Micronutrient Genomics Workshop
Human Variome Project Planning Meeting @ UNESCO
Paris, France
Jim Kaput1, John Hesketh2, Sue Fairweather-Tait3, Ahmed El-Sohemy4, Lucia Ribeiro5, James
Camakaris6, Georg Lietz7, Barbara Burlingame8, Baitang Ning1, and Chris Evelo9.
1
2
3
4
5
6
7
8
9
Division of Personalized Nutrition and Medicine. FDA/National Center for Toxicological Research.
Jefferson AR. USA. James.kaput@fda.hhs.gov
Institute for Cell & Molecular Biosciences and Human Nutrition Research Centre, University of
Newcastle. Newcastle upon Tyne, United Kingdom. j.e.hesketh@ncl.ac.uk
School of Medicine, University of East Anglia. Norwich, United Kingdom
s.fairweather-tait@uea.ac.uk
Department of Nutritional Sciences, University of Toronto. Toronto, ON, Canada
a.el.sohemy@utoronto.ca
State University of São Paulo, UNESP. Botucatu, São Paulo, Brazil. lribeiro@fmb.unesp.br
Department of Genetics, University of Melbourne. Victoria, Australia j.camakaris@unimelb.edu.au
School of Agriculture, Food and Rural Development, Human Nutrition Research Centre, University
of Newcastle. Newcastle upon Tyne, United Kingdom. georg.lietz@ncl.ac.uk
Nutrition Planning, Assessment and Evaluation Service, Food and Agriculture Organization of the
United Nations. Rome, Italy. Barbara.Burlingame@fao.org
Department of Bioinformatics – BiGCaT, Maastricht University. Maastricht, The Netherlands
chris.evelo@bigcat.unimaas.nl
Vitamins and minerals, collectively called micronutrients, are essential cofactors of physiological
processes in biological organisms. Micronutrient deficiencies cause specific illnesses in humans, and
sub-optimal intakes may predispose to a number of chronic diseases. High micronutrient doses that may
be consumed in supplements may also be detrimental to health (e.g., (Hoey, et al., 2009)). The biological
effect of these dietary chemicals depends on chemical, physical, and physiological processes, including
absorption, distribution, metabolism (biotransformation), excretion (collectively known as ADME), and
nutrient and physiological status of the host (van Ommen, et al., 2008). These complex physiological
processes are carried out by products of genes which can differ significantly between individuals. In
addition, nutrients and other environmental factors alter the expression of genetic information directly,
through signalling pathways, and through epigenetic changes (Kaput and Rodriguez, 2004; Zhang and
Meaney, 2010).
The dietary recommended intakes (DRI) of micronutrients are based on best available science and
usually are calculated to meet the needs of ~97.5% of the population (Suitor and Meyers, 2006). Since a
DRI is based on the average response of a population, individuals within that population may consume
too much or too little because of genetic or environmental differences. Genetic association studies and
molecular genetic analyses are beginning to link genetic loci and gene expression patterns with intakes of
different amounts of nutrients. However, many of these studies rely on small populations of one ancestral
background, do not assess the broad physiological processes involved in nutrient–related health, and
usually do not measure environmental variables which may influence metabolism. A key limitation of
many of these studies is that they only examine the most commonly known single nucleotide
polymorphisms (SNPs) and do not account for rare polymorphisms in the candidate genes. The limited
scope of the research, the continued use of ‘pre-genomic’ strategies, and the reliance on incomplete
knowledge of genetic variation, results in data that can not be readily applied to personal and public
health. The seemingly intractable challenge of determining optimal nutrient intakes necessarily depends
on the characterization of genetic variation in nutrient metabolism genes and other genes influenced by
them.
Micronutrient Genomics Project Workshop Report
The Nutrigenomics Organization and Human Variome Project organized a Micronutrient Genomics
Project (MGP) Workshop, the fourth in a series of meetings to establish and organize the creation of an
international micronutrient genomics knowledge base and research effort. Previous workshops were held
at NuGOweek in Potsdam, Germany (September 2008), Vancouver Canada (February 2009), and
NuGOweek in Montecatini, Italy (September 2009). The 5th workshop will be held in Guaraja, Sao Paulo,
Brazil, in conjunction with the International Conference on Nutrigenomics in September 2010. A Variome
Project Workshop will also be held at that meeting.
