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Nutrigenomics is the science of analyzing and understanding gene–nutrient interactions, which because of the genetic heterogeneity, varying degrees of interaction among gene products, and the environmental diversity is a complex science. Although much knowledge of human diversity has been accumulated, estimates suggest that ~90% of genetic variation has not yet been characterized. Identification of the DNA sequence variants that contribute to nutrition-related disease risk is essential for developing a better understanding of the complex causes of disease in humans, including nutrition-related disease. The Human Variome Project (HVP; http://www.humanvariomeproject.org/) is an international effort to systematically identify genes, their mutations, and their variants associated with phenotypic variability and indications of human disease or phenotype. Since nutrigenomic research uses genetic information in the design and analysis of experiments, the HVP is an essential collaborator for ongoing studies of gene–nutrient interactions. With the advent of next generation sequencing methodologies and the understanding of the undiscovered variation in human genomes, the nutrigenomic community will be generating novel sequence data and results. The guidelines and practices of the HVP can guide and harmonize these efforts.
Nutrigenomics has been called a “post-genome” field of research (e.g., ) because it could only develop in a meaningful way after the completion of the sequencing of the human genome. Ideally, nutrigenomics experiments are to be designed, conducted, and analyzed with specific knowledge of genes involved in nutrient metabolism and physiological processes. Data from the Human Genome project and subsequent haplotype mapping projects [14, 59–61, 70] demonstrated that any two humans will differ by 3–5 million bases. However, ongoing re-sequencing of individual genomes has now identified ~18 million single nucleotide polymorphisms [4, 29, 47]. More recent studies have also shown structural variation in the human genome indicating that approximately 13% of the variation between humans may be due to copy number [1, 31, 41, 50, 68, 71]. The ongoing discovery of new SNPs and structural variants shows that the genomic era is far from ending, particularly since the next generation sequencing technologies  will soon allow for complete analyses of all coding sequences (i.e., the exome) of all individuals in a research study (e.g., ) or even for the complete sequencing of individual genes, including the regulatory regions.
The catalog of genetic variation is being done by the HapMap and 1,000 Genomes [37, 55] projects. While these projects are providing fundamental information about human genetic variation, they are by design limited by (i) the populations analyzed, (ii) the goal of characterizing variants that are greater than 1% in the population, and (iii) they are unlinked to phenotype. The HapMap project [14, 61] analyzed 45 Han Chinese in China, 45 Japanese in Tokyo, 90 Africans in the Yoruba tribe of Nigeria, and 90 Europeans of Northern European origin. The recently released HapMap3 data  extended the analyses to almost 700 individuals but found that 77% of the SNPs analyzed in their study had not been previously characterized. The goal of the 1,000 Genomes project is to analyze ~2,000 individuals from 23 populations (Table 1). Due to these sample sizes, the diversity projects will only be able to detect variants that are greater than ~1% in the populations tested; some rare variants  are found during targeted re-sequencing that occurs in these projects yet variation in the many populations not analyzed will not be found. Rare variants are increasingly suspected of being involved in healthy and disease phenotypes . Finally, the goal of these projects is simply to catalog the variants for future use in research linking genotype to phenotype, although some phenotype data are available to research in the consortium. Both HVP and NuGO (Nutrigenomics Organization) aim to document variation causing phenotypic changes such as disease and good health.
The Human Variome Project (HVP; http://www.humanvariomeproject.org/) is an international effort to systematically identify genes, their mutations, and their variants associated with phenotypic variability and indications of human disease or phenotype [15, 16, 33, 51]. The goal of the HVP is to link clinical, medical, and research laboratories for developing knowledge. This knowledge will be accessible to the research and medical communities to improve research strategies and clinical medical practice. One of the key deliverables of the HVP is the creation of a cyber infrastructure to link locus-specific databases (LSDBs ). These databases have similar architecture, ontologies, and data elements allowing for interoperability and are curated by local experts. Over 700 LSDBs are maintained across the world and accessible at the Human Genome Variation Society website (http://www.hgvs.org/dblist/glsdb.html). Some, but not all, of the information in LSDBs are consolidated in national and international databases such as at the National Center for Biotechnology Information (NCBI—http://www.ncbi.nlm.nih.gov/) and the European Bioinformatics Institute (EBI—http://www.ebi.ac.uk/).
The HVP has 10 key objectives (Fig. 1):
NuGO was established as an association of 23 universities and research institutes focusing on jointly developing the exiting research area of nutrigenomics and nutritional systems biology. NuGO evolved from an EU Sixth Framework Network of Excellence and has now transitioned into a global association encompassing individuals and institutions around the globe.
