“10 001 Dalmatians:” Croatia Launches Its National Biobank

 EDITORIAL doi: 10.3325/cmj.2009.50.4 “10 001 Dalmatians:” Croatia Launches Its National Biobank In 2006, the Croatian Ministry of Science, Education, and Sports has completed the review process of more than 3000 research proposals for the new 5-year funding cycle (2007-2011). The grant submission process was similar to the procedure used by the European Commission (Framework Programmes, FP). The new grant program encouraged the formation of national-level consortia, which linked several research projects from diferent institutions into greater and more eicient programs, and favored the projects with international collaboration. It also ensured greater attention to ethical aspects of the submitted proposals (1). Aside from some persisting problems such as excessive length of the review process, which took 10 months, and high overall success rate, which was over 70% after the irst call, the new process nevertheless represented a substantial improvement over previous practices in terms of transparency, supporting web-based technology, and the attention it paid to ethical aspects of the proposed research. The most interesting outcome of this process were a few rare and genuine attempts to synchronize and coordinate several institutions within the country into larger “research programs.” Such clusters of research groups aim to become competitive at the European level and join the successful consortia within the new FP7. There is hope that they could serve as examples that could increase the international impact of the Croatian scientiic production, which was heavily afected during and after the war years (1991-1995). One of the best examples is “The Croatian National Biobank,” a consortium now linking more than 20 research projects, either awarded or presently under review, from all four Medical Schools in Croatia, several teaching hospitals, and public health institutes. It is coordinated from the recently founded Croatian Centre for Global Health, based at the University of Split School of Medicine (2). In its infancy, the national Biobank will rely on 3 large resources that should ensure and maintain its international competitiveness: 1) “10 001 Dalmatians” study of Croatian island isolates; 2) a hospital-based DNA bank with thousands of cases with most common complex diseases; and 3) a large cohort from general population to serve as a control sample. www.cmj.hr Igor Rudan [email protected] Ana Marušić Stipan Janković Krešimir Rotim Mladen Boban Gordan Lauc Ivica Grković Zoran Đogaš Tatijana Zemunik Zoran Vatavuk Goran Benčić Diana Rudan Rosanda Mulić Vjekoslav Krželj Janoš Terzić Dražen Stojanović Dinko Puntarić Ervina Bilić Darko Ropac Ariana Vorko-Jović Ariana Znaor Ranko Stevanović Zrinka Biloglav Ozren Polašek The irst resource is an internationally already recognized study of genetic and environmental determinants of health and disease in genetic-isolate island populations from Dalmatia, Croatia. This efort, aiming to recruit 10 001 examinees, has developed during the recent years, in collaboration mainly with the scientists from Scotland, but also from Sweden, The Netherlands, Italy, and Germany. In the period 2001-2007, it already received substantial competitive funding from The Croatian Government, European FP6, UK Medical Research Council, UK Royal Society, The Wellcome Trust, US National Institutes of Health, and The British Council. This “lagship” of the post-war Croatian science has had 3 publications in one of the leading journals in the ield of genetics, Nature Genetics (3-5) and several more articles in other high-impact genetics journals (6-13). The project has also contributed to the characterization of the two indigenous Mendelian genetic disorders (14,15). In 2006, the Croatian Medical Journal devoted a theme issue, with 17 articles, to the results arising from this research program (16,17). The second resource, planned as a large and important building block of the Croatian National Biobank, is a net-  Rudan et al: “10 001 Dalmatians:” Croatia Launches Its National Biobank work of hospital-based registries of patients with speciic diseases. The project, which received ethical approval of the ethics committee of the Sisters