**3. The origin of genetic predisposition or "genomics: A base of preclinical medicine"**

Our knowledge of pathological processes occurring in the human organism has progressed considerably in the past decades, but the mechanisms of many human diseases are still poorly understood. Recent developments in genomics made it possible to discover a wide variety of novel genes and genetic variations including clinically important ones. i.e., those triggering pathological processes in various body tissues and cells. Every year, the clinical diagnostic instrumentarium is supplemented with efficient analytical techniques for detecting single-nucleotide polymorphisms (SNP's) which determine the susceptibility of

Preclinical and Predictive Algorithms in Monitoring

**3.2 MHC: Genes of instability** 

occurrence during the patient's lifetime.

for treatment of rarely occurring and common diseases.

Patients with Autoimmune Diseases and Their Relatives-at-Risks 197

the development of state-of-art diagnostic, prognostic, preventive and therapeutic strategies

The use of high-throughput technologies in human genome studies was a step forward towards getting a deeper insight into pathogenetic mechanisms of many human diseases including insulin-dependent type 1 diabetes mellitus (T1D). Recent developments in the field of genetic factors and their pathogenetic roles suggest their high utility in the design of novel predictive strategies, stratification of patients according to disease risk and a search for new therapeutic targets. Among the immense variety of T1D strategies, two approaches are used methods of choice, viz.: (I) linkage studies of pairs of affected relatives (typically, siblings) aimed at a search for rarely occurring risk factors having large effective sizes; (II)

As can be seen, identical genes can simultaneously trigger a variety of body-related autoimmune disorders. The latter form a disease-based cluster, which further develops into

Fig. 2. The role of MHC genes in the development of diseases the key pathogenetic role in which is played by genetic predisposition. Some genes (DR7, DR8) determine the risk for only one disease (DR7, DR8), while others are responsible for two (DR1, DR10), three or even more (DR4) diseases. However, their presence is not prerequisite to the development of pathological processes, but, rather, significantly increases the likelihood of their early

MHC represents a large family of genes encoding molecules of three major HLA classes, viz., HLA class I, HLA class II and HLA class III. MHC plays an essential role in the functional activity of the immune system being directly involved in presentation of peptide antigens to APCs and formation of the so-called MHC restriction phenomenon. To-date, MHC is the most thoroughly investigated gene family in the human genome by virtue of its extremely close linkage to autoimmune diseases, hypersensitivity to infections and hyperbolic immune responsiveness. These genes are usually present in patients with severe autoimmune disorders and/or imbalances, e.g., rheumatoid arthritis (RA), multiple sclerosis

**3.1 IDDM1 as an example of crucial role of genomics in clinical researches** 

association studies into more common risk factors having small effective sizes.

a polyglandular autoimmune syndrome. (Fernando MM et al., 2008)

the organism to diseases, drugs and/or environmental factors. A deeper insight into gene structure and regulatory mechanisms can significantly facilitate diagnosis and treatment of individuals at risk and, in a more distant future, provide the physician with potent tools for diagnosing diseases, preventing their progression and implementing effective therapy as early as the preclinical stage.

Rapid progress in science and technology created necessary prerequisites for highthroughput screening of several hundreds of thousands of SNP variants and enabled adequate involvement of all human DNA blocks in selection of the disease associated variant provided the latter is present in the genome. From theoretical standpoint, linking of genotyping data to epidemiological findings provides a way to identification and/or characterization of gene sequences and gene interactions with the environment determining the susceptibility of various body cells and tissues to normal genetic variations and/or the underlying disease.

Genomewide association studies represent an effective tool for detecting genetic associations between specific genetic variations and complex pathological conditions in large cohorts of the general population and provides a deeper insight into mechanisms underlying genetic predisposition to various diseases.

The contribution of SNP's to the pathogenesis of many common diseases is relatively small and does not exceed 5–10%, which significantly restricts their application as markers for predicting disease risks. However, today well-established associations number in hundreds and their panel grows with every passing week. Taking into account considerable investments in the search for hitherto unidentified sources of inherited risks, it may be expected that existing (both genomic and nongenomic) models for estimating potential risks will soon be improved and rationalized.

The current need for highly multiplexed tests increases with every passing day. Innovative gene chip- and sequencing-based technologies displace rapidly traditional methods for establishing variations and mutations in the human genome. In future, the advent of improved nanotechnological sequencing protocols may further increase the accuracy and reduce the cost of genetic analysis. The idea of complete sequencing of the human genome at the cost of \$1000 is becoming more and more realistic. The project, which got the name "\$1000 genome", is expected to improve existing protocols through direct sequencing of individual DNA molecules. This approach is potentially oriented at elimination of the amplification step, further reduction of chemical reagents expenditure and construction of a high-precision database of genetic sequences in the foreseeable future.

The feasibility of reliable and low-cost estimation of human genetic variations put forward the idea of personalized medicine as an indispensable element of modern-day public health care. The key principle of personalized medicine is in that the health status of any human individual is most effectively controlled through implementation of individual preventive and curative treatment schedules. Although unsolvable controversies between principles of personalized medicine and populational (probative) medicine really exist, they are not inconsistent. Novel decisions are being taken in the private and public sectors, and those would enable progressive studies to provide the linkage between personalized and probative medicine.

All-round cognition of gene structure and genetic regulatory mechanisms is extremely important not only from theoretical, but also from practical point of view, particularly, for the development of state-of-art diagnostic, prognostic, preventive and therapeutic strategies for treatment of rarely occurring and common diseases.

#### **3.1 IDDM1 as an example of crucial role of genomics in clinical researches**

The use of high-throughput technologies in human genome studies was a step forward towards getting a deeper insight into pathogenetic mechanisms of many human diseases including insulin-dependent type 1 diabetes mellitus (T1D). Recent developments in the field of genetic factors and their pathogenetic roles suggest their high utility in the design of novel predictive strategies, stratification of patients according to disease risk and a search for new therapeutic targets. Among the immense variety of T1D strategies, two approaches are used methods of choice, viz.: (I) linkage studies of pairs of affected relatives (typically, siblings) aimed at a search for rarely occurring risk factors having large effective sizes; (II) association studies into more common risk factors having small effective sizes.