NuGO has two major objectives:
The HVP established committees to develop action plans to meet the 10 key objectives, which overlap or parallel the goals described in a consensus statement authored by 89 international scientists in the nutrigenomics community , which was co-authored by the members of NuGO. The parallel objectives of the HVP and NuGO are the common grounds upon which the two scientific communities base their interaction, as schematically described in Fig. 1.
The HVP captures and classifies genetic variation from voluntary contributions from unlinked clinical, research, diagnostic, and service laboratories. The nutrigenomic community had not specifically designated the identification and characterization of variation as a goal, even though many researchers interested in nutrient–phenotype associations use that knowledge in their experiments (e.g., [45, 56]). The emerging consensus that rare polymorphisms (i.e., <1% in the population) and copy number variants  may influence health, disease, and nutrient–gene interactions makes it imperative that nutrigenomic researchers adopt and use sequence technologies and methods as a part of their experimental design and procedures.
Deleterious gene–phenotype associations are described as pathogenicity in clinical settings and are described by genetic, clinical phenotype, and pathology. Basic researchers use the term deep phenotyping  when analyzing large numbers of genes, metabolites, proteins, or transcripts, or combinations of omic technologies. These methodologies are being adopted to the clinic for assessments (e.g., [24, 57]) and have led to the application of interdisciplinary, primary care, community-based, and translational research [25, 40, 69] to health and disease studies, blurring the distinction between basic and clinical research .
Data transfer, integration, and access are among the major challenges facing the biomedical researcher in the 21st century. The abstracts for over 19 million are available in PubMed in the U.S. National Library of Medicine’s database of publications. Inclusion of quantitative measures of genetic and environmental variations would likely influence the results of many of these studies. However, only a small fraction of full texts and additional data for these publications is electronically accessible. Moreover, much of these data are discipline specific, making it a challenge to mine public-domain results for linked data or knowledge. The HVP is developing standards with international databases (NCBI and EBI) and projects (e.g., European Union Gen2Phen initiative—http://www.gen2phen.org). The nutrigenomic community faces a greater challenge since few tools or databases are available for nutrition-related research . Two related initiatives are underway to address these limitations. The Nutrigenomics Organization has begun the development of a nutritional phenotype database (dbNP—), a research and collaboration tool, and knowledge base which will allow access to publically available data. A separate yet key component of dbNP is WikiPathways [36, 48], an open, collaborative platform for the curation of biological pathways (http://www.wikipathways.org) based on all data available to the curator.
About 90% of known SNPs are shared between Asians, Europeans, and Africans and the remaining polymorphisms, called private SNPs, are distributed among these populations [26, 30]. The recent sequencing of the genomes of several individuals (e.g., [5, 38, 66, 67]), along with gene-specific re-sequencing efforts suggest that a larger number of SNPs than previously determined, as well as other sequence variation, exist in the human population. Estimates from African genetic diversity and the Pan Asian SNP initiative indicate that 80 to 90% of human genomic variation resides in the world’s emerging countries. The Population Reference Sample (POPRES ) targets populations not previously included in the HapMap project, similar to the 1,000 Genomes initiative. The main focus of the HVP effort is the inclusion and analyses of clinical samples from diverse ethnic groups. One of the advantages of including some ethnic populations is the opportunity to study genetic diseases due to consanguinity, large family size, and potential founder effects (e.g., [10, 11, 52]). Although nutrigenomic researchers do not necessarily include such populations, unique genetic groups may yield valuable insights into understanding the distribution of gene–nutrient interactions in health and disease processes .
Biomedical research has not typically been the focus of resource for poor countries, even though such activities are likely to produce economic and health benefits for all [20, 54]. The recently announced global alliance for chronic disease (GACD—) addresses the increasing consensus that emerging economies face not only malnutrition but also the development of chronic diseases, a double economic and health burden. Education of health care providers, the public, and government officials is needed for demonstrating the universal nature of the HVP’s and NuGO’s research efforts, the need to include populations in developing countries, and the benefits from cooperating in biomedical research ([8, 13, 53, 62].
The NIH National Center for Minority Health and Health Disparities (NCMHD) recently called for a paradigm shift to include minority, low socioeconomic and rural populations, and individuals in biomedical research [21, 22]. From the perspective of the science underlying both the HVP and nutrigenomic research efforts, understanding the full spectrum of genetic or metabolic spectra will not be possible without the involvement of all ancestral groups. Including these populations and individuals may allow for a more rapid translation of basic science to society. Community-based participatory research collaborations may provide forums for addressing cultural and ethical concerns of biomedical research . The genomic sovereignty/equality for all countries to be involved in their research efforts is an accepted norm of the HVP and nutrigenomic research communities. The value of ‘human capital’ within all populations is acknowledged and treasured. Real and tangible benefits of biomedical research to improve health will be generated for participating populations; the voluntary participation of the greatest number of countries would ensure targeted interventions to improve personal and public health.
