Farmakogenetika je vedný odbor, ktorý skúma efekt jednotlivých liekov v závislosti od genotypu. V súčasnosti sú liečebné odporúčania pre liečbu niektorých monogenénových diabetov založené na genetickej diagnostike. Aj v oblasti farmakogenetiky perorálnych antidiabetík boli už publikované prvé štúdie, ktoré zistili asociácie jednotlivých génových variantov s liečebnou odozvou. Odozva na deriváty sulfonylurey bola signifikantne asociovaná s variantmi KCNJ11/ABCC8, TCF7L2 a CYP2C9. Odozva na liečbu metformínom bola asociovaná s variantmi génov ATM a SLC47A1. Odozva na liečbu glitazónmi bola asociovaná s variantom génu PPARG. Terapeutická odozva na liečbu gliptínmi bola asociovaná s variantmi génov TCF7L2 a CTRB1/2. Je možné očakávať, že v blízkej budúcnosti budú farmakogenetické poznatky využívané aj pri personalizácii liečby diabetu 2. typu., Pharmacogenetics is the study of how genes (individual genotypes) affect a person‘s response to drugs. At present, recommendations made about the treatment of some monogenic forms of diabetes are based on genetic diagnostics. The first studies in the field of pharmacogenetics of oral antidiabetics have now been published which have identified associations of individual genetic variants with response to treatment. The response to sulfonylurea derivatives was significantly associated with the variants KCNJ11/ABCC8, TCF7L2 and CYP2C9. The response to metformin treatment was associated with the genetic variants ATM and SLC47A1. The response to treatment with glitazones was associated with the genetic variant PPARG. The therapeutic response to the treatment with gliptins was associated with the genetic variants TCF7L2 and CTRB1/2. It may be expected that in the near future pharmacogenetic knowledge will also be used within personalized treatment of type 2 diabetes., and Ivan Tkáč
A total genome scan and pharmacogenetic study were designed to search for genetic determinants of blood pressure (BP) as well as heart and kidney weights. Genome scanning was carried out in 266 F2 intercrosses from Prague hypertensive hypertriglyceridemic rats for phenotypes of organ weights, baseline BP, BP after blockade of the renin-angiotensin system (RAS) by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester. Pharmacogenetic analysis showed that, in males, BP was controlled by two loci on chromosomes 1 and 5 (Chr1, Chr5) through the SNS, and these loci showed a positive contribution for relative kidney weight (KW/BW). On the other hand, baseline BP in females was controlled by two loci on Chr3 and Chr7. The effect of these loci was not mediated by the RAS, SNS or NO system. These loci did not show any effect for KW/BW. Negatively-linked loci for KW/BW and relative heart weight (HW/BW) were identified on Chr2 in both genders. Another negatively-linked locus for KW/BW, located on Chr8 in males, affected BP through the SNS. This locus on Chr8 overlapped with a previously-reported modifier locus for polycystic kidney disease (PKD). In conclusion, this pharmacogenetic study determined two loci for BP and relative organ mass implicating sympathetic overactivity. Concordance of the identified locus for KW/BW and BP through the SNS on Chr8 with the PKD locus revealed the importance of this region for renal complications in various diseases., T. Ueno, J. Tremblay, J. Kuneš, J. Zicha, Z. Dobešová, Z. Pausová, A. Y. Deng, Y. Sun, H. J. Jacob, P. Hamet., and Obsahuje bibliografii
Cíl studie: Cílem práce je popsat frekvenci výskytu variantních alel genu enzymu CYP2C9 v české populaci. CYP2C9, jeden z enzymů cytochromu P450, metabolizuje přibližně 16 % běžně užívaných léčiv, genetický polymorfismus jeho genu může ovlivňovat míru schopnosti odbourávat své substráty, a být proto vysvětlením pro variabilní odpověď pacientů na léčbu. Materiál a metody: 254 zdravých, nepříbuzných dobrovolníků bylo po podepsání informovaného souhlasu zařazeno do studie. Z leukocytární DNA byl stanoven výskyt variantních alel CYP2C9*2 a CYP2C9*3 metodou PCR-RFLP. Výsledky: Frekvence výskytu CYP2C9*1, CYP2C9*2 a CYP2C9*3 alel v české populaci je 81,9 %, 12,2 % a 5,9 %. Jejich distribuce odpovídá Hardy-Weinbergově rovnováze. Zastoupení genotypů heterozygotů