Zbornik - Društvo genetičara Srbije
Zbornik - Društvo genetičara Srbije
Zbornik - Društvo genetičara Srbije
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V-Usm-8 ZBORNIK ABSTRAKATA III KONGRESA GENETIÈARA SRBIJE 191<br />
Subotica, 30. novembar - 4. decembar 2004.<br />
VARIJABILNOST GENA ZA TIOPURIN S-METILTRANSFERAZU<br />
U SRBIJI – FARMAKOGENETIKA U KLINIÈKOJ PRAKSI<br />
B. Petruèev 1 , J. Jovanoviæ 1 , N. Tošiæ 1 , D. Janiæ 2 ,<br />
L. Krivokapiæ-Dokmanoviæ 2 i S. Pavloviæ 1<br />
1<br />
Institut za molekularnu genetiku i genetièko inenjerstvo, Beograd<br />
2<br />
Univerzitetska deèja klinika, Beograd<br />
Ova studija predstavlja jedno od pionirskih farmakogenetièkih istraivanja u našoj<br />
populaciji. Tiopurin S-metiltransferaza (TPMT) je citoplazmatski enzim koji katalizuje<br />
S-metilaciju (inaktivaciju) tiopurinskih lekova kao što su antitumorski agensi i<br />
imunosupresanti. Smanjena aktivnost TPMT enzima se manifestuje sa teškom<br />
hematopoetskom toksiènošæu posle primene standardnih doza ovih lekova. Aktivnost<br />
TPMT enzima zavisi od genetske varijabilnosti. Nekoliko mutacija u genu za TPMT<br />
utièe na smanjenu fenotipsku aktivnost enzima. Nemutirani alel je oznaèen kao<br />
TPMT*1, a mutirani aleli su: TPMT*2 (G238C), TPMT*3A (G460A i A719G),<br />
TPMT*3B (G460A) i TPMT*3C (A719G). Genotipovi su odreðivani kod 70 dece sa<br />
akutnom limfoblastnom leukemijom (ALL) u Srbiji, korišæenjem lanèane reakcije<br />
polimeraze i analize polimorfizama duine restrikcionih fragmenata (PCR-RFLP) i<br />
alel-specifiènog PCR-a. 60 pacijenata je imalo normalan genotip (85,8%), devet<br />
pacijenata TPMT*2/TPMT*1 genotip (12,8%) i jedan pacijent TPMT*3A/TPMT*1<br />
genotip (1,4%). Da bismo odredili uèestalosti TPMT alela u srpskoj populaciji, 100<br />
zdravih davalaca krvi je takoðe analizirano. 96% analiziranih je imalo normalan TPMT<br />
genotip, 3% TPMT*1/TPMT*3A genotip i jedan TPMT*1/TPMT*3B genotip. Naši<br />
rezultati su pokazali da je uèestalost mutiranih alela TPMT*3A veoma visoka kod dece<br />
sa ALL. Uoèena je statistièki znaèajna razlika izmeðu uèestalosti mutiranog alela<br />
TPMT*3A kod dece sa ALL i kod zdravih osoba. Svi pacijenti sa genetskim varijacijama<br />
razvili su neutropeniju tokom primene standardnih doza tiopurina.<br />
THIOPURINE S-METHYLTRANSFERASE GENETIC VARIATION IN<br />
SERBIA – PHARMACOGENETICS IN CLINICAL PRACTICE<br />
This study represents one of the pioneer pharmacogenetic research in our population.<br />
Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyzes<br />
S-methylation (inactivation) of thiopurine drugs such as anticancer and<br />
immunosupressant agents. Decreased activity of TPMT is associated with severe<br />
hematopoietic toxicity after using standard doses of these drugs. Activity of TPMT enzyme<br />
depends on genetic background. There are several mutations in TPMT gene which<br />
give rise to low phenotypic activity. The wild type allele is designated as TPMT*1 and<br />
the mutant alleles are: TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B<br />
(G460A) and TPMT*3C (A719G). Genotypes were determined in 70 Serbian children<br />
with acute lymphoblastic leukemia (ALL), using polymerase chain reaction (PCR)-restriction<br />
fragment length polymorphism and allele-specific PCR assays. 60 patients had<br />
wild type genotype (85,8%), nine patients TPMT*3A/TPMT*1 genotype (12,8%) and<br />
one patient TPMT*2/TPMT*1 genotype (1,4%). In order to determine the frequencies of<br />
TPMT alleles in Serbian population, 100 volunteer blood donors were analysed as well.<br />
96% of them had wild type TPMT genotype, 3% TPMT*1/TPMT*3A genotype and 1%<br />
TPMT*1/TPMT*3B genotype. Our results revealed that the frequency of mutated allele<br />
TPMT*3A is very high in children affected with ALL. Statistically significant difference<br />
between the frequency of mutated allele TPMT*3A in children affected with ALL and in<br />
healthy individuals was observed. All the patients with genetic variations revealed<br />
neutropenia during full dose of thiopurine administration.