Genomic Medicine in Developing Countries and Resource-Limited Environments T. Katsila1, a, K. Mitropoulos2, a, Z. Mohamed3, D.A. Forero4, P. Laissue5, A. Wonkam6, C. Lopez-Correa7, W. Chantratita8, A. Llerena9, B.R. Ali10 and G.P. Patrinos1, 10 1
University of Patras School of Health Sciences, Patras, Greece; 2The Golden Helix Foundation, London, United Kingdom; 3University of Malaya, Kuala Lumpur, Malaysia; 4Universidad Antonio Nariño, Bogotá, Colombia; 5Del Rosario University, Bogotá, Colombia; 6University of Cape Town, Cape Town, South Africa; 7Genome Quebec, Montreal, QC, Canada; 8Mahidol University, Bangkok, Thailand; 9Extremadura University Hospital and Medical School, Badajoz, Spain;
United Arab Emirates University, Al-Ain, United Arab Emirates
26.1 INTRODUCTION The advent of genomics and related technologies has revolutionized mainstream medical practices (McCarthy et al., 2013). The advent of genome-wide studies has catalyzed the translation of genomic ﬁndings into health care (Mardis, 2011). New technologies, particularly nextgeneration sequencing (NGS) approaches, are being adopted by diagnostic laboratories and hospitals in the United States and Western Europe. In terms of regulation, several guidelines from the United States Food and Drug Administration (http://www.fda.gov) and the European Medicines Agency (http://www.ema.europa.eu) are being announced regarding the translation of genomic medicine into the clinic. However, genomic medicine is implemented at a different pace when developing and resource-limited countries are considered. In these countries, signiﬁcant barriers exist, which often relate to limited resources and a lack of technology and knowledge transfer. As such, the potential of genomic medicine is often hardly understood by biomedical scientists and healthcare professionals. Considering that approximately 85% of the world’s population lives in developing/resource-limited countries, access to genomic medicine becomes fundamental. Today, there have been some examples from the successful a
implementation of genomic medicine in developing countries in Europe and Asia that rely on several related and intersected disciplines (population genomics, pharmacogenomics (PGx), informatics, and public health genomics). We feel that the examples described in the following relate to the previously mentioned disciplines and can serve as model cases toward the implementation of genomic medicine in resource-limited environments.
26.1.1 Euro-PGx Project: A European-Wide Pharmacogenomics Map In Europe, PGx is implemented in the various health systems at a rather heterogeneous pace. This is due to the lack of harmonization of the national guidelines within Europe and, most importantly, differences in resource availability (Mitropoulos et al., 2011). Furthermore, taking into account that the pharmacogenomic biomarker allele frequencies in various European populations are hardly known, it becomes challenging to deﬁne the actionable pharmacogenomic biomarkers on which drugedose recommendations will be set. The Euro-PGx project (http://www.goldenhelix. org/index.php/research/pharmacogenomics-in-europe) focuses on the determination of the varying pharmacogenomic biomarker allele frequencies in a large number of mostly developing European countries to produce druge dose recommendations. Preliminary ﬁndings from a large-
These authors contributed equally to this work.
Molecular Diagnostics. http://dx.doi.org/10.1016/B978-0-12-802971-8.00026-2 Copyright © 2017 Elsevier Ltd. All rights reserved.
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scale genotyping effort using the Drug-Metabolizing Enzymes and Transporters Plus microarray (Affymetrix, Santa Clara, CA, USA) suggest that several pharmacogenomic biomarker allele frequencies vary signiﬁcantly, despite the strong Caucasian genetic component of the vast majority of the European populations. Data access to the scientiﬁc community is anticipated through the FINDbase database (http://www.ﬁndbase.org) via the microattribution approach (Giardine et al., 2011). The Euro-PGx project also facilitates the organization of PGx educational activities in various European countries (as of May 2016, 16 different events have been organized in 10 European, mostly developing, countries). These educational events, also known as the Golden Helix PGx Days (http:// pharmacogenomicsdays.goldenhelix.org), aim to educate healthcare professionals and increase PGx awareness.