of Mercy University Hospital in Zagreb, aims to create a large DNA bank of up to 20 000 cases of complex chronic diseases by 2011. To achieve this, participating hospitals and public health institutes will form several national registries of diseases of unknown etiology and without preventable risk factors, such as amyotrophic lateral sclerosis, multiple sclerosis, diabetes type 1, speciic early-onset cancers, and a spectrum of childhood illnesses. In addition, cases of the most common complex diseases, which form the greatest share of the overall disease burden in the Croatian population, will be collected: myocardial infarction; cerebral stroke; breast, lung, and colorectal cancer; type 2 diabetes; depression; schizophrenia; renal stones and gallstones; gout; eye diseases; Parkinson and Alzheimer diseases; osteoporosis; rheumatoid arthritis; and others. Figure 1. Finally, a representative sample of several thousands of individuals from general Croatian population will be collected from many of the participating institutions as a control population for the two resources described above. This will be a “targeted sample,” which will correspond closely to the demographic characteristics of the Croatian population. It will also be DNA-based. In this sample, information on the lifestyle, habits, exposure to health risks, health attitudes, and medical history will be documented using standard and internationally validated questionnaires. The main aim of the research within the Croatian National Biobank will be to discover and illuminate the nature of the relationships between: 1) genomic sequence and sophisticated circulating metabolites; 2) circulating metabolites and quantitative biological traits of relevance to human health and disease; and 3) quantitative biological traits and human diseases of complex etiology. The Croatian National Biobank will take into consideration 4 general levels of complexity involved in the development of human diseases: 1) genomics level; 2) “metabolomics” level (including proteomics, glycomics, and lipidomics); 3) level of intermediate quantitative traits (eg, blood pressure, forced expiratory capacity, cholesterol levels, etc.); and 4) endpoint that results in a complex disease phenotype. It will probably be easier to demonstrate and explore the associations between “neighboring” levels of complexity, while the associations across the levels will be more likely to be weak and of relatively small efect size. At each of these levels, modiiers such as environmental, cultural, socio-economic, and psychological inluences can also play an important role. Schematic representation of the resources that will contribute to The Croatian Biobank in the future. HPLC – high-performance liquid chromatography. The interactions between those “outside” inluences and biological factors will also be studied. Figure 1 shows the structure of the Croatian National Biobank, presenting all contributing resources. The central resource will be a databank of 10 001 examinees collected at the Croatian Centre for Global Health in Split, Croatia. In these healthy examinees, genome scanning will be performed (using dense genome-wide scans with hundreds of thousands of genomic markers), followed by sequencing. In addition, hundreds of metabolites will be measured in plasma of all individuals, based on high-throughput technologies such as mass-spectrometry and high-performance liquid chromatography. This will involve proteomics, glycomics, and lipidomics measurements (“metabolomics”). Genetic sequence variants and structural genetic variants will then be associated with chang- www.cmj.hr  EDITORIAL es in the levels of individual metabolites and the efects of metabolite changes on complex quantitative traits will also be assessed. Eventually, public health relevance of identiied genetic variants that could be used in genetic testing, metabolites that could potentially represent disease markers, and quantitative traits that could represent signiicant health risks will then be assessed in large collections of diseased individuals and controls from the general population. The diseased individuals will be approached in participating hospitals, while the examinees for the control sample will be recruited through a network of collaborating institutions (such as the National Institute for Public Health and 4 University Medical Schools in all parts of Croatia) (Figure 1). Croat Med J. 2009; 50: 4-6 J Med Genet. 