The MGP is planning a bioinformatics resource available through an online portal that will be a knowledge
base of existing tools and databases, but will also allow for new research results to be stored, managed,
and retrieved for analyses under appropriate consents and permissions. The three components of the
MGP knowledge base are (i) a genetic variation module for all micronutrient-relevant variations, (ii) a
micronutrient pathway module that links pathways and gene – nutrient interactions at the level of RNA,
protein, and metabolites which has been established in WikiPathways
(http://micronutrients.wikipathways.org), and (iii) a database of omics data, phenotype, and study design.
Working groups consisting of researchers and experts have been or are being established for each
micronutrient. These groups will (i) collect all available knowledge via systematic reviews which also will
identify knowledge gaps, (ii) collaborate with bioinformatics teams towards collecting and structuring the
relevant gene and polymorphism information and constructing the pathways and biological networks, and
(iii) publish their findings on a regular basis.
The MGP is using selenium as an exemplar of its project since the ~25 genes are well defined, a network
map has been produced in WikiPathways (http://www.wikipathways.org/index.php/Pathway:WP15), some
functional SNPs have been identified (although more are likely to be discovered), and some microarray
data which describe changes in gene expression following altered selenium intake are available. Projects
in individual laboratories, for example with vitamin A and copper, illustrate the complexities of linking
nutrient intake to genes and their variants. Variations in absorption, bioavailability, and bioefficiency are
all affected by genetic variation, environmental differences in food availability and preparation, and
lifestyle choices such as alcohol intake, smoking, or exercise. In addition, defects in enzymes which
interact with these and other micronutrients produce genetic diseases, some of which can be ameliorated
by altering nutrient intakes. Genome wide association studies are underway to analyze loci associated
with blood levels of various micronutrients in an urban population.
Next generation sequencing may dramatically alter the ability to identify and characterize undiscovered
genetic variation. While whole genome sequencing is still too expensive for large populations or with
funding for basic science in most economies, capturing and sequencing the exomes of micronutrient
genes may be an intermediate goal for comparing genotypes throughout the world. Data mining surveys
indicate that ~450 genes are involved in metabolizing or interacting with ascorbic acid, biotin, folate,
niacin, patnothenic acid, riboflavin, thiamine, and vitamins A, B6, B12, D, E and K. The MGP is
considering developing the information content for micronutrient gene whole exome capture reagents.
Providing well designed reagents will enable more researchers to contribute to the MGP and Human
Variome Projects.
The MGP partners will be collaborating with an existing European Union funded project called the
European micronutrient recommendations aligned (EURRECA - http://www.eurreca.org), a network of
excellence consisting of ~35 partners from 17 European countries to produce a transparent, systematic,
and sustainable framework for setting dietary recommendations in Europe. EURRECA parallels and
overlaps with several key initiatives within the MGP, particularly with integrating activities to assess the
influences of individuality, variability, and vulnerability. The United Nations Food and Agriculture
Organization (FAO) Nutrient Assessment and Requirements group interacts with EURRECCA and the
NuGO team and will be kept informed on progress of the MGP. The FAO is interested in and supports
initiatives to include populations in emerging economies and has expertise in addressing the challenges
for developing micronutrient requirements for international populations. MGP seeks to produce the data,
results, knowledge, tools and databases to aid researchers and policy experts to translate basic science
to applications to improve personal and public health.
Micronutrient Genomics Project Workshop Report
Note: The views presented here are those of the authors and do not necessarily reflect official positions of
the FDA or FAO.
References
Hoey L, McNulty H, Strain JJ. 2009. Studies of biomarker responses to intervention with riboflavin: a
systematic review. Am J Clin Nutr 89(6):1960S-1980S.
Kaput J, Rodriguez RL. 2004. Nutritional genomics: the next frontier in the postgenomic era. Physiol
Genomics 16(2):166-77.