HVP and nutrigenomic researchers are committed to adhering to the highest ethical principles governing research, data sharing, and ultimately enabling this new knowledge to benefit all of the humanity. Ethical guidelines specifically for LSDBs were previously published , and new guidelines are in process . NuGO has also published bioethical guidelines [6, 7]. The ethics of international health research continue to evolve with a greater emphasis on development and social justice , values which are consistent with the stated goals of the HVP and nutrigenomics researchers [34, 51].
A key ethical concern for the Human Variome Project and eventually for data generated from individuals in nutrigenomics research is the accessibility of research data on public websites. For HVP, rare mutations in a population open the possibility of identifying the research participant. For both fields of research, polygenic analyses (e.g., whole genome scans) have yielded the identification of single participants in research studies. Such polygenic analyses generate data that could be used for re-identifying individual patients  but is less likely in single gene diseases.
The HVP is developing an ethics review committee with a subcommittee focused on issues related to LSDB for (i) providing counsel when dilemmas arise, (ii) overseeing guidelines, (iii) identifying best practices, (iv) determining how best to ensure privacy in all situations, (v) formulating how to handle data for which explicit consent does not exist or is not possible to achieve, and (vi) developing a consent form that is consistent for all LSDBs but which can be adapted to the requirements of individual countries. NuGO has an ethics committee, and several members are also members of the HVP ethics group.
International collaborations of the scope of the HVP and nutrigenomics efforts are rarely funded. Rather, both organizations believe that distributed financing for distributed science is more likely to occur. To make a distributive model feasible, best practices and harmonized protocols are necessary. The HVP is developing the standards for LSDB’s and reporting, and NuGO has a rich tradition of developing standard operating procedures for methodologies (http://www.nugo.org/sops). Several international efforts are currently being designed for type 2 diabetes and micronutrient genomics . Guidelines and policies of the HVP will be adopted for both of these protocols since both require analyses of phenotype based on genetic differences in study participants. The HVP is managed by the Genomic Disorders Research Center (Melbourne, Australia; http://www.genomic.unimelb.edu.au), and NuGO has a coordinating council consisting of European scientists from member Institutions.
Large scale science requires novel approaches for attributing contributions. High throughput technologies generate a large number of raw data whose availability represents a great advantage to all scientists working in the field. These data sets are often unpublished and made available to all through deposition in public databases. This creates the need to define new criteria for the attribution of unpublished data and requires a policy of credits and incentives to be coordinated between database curators and the editors of scientific journals. For the nutrigenomics projects, harmonized, distributive funding allows for the publication of local studies, and the possibility of comprehensive analyses of all data by a team consisting of individuals from multiple disciplines and regions. The HapMap project and other international projects have previously developed procedures for publication credit. The HVP faces additional challenges since clinics and service laboratories describe pathogenicity and genetic variation, but academic incentives to publish are not paramount for these professions. Novel approaches for attribution have been proposed [23, 33, 43] and are starting to be applied by some databases and continue to be developed by the HVP. A public debate is also in progress among the editors of genetics journals to coordinate efforts toward the attribution of data deposition and database linking (http://www.gen2phen.org/wiki/hvp-publication-credit-and-incentives-recommendations).
Members of the HVP and nutrigenomics community have attended conferences and workshops, including the 3rd Asia Pacific Nutrigenomics conference (Melbourne, 2008), the Fifth China Health Annual for the announcement of the HVP node in Beijing (2008), the Symposium of Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders (King Abdulaziz University. Jeddah, Saudi Arabia), the Third HVP planning meeting (Costa Brava, Spain) and at the Fourth HVP meeting (Roadmap: Project structure) at UNESCO (Paris, France). NuGO organized a micronutrient genomics workshop at the UNESCO meeting. Future meetings include co-hosting workshops at the International Conference on Nutrigenomics (ICON) in Guaruja’, Brazil (September 2010). The HVP and NuGO are exploring the best means to formally recognize their ongoing interactions. The HVP has a similar ongoing relationship with the International Society for Gatrointestinal Hereditary Tumors (http://www.insight-group.org).
Organisms are complex systems that are regulated by interactions between multiple environmental factors and multiple genes. Analyzing complex systems requires a multidisciplinary and multi-technological approach (i.e., omics). Since each person or team has a limited level of complexity, the ideal, and indeed, the only, approach to understand biological systems is to distribute the task among many teams (see ). The interaction between the HVP and nutrigenomics researchers leverages the expertise of both groups and fosters a more complete analysis of the human organism. These articles will assist the process of populating the human genome sequence with variations which are biologically and medically relevant and eventually provide the complete “human variome.”
Note: The views in this article do not necessarily represent those of the U.S. FDA.