2003;40:925-32. Medline:14684692 doi:10.1136/ jmg.40.12.925 9 Barac L, Pericic M, Klaric IM, Rootsi S, Janicijević B, Kivisild T, et al. Y chromosomal heritage of Croatian population and its island isolates. Eur J Hum Genet. 2003;11:535-42. Medline:12825075 doi:10.1038/sj.ejhg.5200992 10 Vitart V, Biloglav Z, Hayward C, Janicijevic B, Smolej-Narancic N, Barac L, et al. 3000 years of solitude: extreme diferentiation in the island isolates of Dalmatia, Croatia. Eur J Hum Genet. 2006;14:47887. Medline:16493443 doi:10.1038/sj.ejhg.5201589 11 Campbell H, Carothers AD, Rudan I, Hayward C, Biloglav Z, Barac L, et al. Efects of genome-wide heterozygosity on a range of biomedically relevant human quantitative traits. Hum Mol Genet. 2007;16:233-41. Medline:17220173 doi:10.1093/hmg/ddl473 12 Rudan I, Carothers AD, Polasek O, Hayward C, Vitart V, Biloglav Z, et al. Quantifying the increase in average human heterozy- More than 150 Croatian researchers from a variety of scientiic backgrounds and disciplines will also be involved in this project and will continuously seek and expand their international collaborations. This should ensure sustainable growth of the program and its lasting international competitiveness. We hope that the Croatian National Biobank could substantially increase international visibility and productivity of Croatian biomedical research in the 21st century. gosity due to urbanisation. Eur J Hum Genet. 2008;16:1097-102. Medline:18322453 doi:10.1038/ejhg.2008.48 13 McQuillan R, Leutenegger AL, Abdel-Rahman R, Franklin CS, Pericic M, Barac-Lauc L, et al. Runs of homozygosity in European populations. Am J Hum Genet. 2008;83:359-72. Medline:18760389 doi:10.1016/j.ajhg.2008.08.007 14 Zgaga L, Hayward C, Vatavuk Z, Bencic G, Zemunik T, Valkovic A, et al. High prevalence of glaucoma in Veli Brgud, Croatia, is caused by a dominantly inherited T377M mutation in the MYOC gene. Br J Ophthalmol. 2008;92:1567-8. Medline:18952665 doi:10.1136/ bjo.2008.143552 15 Bakija-Konsuo A, Basta-Juzbasic A, Rudan I, Situm M, Nardelli- References Kovacic M, Levanat S, et al. Mal de Meleda: genetic haplotype 1 Projects of the Ministry of Science. Education, and Sports (in analysis and clinicopathological indings in cases originating from Croatian). Available from: http://zprojekti.mzos.hr/Home_hr.htm. the island of Mljet (Meleda), Croatia. Dermatology. 2002;205:32-9. Accessed: January 19, 2009. 2 Croatian Centre for Global Health Available from. http://www2. 3 Rudan I, Campbell H, Carothers AD, Hastie ND, Wright AF. Contribu- mefst.hr/default.asp?ID=331. Accessed: January 19, 2009. 4 Ropac D, et al. Efects of inbreeding, endogamy, genetic admixture, Nat Genet. 2006;38:1224-5. Medline:17072294 doi:10.1038/ and outbreeding on human health: a (1001 Dalmatians) study. ng1106-1224 Croat Med J. 2006;47:601-10. Medline:16909458 Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, et al. rum urate concentration, urate excretion and gout. Nat Genet. 2008;40:437-42. Medline:18327257 doi:10.1038/ng.106 Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, et al. Loci inluencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 2009;41:47-55. Medline:19060911 doi:10.1038/ng.269 6 Wright A, Charlesworth B, Rudan I, Carothers A, Campbell H. A polygenic basis for late-onset disease. Trends Genet. 2003;19:97106. Medline:12547519 doi:10.1016/S0168-9525(02)00033-1 7 Rudan I, Smolej-Narancic N, Campbell H, Carothers A, Wright A, Janicijevic B, et al. Inbreeding and the genetic complexity of human hypertension. Genetics. 2003;163:1011-21. Medline:12663539 8 ture. Croat Med J. 2006;47:526-31. Medline:16909449 17 Rudan I, Biloglav Z, Vorko-Jovic A, Kujundzic-Tiljak M, Stevanovic R, tion of consanguinuity to polygenic and multifactorial diseases. SLC2A9 is a newly identiied urate transporter inluencing se- 5 Medline:12145432 doi:10.1159/000063151 16 Rudan I. Health efects of human population isolation and admix- Rudan I, Rudan D, Campbell H, Carothers A, Wright A, SmolejNarancic N, et al. Inbreeding and risk of late onset complex disease. www.cmj.hr