Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies

FINDbase (http://www.findbase.org) is a comprehensive data repository that records the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants leadingmostly tomonogenic disorders and pharmacogenomics biomarkers. The database also records the incidence of rare genetic diseases in various populations, all in well-distinct data modules. Here, we report extensive data content updates in all data modules, with direct implications to clinical pharmacogenomics. Also, we report significant new developments in FINDbase, namely (i) the release of a new version of the ETHNOS software that catalyzes development curation of national/ethnic genetic databases, (ii) the migration of all FINDbase data content into 90 distinct national/ethnicmutation databases, all built around Microsoft's PivotViewer (http://www.getpivot.com) software (iii) new data visualization tools and (iv) the interrelation of FINDbase with DruGeVar database with direct implications in clinical pharmacogenomics. The abovementioned updates further enhance the impact of FIND-base, as a key resource for Genomic Medicine applications

Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies

FINDbase (http://www.findbase.org) is a comprehensive data repository that records the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants leading mostly to monogenic disorders and pharmacogenomics biomarkers. The database also records the incidence of rare genetic diseases in various populations, all in well-distinct data modules. Here, we report extensive data content updates in all data modules, with direct implications to clinical pharmacogenomics. Also, we report significant new developments in FINDbase, namely (i) the release of a new version of the ETHNOS software that catalyzes development curation of national/ethnic genetic databases, (ii) the migration of all FINDbase data content into 90 distinct national/ethnic mutation databases, all built around Microsoft’s PivotViewer (http://www.getpivot.com) software (iii) new data visualization tools and (iv) the interrelation of FINDbase with DruGeVar database with direct implications in clinical pharmacogenomics. The above mentioned updates further enhance the impact of FINDbase, as a key resource for Genomic Medicine applications

Expanded national database collection and data coverage in the FINDbase worldwide database for clinically relevant genomic variation allele frequencies

Peer reviewe

Documentation of clinically relevant genomic biomarker allele frequencies in the next-generation FINDbase worldwide database

FINDbase (http://www.findbase.org) is a comprehensive data resource recording the prevalence of clinically relevant genomic variants in various populations worldwide, such as pathogenic variants underlying genetic disorders as well as pharmacogenomic biomarkers that can guide drug treatment. Here, we report significant new developments and technological advancements in the database architecture, leading to a completely revamped database structure, querying interface, accompanied with substantial extensions of data content and curation. In particular, the FINDbase upgrade further improves the user experience by introducing responsive features that support a wide variety of mobile and stationary devices, while enhancing computational runtime due to the use of a modern Javascript framework such as ReactJS. Data collection is significantly enriched, with the data records being divided in a Public and Private version, the latter being accessed on the basis of data contribution, according to the microattribution approach, while the front end was redesigned to support the new functionalities and querying tools. The abovementioned updates further enhance the impact of FINDbase, improve the overall user experience, facilitate further data sharing by microattribution, and strengthen the role of FINDbase as a key resource for personalized medicine applications and personalized public health

Genomics as a basis for precision medicine

Summary. Precision medicine, also known as genome-based medicine and personalized medicine, uses knowledge of the molecular basis of a disease in order to individualize treatment for each patient. The development of novel, powerful, high-throughput technologies has enabled better insight into the genomic, epigenomic, transcriptomic and proteomic landscape of many diseases, resulting in the application of personalized medicine approaches in healthcare. Research in the field of biomedicine in Serbia has followed the modern trends and has made a great contribution to the implementation of genomics in Serbian clinical practice. This is a review of the state of the art of scientific achievements and their application, which have paved the way for personalized medicine in Serbia

