2006. aasta Nobeli auhind füsioloogias ja meditsiinis

2006. aasta Nobeli auhinna füsioloogia ja meditsiini alal pälvisid Andrew Z. Fire ja Craig C. Mellouurimuse eest teemal “RNA interferents – geenidevaigistamine kahe ahelalise RNA abil” (“RNAinterference – gene silencing by double-stranded RNA”). Eesti Arst 2006; 85 (11): 790–79

Uute tiopuriinmetüültransferaasi aktiivsust mõjutavate biomarkerite otsingul

Väitekirja elektrooniline versioon ei sisalda publikatsiooneRavimite vähene efektiivsus ja kahjustavad kõrvaltoimed on üks farmakoteraapia oluline probleem. Farmakogenoomika on saamas personaalmeditsiini oluliseks osaks, mille eesmärk on aidata arstil määrata patsiendile ravim või ravimidoos vastavalt tema individuaalsele geneetilisele profiilile. Tiopuriinmetüültransferaas (TPMT) on ensüüm, mis inaktiveerib lapseea leukeemia ja autoimmuunhaiguste ravis ning siirdamisjärgse äratõukereaktsiooni vältimiseks kasutatavaid tiopuriinravimeid. Uuringutest on selgunud, et TPMT aktiivsuse alusel võib inimesed jagada kolme rühma; ~0,3% indiviididest omab väga madalat ensüümi aktiivsust, ligikaudu 11%-l on ensüümi aktiivsus osaliselt vähenenud (nn keskmine) ja 89%-l on ensüümi aktiivsus normaalne. Seega teoreetiliselt on umbes 11% patsientidest ohustatud kõrvaltoimete tekkest tiopuriinravimite standarddooside kasutamisel. Hoolimata mitmetest teadaolevatest TPMT ensüümi aktiivsust vähendavatest TPMT geeni variantidest, on kliinilises praktikas suureks probleemiks TPMT genotüübi-fenotüübi erinevused, eriti nn keskmise ensüümi aktiivsusega indiviidide seas – vähenenud ensüümi aktiivsusega inimesed omavad normaalset TPMT genotüüpi ja vastupidi. See fakt annab alust oletada, et lisaks teadaolevatele TPMT geenivariantidele on veel faktoreid, mis ensüümi aktiivsust mõjutavad. Antud töö kirjeldab TPMT genotüübi-fenotüübi uuringut, mille käigus analüüsiti hetkel teadaolevate TPMT geeni markerite seost ensüümi aktiivsusega ning otsiti uusi, nii mitte-geneetilisi kui ka geneetilisi biomarkereid. Töö tulemusena tuvastasime uue mitte-geneetilise biomarkeri (SAM), mis mõjutab TPMT aktiivsust. Edasised kinnitavad uuringud on olulised selle juurutamiseks kliinilisse kasutusse. Samas, me ei leidnud uusi geneetilisi markereid ja ei kinnitunud teaduskirjanduses varem avaldatud geneetiliste markerite seos (peale TPMT geeni) TPMT ensüümi aktiivsusega. Hetkeseisuga ei ole võimalik kliinilises praktikas kasutada TPMT ensüümi aktiivsuse ja ravimvastuse ennustamiseks ainult TPMT genotüüpi. Hoolimata juhenditest geneetiliste markerite kasutamise ja tulemuste tõlgendamise kohta, tuleb arstidel jälgida patsiendi ravi kulgu kasutuses olevate raviskeemide alusel.The lack of efficiency and severe adverse reactions of drugs are serious problem in pharmacotherapy. Pharmacogenomics is becoming a part of personalized medicine, the practice of administering treatments based on the individual’s genomic profile and informing treatment decisions and allowing for more accurate and efficient selection of therapies that are best suited for specific patients. Thiopurine methyltransferase (TPMT) is an enzyme that inactivates thiopurine drugs, which are used to treat acute lymphoblastic leukemia, autoimmune diseases and to prevent rejection of transplanted organs. It has been shown in population studies that TPMT activity is trimodally distributed: approximately 0.3%, 11%, and 89% have deficient/low, intermediate, and normal TPMT activity, respectively, indicating that some 11% of individuals in this population may be prone to adverse drug events. Aside from identifiable inactivating variants of TPMT, there are additional geno- and phenotype variances (e.g., individuals without known genetic variants, but with intermediate TPMT activity and vice versa), especially among individuals with intermediate TPMT activity. This indicates that there are non-genetic and genetic biomarkers other than TPMT genotype influencing TPMT activity. The aim was to carry out a genotype-phenotype association study of TPMT activity to analyze the correlation between known TPMT variants and enzyme activity. In addition, new genetic and non-genetic biomarkers influencing variation in TPMT activity were investigated. As a result, we showed for the first time that SAM is an important modulator of TPMT activity. Therefore prospective studies are necessary to evaluate the clinical usefulness of determining SAM levels as a predictive factor of thiopurine therapy response. Additionally, our results indicate that TPMT genetics have a fundamental impact on TPMT activity in humans and provide little support for the proposal that other genes may significantly contribute to the inter-individual variability of TPMT activity. Although our data confirm that TPMT genotype is a robust predictor of TPMT activity in most individuals, TPMT genotype alone is insufficient to predict TPMT activity reliably. Despite guidelines of how to use genetic markers and interpret the results from genetic analysis, doctors should follow the course of the therapy of every individual according to the existing regimen