Suitor C, Meyers L. 2006. Dietary Reference Intakes Research Synthesis: Workshop Summary. National
Academies Press online.
van Ommen B, Fairweather-Tait S, Freidig A, Kardinaal A, Scalbert A, Wopereis S. 2008. A network
biology model of micronutrient related health. Br J Nutr 99 Suppl 3:S72-80.
Zhang TY, Meaney MJ. 2010. Epigenetics and the environmental regulation of the genome and its
function. Annu Rev Psychol 61:439-66, C1-3.
Micronutrient Genomics Project Workshop Report
Micronutrient Genomics Project
Co-ordinating committee
John Hesketh (chair)
Institute for Cell & Molecular Biosciences and Human Nutrition Research
Centre, University of Newcastle. Newcastle upon Tyne, United Kingdom.
j.e.hesketh@ncl.ac.uk
Jim Kaput
Division of Personalized Nutrition and Medicine. FDA/National Center for
Toxicological Research. Jefferson AR. USA.
Harry McArdle
Rowett Institute of Nutrition and Health, University of Aberdeen Aberdeen
AB21 9SB
Michael Fenech
CSIRO Food and Nutritional Sciences, PO Box 10041 Adelaide BC, SA
5000, Australia
Ahmed El-Sohemy
Department of Nutritional Sciences, University of Toronto. Toronto, ON,
Canada
Chris Evelo
Department of Bioinformatics – BiGCaT, Maastricht University. Maastricht,
The Netherlands
Linda Penn (administrator)
Institute for Cell & Molecular Biosciences and Human Nutrition Research
Centre, University of Newcastle. Newcastle upon Tyne, United Kingdom.
l.d.penn@ncl.ac.uk )
Liaison team & Technical teams
Ben van Ommen
TNO Quality of Life, P.O. box 360, 3700 AJ Zeist, The Netherlands,
Jim Kaput
See above
Chris Evelo
See above
A) Micronutrient genetic variation portal
Jim Kaput
See above
Henk van Kranen
RIVM, Postbus 1, 3720 BA Bilthoven The Netherlands
Laurence Parnell
USDA, Agricultural Research Service, Jean Mayer USDA HNRCA at Tufts
University. 711 Washington Street. Boston, MA 02111-1524
Chris Evelo
See above
Richard Cotton
Genomic Disorders Research Centre. Howeard Florey Research Institute.
Melbourne, Australia
Mazda Jenab
Lifestyle, Environment and Cancer Group, International Agency for
Research on Cancer, Lyon, France.
B) Micronutrient pathway visualisation portal
Chris Evelo
See above
Micronutrient Genomics Project Workshop Report
Suzan Woperis
TNO Quality of Life, P.O. box 360, 3700 AJ Zeist, The Netherlands
Duccio Cavalieri
Jildau Bowman
TNO Quality of Life, P.O. box 360, 3700 AJ Zeist, The Netherlands
Damariz Rivero
Department of Pharmacology – University of Florence Viale Pieraccini 6
50139, Florence, Italy
Micronutrient
Team leader
Selenium
John Hesketh
See above
Zinc
Giuditta Perozzi
Department of Nutritional Sciences – INRAN,
National Research Institute on Food & Nutrition,
Via Ardeatina 546, 00178 Roma, Italy
Folate & Vitamin B 12
Michael Fenech
See above
Iron & Copper
Harry McArdle
See above
Carotenoids & Vitamin A
Georg Lietz
Human Nutrition Research Centre, School of
Agriculture, Food and Rural Development,
Newcastle University, Kings Road, Agriculture
Building, Newcastle upon Tyne NE1 7RU, UK
Vitamin C
Ahmed El-Sohemy
See above
Vitamin D
Lucia Regina Ribiero
State University of São Paulo, UNESP. Botucatu,
São Paulo, Brazil.
Vitamin E
Regina Brigelius Flohe
Department of Biochemistry of Micronutrients,
German Institute of Human Nutrition, Nuthetal,
Germany
Biotin
Deborah Hansen
Division of Personalized Nutrition and Medicine.
FDA/National Center for Toxicological Research.
Jefferson AR. USA
Choline
Steven Zeisel
Department of Nutrition, School of Public Health
and School of Medicine, University of North
Carolina at Chapel Hill, Chapel Hill, NC
Iodine
Michael Zimmerman