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Research Program of Molecular Medicine
Mission
Mission: The mission of the Research Program on Molecular Medicine is to capitalize the possibilities provided by the special population and well characterized study sample resources of Finland using updated molecular methods and new biocomputational strategies to collect genetic and molecular information of diseases with complex etiology. We aim to characterize some of the largely unknown relationships between various components of disease phenotypes and genetic make up of individuals. The Program bridges the clinical and basic research, being well-rooted in the excellent clinical expertise and in the health care system of the special population of Finland. The general strategy of the research program:
Goals for 2006-2009
The target diseases or our research program represent common health problems with complex genetic and life style risks: cardiovascular, neuropsychiatric and immunological diseases. After initial characterization of the involved genes and alleles we are in an excellent position to define genetic and environmental/ life style risk factors for specific subtypes of the diseases and their trait components and even address the differences in drug response in patients with different genetic profiles. The approacher to reach these goals are presented in more details below
1) To characterize the genetic background of selected neuropsychiatric, cardiovascular and immunological diseases and their critical trait components and intermediate phenotypes using Finnish study samples. This means identification of involved genes and specific alleles of these genes predisposing to common diseases. We expect that the initial gene identification will mostly take place via genome-wide analyses in families, ascertained for well defined clinical phenotypes facilitating novel clustering of trait components for genetic analyses.
2) To determine the role of different alleles in the genetic risk and assess their population impact in epidemiological study samples from Finland. To maximize the power of our study samples we need to develop novel statistical methods to address the issues like: what is the necessary study type and sample size to detect genetic effects and how to model the diseases and their quantitative trait components in statistical analyses. Most probably intermediate, quantitative phenotypes are more accessible to molecular tools since they more directly reflect the effect of contributing alleles. An example of a candidate gene based approach is our study plan for “periodic diseases” epilepsy, cardiac arrhythmias and migraine.
3) To characterize the relative role of genetic and environmental/life style risk factors for disease outcome especially in cardiovascular diseases, diabetes, asthma and neuropsychiatric disorders. Here we expect to use both families with extensive information on quantitative phenotypes as well as epidemiological study cohorts with excessive amount of life style information. (The description of these cohorts is provided on the website (www.nationalbiobanks.fi).
4) To use the vast resources of genomics of other species (Drosophila/Mouse/Dog) to address the functional relevance of identified disease genes as well as to study their developmental and tissue expression to guide our thinking of the molecular and cellular processes resulting in human diseases.
The groups have already vast expertise in the use of mouse as a model organism to study disease mechanisms of human monogenic diseases. The use of mouse models is also a powerful approach for the genetics dissection of multifactorial traits. Examples of complex trait mouse models include mutants for migraine and psoriasis.
Canine genetics will be introduced as a novel tool to facilitate gene discoveries in human. The dog genome is sequenced and marker maps exist. Compared to mice, dog will have many benefits as a model organisms to study human disease mechanisms, including excellent breeding records, specific behavioural traits and a complex brain structure, which has direct relevance to several neuropsychiatric and neurobehavioural disorders studied within the program.
Fruit fly, Drosophila melanogaster, has proven to be a valuable in vivo model for studying the function, interactions and the involved molecular pathways associated with a defected gene. As a model system, its advantages include a long research history, availability of the genome sequence and gene manipulation techniques, together with its small size and rapid reproduction. Particularly, genome-wide modulator screens provide novel information of molecular pathways, independent of the existing hypotheses.
5) To establish common databases, a systematic collection of information for phenotypes and genotypes in various study samples and to develop new biocomputational tools for more efficient analyses of genetic and life style risk profiles. Certain parts of this database (anonymized data) will be made accessible to other investigator so that we contribute to the global efforts of complex disease genetics. We have experience in database construction of and harmonization of data via our European collaborations, especially GenomEUtwin.
6) To carry out systematic pharmacogenomic studies in cardiovascular, metabolic, neurologic and inflammatory diseases. For example, we have defined a platform for pharmacogenomics of human essential hypertension, using ambulatory blood pressure recordings in patients with moderate hypertension, each undergoing four different monotherapies under double-blind conditions. Similarly, the implication of GPRA (GPR154) as an asthma susceptibility gene is highly interesting for pharmaceutical applications. Our research aims to understand whether agonists or antagonists would be beneficial.
7) To analyze genotype-phenotype correlations facilitated by panels of subphenotypes. We will use the combination of information obtained from cellular electrophysiological studies in mammalian cells and amphibian oocytes and modern in vivo clinical electrophysiological methods including 24-h ECG recordings, body surface mapping and magnetocardiography.
8) To design panels based on subphenotypes together with genetic and environmental risk factors to predict common diseases, treatment success or disease complications. These panels can be used to recluster the trait components of common diseases for genetic analyses and in future will help to assign study subjects to different preventive or treatment options in a clinical study setting. The planned studies include prevention of type 2 diabetes and/or metabolic syndrome in the PPP-Botnia Study: effect of dietary modification and exercise in subjects stratified for risk alleles in PPARg, calpain 10, adiponectin and glucogen synthase genes. Also, we are currently performing a genome-wide SNP-scan in 1550 cases and 1500 controls to analyse the relationship of common variation and complications of diabetes.
Core facilities
The molecular and biocomputational analyses needed in these efforts are greatly advanced by the expert infrastructure of the Biomedicum Helsinki (www-site) core facilities and the Finnish Genome Center (www-site). The program has a major role in the continuing development of Genome Informatics Unit (GIU) of Biomedicum, (www-site).