je následující: CYP2C9*1/ *2 - 20,1 %; CYP2C9*1/*3 - 9,8 %; CYP2C9*2/*3 - 0,4 %. Pět subjektů (2,0 %) klasifikujeme jako variantní homozygoty CYP2C9*2/*2, 0,8 % jako homozygoty CYP2C9*3/*3. Závěr: Frekvence výskytu variantních alel genu CYP2C9 v české populaci je podobná ostatním kavkazským populacím., Objective: The aim of this study was to investigate the frequency of functionally important variant alleles of CYP2C9 gene through the Czech population. Setting: Clinical Pharmacology Unit, First Faculty of Medicine, Charles University, Prague, Czech Republic. Methods: 254 unrelated, healthy volunteers were enrolled in the study after giving written consent. Leucocyte DNA was analysed to detect the presence of CYP2C9*2 and CYP2C9*3 variant alleles by PCR-RFLP. Results: The variant allelic frequencies in our population are 81.9%, 12.2% and 5.9%, for CYP2C9*1, CYP2C9*2, CYP2C9*3, respectively. The distribution of variant alleles complies to the Hardy-Weinberg equilibrium. Prevalence of heterozygous genotypes is as follow: CYP2C9*1/*2 – 20.1%; CYP2C9*1/*3 – 9.8%; CYP2C9*2/*3 – 0.4%. Five subjects (2.0%) are classified as a CYP2C9*2/*2 homozygous, 0.8% as a CYP2C9*3/*3 homozygous. Conclusions: The frequencies of functional variant alleles of CYP2C9 in the Czech population are in concordance with the other Caucasians population., Helena Buzková, K. Pechandová, Ondřej Slanař, and Lit. 21
Osteoporóza je závažné onemocnění charakterizované vysokou morbiditou a mortalitou v důsledku atraumatických fraktur. Kromě vlivu vnějšího prostředí se v patogeneze osteoporózy uplatňují faktory vnitřní (hormonální nerovnováha a genetické pozadí). Článek podává přehled kandidátních genů pro osteoporózu, které klasifikuje podle metabolických okruhů regulujících minerální denzitu nebo kvalitu kosti (okruh estrogenní, RANKL/RANK/OPG, mevalonátový, okruh Wnt, geny pro kolagen a vitamin D). Zabývá se také perspektivou praktického využití farmakogenetiky (identifikace jednotlivých kandidátních genů pomocí PCR) nebo farmakogenomiky (plošné měření škály genů pomocí GWAS) při výběru optimální léčby osteoporózy. Potencionálními prediktory odpovědi na antiresorpční léčbu jsou geny pro ER, FDPS, Cyp19A1, VDR, Col 1A1 a gen pro signalizaci Wnt. Polymorfizmy genů CYP2C, ale také FDPS mohou naopak identifikovat nemocné s vysokým rizikem nežádoucí odpovědi na bisfosfonáty (osteonekróza čelisti). Limitujícím faktorem výzkumu genetiky osteoporózy je nedostatečný konsenzus výsledků asociačních studií. Vysvětlení kontroverzních výsledků lze hledat v rozdílných metodických přístupech (rozsah a homogenita souboru, etnické rozdíly nebo vazebná nerovnováha mezi geny). Klíčovým úskalím asociačních studií je nízká variabilita (7-10 %) kostních fenotypů, které souvisí se zkoumaným genem. Nicméně identifikace nových genů a ověřování jejich asociace s kostními parametry oběma metodami zůstává velkou výzvou s cílem optimalizace prevence a léčby osteoporózy., Osteoporosis is a serious disease characterized by high morbidity and mortality due to atraumatic fractures. In pathogenesis of osteoporosis, except environment, internal factors, such as hormonal dysbalance and genetic background, are also in play. In this review, candidate genes for osteoporosis are classified accorging to metabolic or hormonal pathways, which regulate bone mineral density/and or quality (estrogen, RANKL/RANK/OPG, mevalonate, Wnt circuit, genes for collagen and vitamin D). Authors discuss the perspectives of practical utilization of pharmacogenetics (identification of single candidate genes using PCR) or pharmacogenomics (using genome wide association studies) in choise of optimal treatment of osteoporosis. Potentional predictors of effectivity of antiresorption therapy are genes ER, FDPS, Cyp19A1, VDR, Col1A1 and gene of Wnt pathway. Moreover, polymorphisms of CYP2C gene, but also FDPS may identify patients with high risk of undesirable effects of bisphosphonates (osteonecrosis of jaw). Unfortunately, results of the most association studies has not been confirmed by other investigators. The controversial results could be explained by different methodic approches in individual studies (different sample size, homogenity of investigated groups, ethnic differences or linkage disquilibrium between genes). Key cliff of association studies is low variability (7-10 %) of bone phenotypes associated with investigated genes. Nevertheless, identification of new genes and verification their association with bone denzity and/or quality using both PCR and genome wide association studies remain to be a great challenge targeting optimal prevention and treatment of osteoporosis., and Ivana Žofková, Radoslav Omelka