26.1.2 Implementation of Pharmacogenomics in Clinical Settings In Southeast Asia, particularly Taiwan, the associations of the HLA-B*1502 allele with Stevens-Johnson Syndrome/ Toxic Epidermal Necrolysis (SJS/10) upon carbamazepine administration (Chung et al., 2004) as well as that of the HLA-B*5801 allele with allopurinol-induced severe cutaneous adverse reactions (Hung et al., 2005) support the value of PGx in tailor-made therapeutics. A large clinical study that conﬁrmed the beneﬁt of HLA-B*1502 screening to prospectively identify subjects at genetic risk for the previously mentioned condition (Chen et al., 2011) led the Taiwanese government to begin reimbursing the screening costs in 2010. Today, several PGx biomarkers have been found to be correlated with interindividual drug efﬁcacy and/or toxicity. Nevertheless, health professionals often lack genomics education, so it is urgent to make PGx knowledge readily available in a user-friendly format. The DruGeVar database (http://drugevar.genomicmedicinealliance.org) (Dalabira et al., 2014) was developed to serve as an online knowledge portal for clinical PGx with the aim of triangulating drugsegenesePGx biomarkers (those approved by regulatory agencies) (Fig. 26.1). In Southeast Asia, a pharmacogenomic card has been proposed to record patients’ pharmacogenomic biomarkers. Similarly, the Ramathibodi Hospital in Thailand has launched a “PGx” wallet card. The latter summarizes patients’ HLA gene variant information to predict the risk of developing SJS/10 (Borchers et al., 2008). Such PGx cards could be readily expandable toward tailor-made therapeutics (Fig. 26.2).
In Latin America, the Iberian American Network of Pharmacogenetics and Pharmacogenomics (RIBEF), created in 2006, aims to promote collaborative PGx research. RIBEF, which consists of 43 research groups and more than 200 researchers, aims to promote scientiﬁc studies among its members as well as the clinical implementation of PGx to support the healthcare needs of neglected populations. RIBEF teaching programs and human resources training activities include over 400 events all over Latin America. Moreover, the RIBEF network develops research projects that include Iberoamerican population PGx studies. The Consorcio Europeo e Iberoamericano de Farmacogenética de Poblaciones Consortium (CEIBA) was established among the RIBEF members for this purpose. The MESTIFAR project aimed to determine the variability of polymorphisms in genes involved in the response to drugs in populations of different ethnic origin (Native Americans [Amerindian] and Mestizos [the result of post-Columbian admixture]). In addition to population PGx, RIBEF has projects that relate to clinical PGx in Neurology, Psychiatry, Cardiovascular, and/or Infectious Diseases, resulting in a total of 31 scientiﬁc articles being published so far. In Africa, a disproportionate burden of disease is observed (HIV/AIDS, tuberculosis, and malaria) against a backdrop of an increasing burden of noncommunicable diseases (Niemz et al., 2011). Genomic data have supported the notion that several genetic variants can provide an increased resistance or susceptibility to HIV infections (Sirugo et al., 2008). Notably, a huge variability has been evident regarding the pattern of genetic variations in the CYP genes among African populations. The latter was translated into differential drug responses (Dandara et al., 2014). In the Middle East, particularly the United Arab Emirates (UAE), PGx research was initially conducted on erythrocyte glucose-6-phosphate dehydrogenase deﬁciency (G-6-PD) and its association to drug-induced hemolytic anemia (Bayoumi et al., 1996) and later arylamine Nacetyltransferase (NAT2) (Woolhouse et al., 1997). CYP2D6 allele frequencies were also investigated in the Emirati population, reporting four novel CYP2D6 variants (Qumsieh et al., 2011), while a warfarin PGx study is under way for the Emirati population (Fortina et al., 2014; AlJaibeji et al. unpublished). These studies sparked an interest from Dubai Hospital toward the integration of PGx information for chemotherapeutic agents, while the UAE Health Authority policy of reporting adverse drug reactions in the UAE requires expert pharmacogenomic recommendations within the ﬁrst 24 h related to each adverse drug reaction reported (Abu Dhabi). PGx awareness is gaining
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FIGURE 26.1 DruGeVar database. (A) Overview of data entries (colored boxes) on the basis of Microsoft’s PivotViewer and Silverlight technologies. The querying interface, by which the user can further exploit the database content, is shown on the left. (B) Display items that correspond to a variant of interest in relation to drug toxicity (red sign at the bottom left of the item Dark Gray in print versions) or efﬁcacy (green sign at the bottom left of the item Light Gray in print versions).