Genetic basis of otosclerosis

Uvod Otoskleroza je poremećaj koštane kapsule lavirinta i slušnih koščica uva, koji dovodi do gubitka sluha zbog nemogućnosti provođenja zvuka. Genetički uzrok otoskleroze je nepoznat. Cilj ovog rada je bio da se sačini sveobuhvatni pregled savremenih saznanja o genetičkoj osnovi otoskleroze. Metode Za prikaz podataka o genetici otoskleroze korišćen je narativni pregled literature. Rezultati Genetika otoskleroze nije mnogo izučavana i literaturni podaci o genetičkoj osnovi otoskleroze su oskudni. Međutim, u novije vreme, proširuju se znanja o genetičkoj osnovi otoskleroze. Ovde je prikazan pregled znanja o asocijaciji genetičkih markera i otoskleroze, koja su rezultat analiza genetičke povezanosti, kao i asocijativnih studija gena kandidata i sveobuhvatnih analiza genoma. Zaključak Otoskleroza zbog svoje kompleksnosti nije bolest čija će genetička osnova biti lako rasvetljena. Analize omika i bioinformatika će doprineti razumevanju genetičke osnove otoskleroze.Introduction Otosclerosis is a disorder of the bone labyrinth and stapes resulting in conductive hearing loss. The genetic basis of otosclerosis still remains unknown. We aimed at reporting a comprehensive review of up-to-date knowledge on genetic basis of otosclerosis. Methods Narrative literature review was undertaken to summarize the data about genetics of otosclerosis. Results Genetics of otosclerosis has not been studied extensively and the literature on this topic is scarce. However, knowledge of genetic basis of otosclerosis is recently increasing. We have presented an overview of the knowledge of association of genetic markers with otosclerosis, gained from linkage analyses, candidate-gene studies, and modern high-throughput genomic studies. Conclusion Due to its complex pathophysiology, otosclerosis is not a disease whose genetic base will be easily understood. Multiple omics analysis and bioinformatics will lead to elucidation of genetic basis of otosclerosis

Ugt1a1 (ta)(n) promoter genotype: diagnostic and population pharmacogenetic marker in Serbia

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyper-bilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT I Al activity and non-risk GS allele. Also, the UGT1A1 (TA)(n) promoter genotype is recognized as a clinically relevant phannacogenetic marker. The aim of this study was to access diagnostic value of UGTIAI (TA) n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1(TA)(n) genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess phannacogenetic potential ofUGT1A1 (TA)(n) variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerise chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)(n) promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)(n) promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilimbin in pediatric GS patients at diagnosis wasUGT1A1 (TA)(n) promoter genotype-dependent. We found that the frequency of phannacogenetic relevant UGT1A1 (TA)(n) promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)(n) promoter genoty ping could be recommended for preemptive pharmacogendic testing in Serbia

PHARMACOGENOMICS IN THE EMIRATI POPULATION: APPLICATIONS IN CARDIOVASCULAR DISEASES AND ONCOLOGY

Pharmacogenetic variations contribute to interindividual differences in drug response. Advances in molecular techniques provided insights into interpopulation pharmacogenomic variations. A limited number of pharmacogenetic studies were conducted in the UAE population. The current study aims to explore the variation landscape in important pharmacogenes in Emiratis. Furthermore, it investigates the association between VKORC1 variants and warfarin dose in cardiovascular patients. Finally, this study explores the applied/needed germline pharmacogenetic tests in oncology in the UAE. In 100 healthy Emiratis, variants and star alleles in 100 relevant pharmacogenes were defined by next-generation sequencing. 63% of detected variants were rare, 30% were novel, and 141 variants were novel and damaging. By clinical annotations, filtering variants resulted in 99 clinically actionable variants, from which 44 are highly significant alleles. Revising the results against the clinical pharmacogenetics implementation consortium guidelines demonstrated that 93% of participants have at least one actionable variant with a dosing recommendation. The effect of VKORC1 on warfarin dose was explored in 90 patients. A model built from two VKORC1 variants, rs9923231 and rs61742245, with age, significantly predicted warfarin dose. High incidence rates of adverse chemotherapy effects were reported from 66 pediatric acute lymphoblastic leukemia patients, which indicates the plausibility of pharmacogenetic research to investigate toxicity biomarkers. Few cases had a clinical pharmacogenetic test of TPMT and NUDT15 before starting oral 6-mercaptopurine. Patients who received pharmacogenetic-guided doses suffered from less adverse effects. Exploring the adverse drug effects in a group of 77 breast cancer patients was faced by deficiencies in adverse effects reporting. The reported adverse events suggested suitable candidates for future pharmacogenetic research. This research highlighted population-specific variants, unexplored adverse drug events, and possible pharmacogenomics applications in the UAE. Various research opportunities were illustrated for the scientific community