2009. aasta Nobeli auhind füsioloogias ja meditsiinis

2009. aasta Nobeli auhinna füsioloogia ja meditsiini alal pälvisid kolm teadlast, kes lahendasid ühe olulise probleemi bioloogias: nad selgitasid, kuidas kromosoome rakujagunemise käigus täies pikkuses paljundatakse ning mil viisil need on kaitstud lagundamise eest (“How chromosomes are protected by telomeres and the enzyme telomerase”). Eesti Arst 2010; 89(1):65−6

Ühisrahastusplatvormide määruse kohaldamise võimalused ja vajadused pooltele, kes tegutsevad tarbijatena

https://www.ester.ee/record=b5507475*es

Lasteaiaõpetajate ja eripedagoogi koostöö erivajadustega laste üldoskuste arengu toetamisel

https://www.ester.ee/record=b5196076*es

Genetic and epigenetic regulation of gene expression in fetal and adult human livers

Background: The liver plays a central role in the maintenance of homeostasis and health in general. However, there is substantial inter-individual variation in hepatic gene expression, and although numerous genetic factors have been identified, less is known about the epigenetic factors. Results: By analyzing the methylomes and transcriptomes of 14 fetal and 181 adult livers, we identified 657 differentially methylated genes with adult-specific expression, these genes were enriched for transcription factor binding sites of HNF1A and HNF4A. We also identified 1,000 genes specific to fetal liver, which were enriched for GATA1, STAT5A, STAT5B and YY1 binding sites. We saw strong liver-specific effects of single nucleotide polymorphisms on both methylation levels (28,447 unique CpG sites (meQTL)) and gene expression levels (526 unique genes (eQTL)), at a false discovery rate (FDR) <0.05. Of the 526 unique eQTL associated genes, 293 correlated significantly not only with genetic variation but also with methylation levels. The tissue-specificities of these associations were analyzed in muscle, subcutaneous adipose tissue and visceral adipose tissue. We observed that meQTL were more stable between tissues than eQTL and a very strong tissue-specificity for the identified associations between CpG methylation and gene expression. Conclusions: Our analyses generated a comprehensive resource of factors involved in the regulation of hepatic gene expression, and allowed us to estimate the proportion of variation in gene expression that could be attributed to genetic and epigenetic variation, both crucial to understanding differences in drug response and the etiology of liver diseases

Selection for Genetic Variation Inducing Pro-Inflammatory Responses under Adverse Environmental Conditions in a Ghanaian Population

BACKGROUND:Chronic inflammation is involved in the pathogenesis of chronic age-associated, degenerative diseases. Pro-inflammatory host responses that are deleterious later in life may originate from evolutionary selection for genetic variation mediating resistance to infectious diseases under adverse environmental conditions. METHODOLOGY/PRINCIPAL FINDINGS:In the Upper-East region of Ghana where infection has remained the leading cause of death, we studied the effect on survival of genetic variations at the IL10 gene locus that have been associated with chronic diseases. Here we show that an IL10 haplotype that associated with a pro-inflammatory innate immune response, characterised by low IL-10 (p = 0.028) and high TNF-alpha levels (p = 1.39 x 10(-3)), was enriched among Ghanaian elders (p = 2.46 x 10(-6)). Furthermore, in an environment where the source of drinking water (wells/rivers vs. boreholes) influences mortality risks (HR 1.28, 95% CI [1.09-1.50]), we observed that carriers of the pro-inflammatory haplotype have a survival advantage when drinking from wells/rivers but a disadvantage when drinking from boreholes (p(interaction) = 0.013). Resequencing the IL10 gene region did not uncover any additional common variants in the pro-inflammatory haplotype to those SNPs that were initially genotyped. CONCLUSIONS/SIGNIFICANCE:Altogether, these data lend strong arguments for the selection of pro-inflammatory host responses to overcome fatal infection and promote survival in adverse environments

Des élèves heureux : réflexion sur la joie à l'école à partir de quelques textes littéraires

Hereditaarne spastiline parapleegia (HSP) on rühm harva esinevaid neurodegeneratiivseid haigusi, millele on iseloomul ik jalgade progresseeruv spastilisus hüperrefl eksiaga. Maailmas on vähe uuringuid, mis spetsiifi liselt ja süsteemselt seda haigust käsitleks. Eestis puudusid HSP-uuringud seni üldse. Nüüd valminud uuringust selgus, et HSP levimus Eestis on 4,4 juhtu 100 000 inimese kohta. Geeniuuringu tulemusena avastati kümme uut varem kirjeldamata muutust haigust põhjustavas SPAST geenis ning kirjeldati nende haigete fenotüüpe. Esmakordne tervisega seotud elukvaliteedi uuring tõestas, et HSPga inimestel esinev elukvaliteedi halvenemine on seostatav peamiselt füüsilise toimetulekuga. Eesti Arst 2010; 89(3):165−17