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FIGURE 26.2 “Pharmacogenomics (PGx)” wallet card that assists in clinical decision making. The card shares information regarding the pharmacogenetics test ordered (HLA-B genotyping) and its outcome (HLA-B*58:01/15:02). Pharmacogenetics data interpretation informs the clinician about the associated risk of allopurinol, carbamazepine, and oxcarbazepine treatment. Such a pharmacogenomic card has been successfully implemented in clinical practice in Thailand at the Laboratory for PGx, Somdech Phra Debaratana Medical Center, Ramathibodi Hospital.
ground in Middle Eastern countries, such as Saudi Arabia (Abu-Elmagd et al., 2015), Oman (Pathare et al., 2012), Lebanon (Ossaily and Zgheib, 2014), and Qatar (Elewa et al., 2015).
26.1.3 Mapping of Stakeholders in Genomic Medicine The genomic medicine puzzle is comprised of several key players and stakeholders, and notably, their genomics awareness and views vary signiﬁcantly. A systematic mapping of those views and different awareness levels would positively impact a better understanding of the policy environment as well as the role of the relevant key stakeholders in the ﬁeld. Mitropoulou and coworkers undertook such an initiative and assessed the level of support or opposition to PGx and genomic medicine in Greece
(Mitropoulou et al., 2014). Similarly, an analysis is currently underway in Middle Eastern countries to determine the stakeholders and their views. The smooth incorporation of genomic medicine into clinical practice is hindered by insufﬁcient genomics education and a lack of genomics awareness among healthcare professionals and the general public (Reydon et al., 2012). The low genomic literacy of the broader public (and patients) is especially challenging for public health genomics as well as health literacy (Syurina et al., 2011). On top of this, genomics education is not uniformly provided in the various academic institutions worldwide (Pisanu et al., 2014; Mai et al., 2014). Such studies might provide a basis for harmonizing PGx education in southeast European countries with those of northwest European countries to create a smoother and more timely integration of PGx into mainstream medical practice. In Latin America there are
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very few postgraduate programs focusing on genomics (Palacios and Collado-Vides, 2007). In Africa, the high cost of genomic services and low private investment are compounded by a relatively low level of medical professionals with an understanding of genomics (Wonkam et al., 2006). An attempt in sub-Saharan Africa to triangulate the views of multiple stakeholders related to prenatal diagnosis of sickle cell disease showed several discrepancies that signal potential value-based conﬂicts and can usefully inform future policy actions (Wonkam and Hurst, 2014). In fact, African-based scientists are participating in studies focusing on the genomics of monogenic diseases (Mercier et al., 2013; Mtatiro et al., 2014; Wonkam et al., 2014; Wonkam, 2015) and multifactorial conditions (Tekola Ayele et al., 2012). These data are concretely assisting the effective practice of genomic medicine that is well established in South Africa (Beighton et al., 2012), in some Northern African countries (Chaabouni-Bouhamed, 2008; El-Beshlawy et al., 2012), and recently initiated in Central Africa (Wonkam et al., 2011). Regional initiatives, such as the Southern Africa Human Genome Project (Pepper, 2011), have been boosted by international funding agencies and academic institutions through major programs, such as the Malaria Genomic Epidemiology Network (http://www. malariagen.net), the Human Heredity and Health in Africa program (H3Africa Consortium et al., 2014), and the African Genome Variation Project (Gurdasani et al., 2015). Latin America populations are characterized by high and heterogeneous levels of admixture that arises from their history and corresponds to different patterns of mating between Native American, European, and African individuals (Ruiz-Linares et al., 2014). The National Institute of Genomic Medicine was built in Mexico with public funds (Jimenez-Sanchez et al., 2008), having several publications in the ﬁelds of population genomics and medical genomics (Silva-Zolezzi et al., 2009; Moreno-Estrada et al., 2014). Brazil and Colombia have also successfully implemented genomic approaches for the study of several human diseases with a high epidemiological impact in those resource-limited countries (Passos-Bueno et al., 2014; Ortega-Recalde et al., 2014; Pinto et al., 2015; Benitez et al., 2010), while the availability of commercial tests by service providers abroad has been considered to be fundamental toward the implementation of genomic medicine.