The aim of our study was to evaluate possible effect of ABCB1, and OPRM1 polymorphisms on the efficacy and safety of remifentanil in women undergoing elective cesarean section under general anesthesia. Women received remifentanil (1 μg/kg i.v.) 30 s prior to the induction to standardized general anesthesia. The ABCB1 (rs2032582, rs1045642) and OPRM1 (rs1799971) polymorphisms were analyzed from maternal peripheral blood. The basal hemodynamic and demographic parameters in the study population (n=54) were similar in all the subgroups. The median ± SD increase of systolic blood pressure at 5 min from the baseline was practically completely abolished in homozygous carriers of ABCB1 variants in comparison with wildtype subjects -2.67±25.0 vs. 16.57±15.7 mm Hg, p<0.05 for rs2032582, and 2.00±23.9 vs. 22.13±16.8 mm Hg, p<0.05, for rs1045642, respectively. While no neonate belonging to ABCB1 wild-type homozygous or OPRM1 variant carrying mothers needed any resuscitative measure, 10.5 % of the neonates belonging to OPRM1 wild-type homozygous mothers received resuscitative support similarly as 11.1 %, and 12.5 % of neonates of mothers carrying variants of rs2032582, and rs1045642, respectively. Decreased stabilizing effects of remifentanil on maternal hemodynamics has been observed in ABCB1 wild type mothers, while the adaptation of the neonates was clinically worse in OPRM1 wild type, and ABCB1 variant allele carriers., H. Bakhouche, P. Noskova, S. Svetlik, O. Bartosova, J. Ulrichova, J. Kubatova, P. Marusicova, A. Parizek, J. Blaha, O. Slanar., and Obsahuje bibliografii
The colorectal cancer ranks high among the malignant tumours in incidence and mortality and irinotecan is standardly used in palliative treatment of metastatic disease in every therapeutic line. Unfortunately, the treatment with irinotecan is often associated with severe toxicities, especially neutropenia and diarrhea. The majority of the toxic manifestation is caused by the insufficient deactivation (glucuronidation) of irinotecan active metabolite SN-38 by UGT1A enzyme. The elevated SN-38 plasma concentration is responsible for the hematological and gastrointestinal toxicity that can become life-threatening. The patients carrying the mutation of the gene encoding UGT1A enzyme lack the ability of bilirubin glucuronidation, and suffer from the inherited un-conjugated hyperbilirubinemia (Gilbert syndrome, Crigler-Najjar type 1 and 2 syndrome). The mutations in other enzyme systems also play role in the etiopathogenesis of the irinotecan toxicity: CYP3A (cytochrome P-450), ABC family of transmembrane transporters (adenosine-triphosphate binding cassette). The goal of the contemporary research is to determine the predictive factors that will enable the individual adjustment of the individual drug dosage while minimising the adverse effects and maintaining the treatment benefit. and A. Paulík, J. Grim, S. Filip
Pojem „personalizovaná medicína“ sa v posledných rokoch spomína čoraz častejšie v súvislosti so snahami čo najlepšie prispôsobiť medikamentóznu, ale aj režimovú liečbu potrebám a požiadavkám jednotlivých pacientov. Personalizácia antidiabetickej liečby prekonala svoj vývoj v kontexte nárastu poznatkov týkajúcich sa cukrovky. Od úrovne empirickej sa posunula na úroveň fenotypickú, ktorá umožnila rozlišovanie medzi jednotlivými typmi diabetu. V rámci diabetu 2. typu sa od 60. rokov minulého storočia aplikovala patogenetická personalizácia, ktorá vychádzala z predpokladov, že u niektorých pacientov prevažuje inzulínová rezistencia a u iných deficit sekrécie inzulínu. Bioštatistická personalizácia (medicína dôkazov) viedla k dôkazom, na základe ktorých bol metformín zaradený do odporúčaní pre liečbu