1L-IL18RAP, IL1A-IL1B, IL21, BLK, ORMDL3, TGFB1). CONCLUSIONS. The results of our investigation support the hypothesis that malaria has exerted a selective pressure on the immune system and has affected is evolution, and provide evidence that common gene regulatory networks could underlie susceptibility to malaria and to immunological disorders such as autoimmune diseases

Investigating the genetic basis of the lower susceptibility to malaria shown by the Fulani of West-Africa.

Despite equivalent exposure to infection and comparable use of protective measures, the Fulani of West Africa have been shown to mount stronger immune responses to Plasmodium falciparum antigens and to be less susceptible to infection and mild disease than sympatric populations. The Fulani also show a higher response to other pathogens, and both their Th1 and Th2 responses are enhanced, suggesting that their resistance to malaria could result from a generally stronger immune activation. Key genes related to T regulatory cell function are indeed down-regulated in the Fulani. This disorder of immune homeostasis could be driven by genetic factors positively selected by P. falciparum and may underlie the reported higher susceptibility of the Fulani to autoimmune diseases. In order to investigate the genetic basis of the lower susceptibility to malaria shown by the Fulani we conducted a large-scale epidemiological study in Burkina Faso consisting of a combination of cross-sectional and longitudinal surveys. We genotyped 363 Single Nucleotide Polymorphisms (SNPs) on 2186 samples, by Sequenom MassArray System. SNPs included polymorphisms previously shown to be involved in resistance to severe malaria, in resistance to infection or in antibody production (www.malariagen.net), as well as polymorphisms at autoimmunity loci. We will show results of: i) inter-ethnic comparison of malaria susceptibility phenotypes; ii) population genetics analysis; iii) genetic association analysis with parasitological, clinical and immunological phenotypes

Investigating the genetic basis of the Fulani’s lower susceptibility to malaria: the role of autoimmunity loci.

Despite equivalent exposure to infection and comparable use of protective measures, the Fulani of West Africa have been shown to mount stronger immune responses to Plasmodium falciparum antigens and to be less susceptible to infection and mild disease than sympatric populations. The Fulani also show a higher response to other pathogens, and both their Th1 and Th2 responses are enhanced, suggesting that their resistance to malaria could result from a generally stronger immune activation. Key genes related to T regulatory cell function are indeed down-regulated in the Fulani. This disorder of immune homeostasis could be driven by genetic factors positively selected by P. falciparum and may underlie the higher susceptibility of the Fulani to diseases with autoimmune pathogenesis reported in the literature. The general aim of our investigation is to explore the genetic basis of the lower susceptibility to malaria observed in the Fulani, and in particular to evaluate the role of autoimmunity loci. We conducted a large-scale epidemiological study in rural villages of Burkina Faso inhabited by Fulani, Mossi and Rimaibe communities. The field study lasted 2 years (2007-8) and consisted in a combination of cross sectional and longitudinal surveys. At each survey we collected relevant parasitological and clinical data. Serological data (IgG levels against P. falciparum and self antigens) were generated by ELISA on plasma samples from the first survey. We genotyped 363 Single Nucleotide Polymorphisms (SNPs) on 2186 samples using the Sequenom System. Principal component analysis revealed that Mossi and Rimaibe (Non-Fulani) are not genetically distinct among themselves, whereas the Fulani are a clearly distinct group. We therefore compared allele frequencies and calculated Fst between Fulani and Non-Fulani. We observed that the proportion of autoimmunity SNPs with Fst>0.05 (indicating moderate/high differentiation and corresponding to at least a two-fold difference in allele frequency) is 20% versus 10% shown by other loci. Genetic association analysis of susceptibility to infection showed, both in Fulani and Non-Fulani, signals of association among genes: i) involved in resistance to severe malaria (ABO, DDC, G6PD, GNAS, IFNG-IL22, MECP2, TNF); ii) lying in the 5q31 region of the genome, which has been previously linked to P. falciparum infection levels (IRF1); iii) related to T regulatory cell function and/or involved in autoimmunity (BLK, CD25, CR1, FCGR2A, IL1A-IL1B, IL1R1L-IL18RAP, IL21, ORMDL3, TGFB1, TGFBR3). These results support the hypothesis that malaria has exerted a selective pressure on the immune system and has affected its evolution, and suggest that common gene regulatory networks could underlie susceptibility to malaria and to immunological disorders such as autoimmune diseases