Zbornik - Društvo genetičara Srbije

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