26.1.4 Advent of Next-Generation Sequencing in Genomic Medicine The advent of NGS technology has marked the beginning of a new era in the analysis of human genome sequences (Hodges et al., 2007; Albert et al., 2007; Shendure and Ji, 2008; Gnirke et al., 2009; see also Chapter 9). Before NGS, Sanger sequencing was widely used for screening, even
though analyses involving numerous genes or large genomic regions were particularly challenging, e.g., a read length encompassing up to 700 base-pairs (bp) per reaction. The NGS approach allows for the simultaneous analysis of millions of bp in only hours, facilitating large-scale explorations of the human genome (McCarthy et al., 2013). Successful screening attempts focus on researching novel recessive disease-related sequence variants, particularly those caused by homozygous mutations as well as monogenic dominant Mendelian disorder. NGS has not been widely used for some complex pathologies in which several variants might contribute toward the phenotype, because data analysis highlights a remarkable complexity, especially for simultaneous interactive network exploration. Three main approaches are employed, which depend on the length of the genome region being analyzed: wholegenome sequencing (WGS), whole-exome sequencing (WES), and custom target sequencing microarrays (TSMs) (McCarthy et al., 2013). WGS is mainly used for research, whereas WES and TSM are used for both research and diagnostic purposes. Although most academic and private technological platforms for the previously mentioned are located in high-income countries, resource-limited countries have performed interesting studies by using NGS outsourcing services (Pinto et al., 2015; Benitez et al., 2010; Diggle et al., 2012). Innovative diagnostic approaches have also been proposed for pathologies with overlapping phenotypes caused by several genes (Pinto et al., 2015; Benitez et al., 2010). Knowledge of the genomes of mammalian species has enabled large-scale comparative genomic approaches, resulting in dissecting loci related to evolution mechanisms, which may contribute to human diseases (Prada and Laissue, 2014). Complex pathologies, such as female infertility, have also been explored via NGS (Fonseca et al., 2015).
26.1.5 Is Genomics-Guided Therapy CostEffective? Genome-based drug treatment is expected to reduce national healthcare expenditures. In resource-limited countries in particular, which in many cases have vast ﬁscal deﬁcits, the economic evaluation of PGx is fundamental (Snyder et al., 2014). Although the ﬁeld of economic evaluation in genomic medicine, PGx, and public health genomics is currently in its infancy, several studies indicate that genotype-guided therapy can be cost-effective and of a high cost beneﬁt. Focusing on resource-limited countries, initial economic evaluation studies in the Thai population indicated that HLA-B*1502-guided carbamazepine treatment is costeffective compared to conventional treatment and can reduce carbamazepine-induced severe adverse drug
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FIGURE 26.3 Encouraging collaboration between developed and developing/resource-limited countries in the ﬁeld of Genomic Medicine. Developing countries are expected to beneﬁt from training opportunities, knowledge transfer, and/or expanding research networks. Developed countries may also beneﬁt through comparative work as well as multicenter projects on rare diseases or unique clinical features from well-deﬁned populations.
reactions (Rattanavipapong et al., 2013; Grosse, 2008). Similar ﬁndings were reported for the Singaporean population, when the cost-effectiveness of HLA-B*1502 genotyping in adult patients with newly diagnosed epilepsy was assessed (Dong et al., 2012). Another study to evaluate cost-effectiveness of warfarin treatment in Croatian elderly ischemic stroke patients with atrial ﬁbrillation indicated that PGx-guided warfarin treatment represented a cost-effective therapy option for the management of those patients (Mitropoulou et al., 2015).
26.2 CONCLUSIONS AND FUTURE PERSPECTIVES When resource-limited environments are considered, genomic medicine can only be implemented via a stronger collaboration in genomics research between developed and developing/resource-limited countries, which is likely to create beneﬁts for all parties. Developing countries will beneﬁt from training opportunities, knowledge transfer, and/or expanding transnational networks, and developed countries may beneﬁt through comparative work and multicenter projects on families with rare diseases and/or unique clinical features Fig. 26.3 (Cooper et al., 2014). Developing countries may suffer from limited resources, but they are also potential-rich in producing data (in the context of genomic medicine-related disciplines, from the perspective of public health genomics). We feel that the success stories presented in this chapter set the paradigm for replication in other countries to acquire more and better insights toward the implementation of genomic medicine and harmonizing the strategies and policies if a fast and smooth adoption of genomic medicine practices occurs in the various national healthcare systems.
ACKNOWLEDGMENTS This chapter was encouraged by the Genomic Medicine Alliance Public Health Genomics Working Group.
FINANCIAL AND COMPETING INTERESTS KM is a scientiﬁc advisor of the Golden Helix Foundation and GPP is a member of the Scientiﬁc Advisory Committee of the Genomic Medicine Alliance. DAF is supported by research grants from Colciencias and VCTI-UAN. The authors declare that they have no competing interests.
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