Pharmacogenomic and pharmacotranscriptomic markers in glucocorticoid treatment of pediatric acute lymphoblastic leukemia: molecular mechanism of action, clinical and population aspects

Personalizovana medicina, medicina XXI veka, nastoji da individualizuje terapiju za svakog pacijenta, kako bi lečenje bilo što efikasnije i sa što manje rizika od toksičnosti. Personalizovana medicina se danas najviše oslanja na farmakogenomiku i farmakotranskriptomiku, koje su već dale svoj doprinos unapređenju lečenja mnogih bolesti, a posebno maligniteta. Akutna limfoblastna leukemija (ALL) predstavlja najčešći hematološki malignitet pedijatrijskog uzrasta. Mada stopa izlečenja dostiže 80-90%, ALL je i dalje glavni uzrok mortaliteta u ovih pacijenata. Terapija izaziva neželjene efekte u 75% pacijenata. Pored toga, u 1-3% pedijatrijskih pacijenata sa ALL smrtni ishod nije posledica bolesti, već je uzrokovan terapijom. Lečenje pedijatrijske ALL nije napredovalo uvođenjem novih lekova, već nastojanjem da se smanje neželjena dejstva onih lekova koji su već sastavni delovi postojećih terapijskih protokola, zbog čega su farmakogenomika i farmakotranskriptomika dobile ključno mesto u ovoj oblasti. Glukokortikoidni lekovi (GK) se koriste u početnoj fazi lečenja ALL u dece, u fazi indukcije remisije. Od početka lečenja do 8. dana se primenjuju isključivo GK. Ipak, farmakogenomske i farmakotranskriptomske studije za glukokortikoidne lekove još uvek nisu dovele do algoritma koji bi mogao biti primenjen u lečenju dečje ALL. Stoga je izuzetno značajno nastaviti sa istraživanjima farmakogenomskih i farmakotranskriptomskih markera relevantnih za uspešnost GK terapije u dece sa ALL. Razumevanje molekularnog mehanizma dejstva GK vodi ka otkrivanju novih markera koji mogu biti iskorišćeni za optimizaciju GK terapije. Nove tehnologije, kao što je sekvenciranje nove generacije (eng, next generation sequencing, NGS) su omogućile dizajniranje panela za farmakogenomske i farmakotranskriptomske markere za različite lekove...Personalized medicine, the medicine of the XXI century, aims to individualize therapy for each patient, in order for the treatment to be as efficient and safe as possible. Today, personalized medicine is the most reliant on pharmacogenomics and pharmacotranscriptomics, which have already given their contribution to enhancing treatment of many diseases, especially malignancies. Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy of childhood. Even though the percentage of cured patients reaches 80-90%, ALL is still the main cause of mortality in this group of patients. Therapy causes side effects in 75% of patients. Aside from that, 1-3% of pediatric ALL patients die because of therapy side effects rather than the disease itself. Treatment of pediatric ALL wasn’t improved by the introduction of new drugs, but by decreasing the side effects of the drugs which are already included in existing protocols. Due to this fact, pharmacogenomics and pharmacotranscriptomics have gained key positions in this field. Glucocorticoid drugs (GC) are used in the initial phase of childhood ALL treatment, in the phase of remission induction therapy. From the beginning of the treatment until day 8, GCs are exclusively applied. Pharmacogenomic and pharmacotranscriptomic studies for GC drugs have yet to produce an algorithm that could be applied in childhood ALL treatment. Therefore, it is of extreme importance to continue researching pharmacogenomic and pharmacotranscriptomic markers relevant to the success of the GC therapy of children with ALL. Understanding the molecular mechanism of action of GC can lead to discovery of new markers that could be used for the optimization of GC therapy. New technologies, such as next generation sequencing (NGS) have created a possibility for designing panels for pharmacogenomic and pharmacotranscriptomic markers of response to different drugs. Utilization of these panels in population pharmacogenomic studies can lead to new knowledge that could open wide the doors to predictive pharmacogenomic testing..