diabetu 2. typu ako liek prvej voľby. Randomizované štúdie v prvom desaťročí 21. storočia síce nedokázali superioritu žiadnej z iných liečebných modalít ako prídavnej liečby k metformínu, ale viedli k individualizácii cieľov glykemickej kompenzácie. V súčasnej dobe sa personalizácia posúva na úroveň farmakogenetickú, od ktorej môžeme v najbližších rokoch očakávať individualizáciu liečby v zmysle výberu liekov prvej, druhej a tretej voľby v závislosti od panelu kľúčových génových polymorfizmov charakterizujúcich citlivosť jedinca na konkrétne antidiabetiká. V konečnom dôsledku by mala byť „liečba ušitá na mieru“ vybratá na podklade syntézy patogenetických, bioštatistických a farmakogenetických poznatkov, čo bude reflektovať transláciu výsledkov základného biomedicinískeho výskumu do klinickej praxe. Kľúčové slová: diabetes 2. typu – farmakogenetika – medicína dôkazov – patogenéza – personalizovaná liečba, In recent years, the term “personalized medicine“ has been increasingly mentioned in relation to the endeavours to tailor the pharmaceutical as well as regimen therapy to the needs and requirements of individual patients. The personalization of antidiabetic treatment has undergone a dramatic advancement in relation to the expansion of knowledge about diabetes. From the empirical it moved forward to the phenotypic level which made it possible to differentiate between individual types of diabetes. The pathogenetic personalization which began to be used within Type 2 diabetes in the 1960s, was based on the assumption that while insulin resistance predominates in some patients, others are mainly affected by insulin secretion deficit. Biostatistics-personalized medicine (evidence based medicine) gathered evidence based on which metformin was included in recommendations on the therapy for Type 2 diabetes as a first-line drug. Although randomized studies during the first decade of the 21st century did not prove superiority of any other treatment modality as an adjunctive therapy used with metformin, they brought with them individualization of the goals of glycemic control. At present, personalization is heading towards the pharmacogenetic level that will enable in the near future individualized therapy in terms of choice of first-, second- and third-line drugs depending on the panel of key gene polymorphisms which characterize sensitivity of an individual to specific antidiabetics. Finally, the “tailor-maded therapy“ should be chosen based on a synthesis of pathogenetic, biostatistic and pharmacogenetic knowledge that will reflect the translation of results of the basic biomedical research into the clinical practice. Key words: evidence based medicine – pathogenesis – personalized therapy – pharmacogenetics – type 2 diabetes, and Ivan Tkáč
Antikoagulační léčba warfarinem a dalšími deriváty dikumarolu vykazuje významnou interindividuální i intraindividuální variabilitu. Potřebná dávka warfarinu z velké části závisí i na vrozených dispozicích každého jedince. Dávku prokazatelně ovlivňují genetické varianty cytochromu P450 2C9 (CYPP2C9) a reduktázy epoxidu vitaminu K (VKORC1). Ovlivnění dalšími polymorfi smy je předmětem výzkumu. Zdá se, že zahrnutí výsledků genetického testování do algoritmů pro výpočet potřebné úvodní dávky warfarinu by mohlo být přínosem. Podobně znalost polymorfi smů může upozornit na pacienty s vysokým rizikem předávkování a tím i krvácivých komplikací. Dosud to však není jednoznačně prokázané., Sensitivity to anticoagulation treatment by warfarin shows a wide inter-individual and intra-individual variability. The proper warfarin dose also depends largely on inherited predispositions. The dose is signifi cantly infl uenced by genetic variants of cytochrome P450 2C9 (CYPP2C9) and vitamin K epoxide reductase (VKORC1). Other possible polymorphism effects are under investigation. It seems that including genetic testing into algorithms for calculating of the required warfarin dose could be benefi cial. Similarly, knowledge of polymorphisms could alert us to patients with a high risk of overdosing and bleeding complication. If there is a benefi t of genetic testing remains controversial till now., Matýšková M., Čech Z., and Lit.: 35