Hiperkolesterolemik olgularda mevalonat kinaz V377I ve ABC1 gen polimorfizmlerinin incelenmesi
Investigation of mevalonate kinase V377I and ABC1 gene polymorphisms in hypercholesterolemic subjects
Yazar: H. ARZU ERGEN
Danışman: PROF.DR. TURGAY İSBİR
İstanbul Üniversitesi / Sağlık Bilimleri Enstitüsü / Moleküler Tıp Ana Bilim Dalı
Derece: Doktora, 2006
Konu: Moleküler Tıp = Molecular Medicine

Özet:
ÖZETErgen, HA. Hiperkolesterolemik Olgularda Mevalonat Kinaz V377I Ve ABC1 GenPolimorfizmlerinin ncelenmesi, stanbul Üniversitesi Sa l k Bilimleri Enstitüsü, MolekülerT p ABD Doktora Tezi, stanbul, 2006.Adenozin trifosfat ba layan kaset transporter (ABC) gen ailesinin bir üyesi olan ABC1(ABCA1) geni, periferal dokulardan kolesterolü toplayarak karaci ere getiren HDL ninolgunla mas nda ve hücre içindeki kolesterolün HDL ye transferinde önemli roloynamaktad r. Mevalonat kinaz (MVK) geni, izoprenoid/kolesterol biyosentezinde yer alanbir enzim olup kolesterolün biyosentezinde düzenleyici rol oynayabilece i bildirilmi tir.Çal mam zda ABCA1 C6730T, C2665T, T3212C, (E,D)1833,1834, C69T, G191C veMVK V377I gen polimorfizmlerinin miyokard infarktüsü (MI) ve diyabeti olanhiperkolesterolemili hastalarda ve Türk populasyonunda plazma lipid düzeyleri üzerindekietkisini saptamay amaçlad k. Çal mam zda C69T CC genotipi ta yan hiperkolesterolemikhastalarda ve MI grubunda CT genotipine göre VLDL ve trigliserid düzeyleri, tüm grupta iseCC genotipi ta iyanlarda CT genotipi ta yanlara göre VLDL düzeyi anlaml yüksek olaraksaptanm t r (p<0.05). Kontrol grubunda, diyabetik grupla kar la t r ld nda G191C B allelita ma oran istatistiksel olarak yüksek bulunmu tur (p<0.05). Diyabetik hastalarda G191CAA genotipi ta ma riski MI (p:0,023) ve kontrol grubuna (p:0,001) göre anlaml olarakartm t r. Tüm grupta G191C AA genotipi ta yanlarda BB (p:0,017, p:0,036, p:0,004) ve AB(p:0,027, p:0,034, p:0,007) genotipi ta yanlara göre total kolesterol, LDL ve VLDLdüzeyleri anlaml yüksek bulunmu tur. Hiperkolesterolemili hastalarda ve tüm çal magrubunda G191C B alleli ta ma oran erkeklerde kad nlara göre anlaml yüksek oldu ugözlenmi tir (p:0,05). LVH i bulunan MI hastalar n n tamam G191C B alleli ta makta ikenC69T allelleri bak m ndan %75 i T, % 83 ü C alleli ta maktad r. DLA görülen MIhastalarinin ise tamam G191C B alleli ve C69T CT genotipi ta maktad rlar. MI grubundakidört hastada koroner anjiyografi ölçümü yap lm t r. Bu hastalar n hepsi G191C A ve C69TC alleli ta maktad r. Çal mam zda MVK V377I genotipleri ile plazma lipid düzeyleriaras nda bir ili ki bulunmam ve MVK V377I genine ait bir mutasyona rastlanmam t r.Sonuç olarak populasyonumuzda ilk olarak yap lan bu çal mada, G191C ve C69T genmutasyonlar n n hiperkolesterolemili hastalarda ve Türk populasyonunda, MVK V377Imutasyonu aksine, plazma lipid düzeyleri ile ili kili olabilece i izlenimi elde edilmi tir.Anahtar kelimeler: Lipoprotein, Hiperkolesterolemi, ABCA1, MVK, PolimorfizmBu çal ma stanbul Üniversitesi Bilimsel Ara t rma Projeleri Birimi taraf ndan T-380/08032004 no lu proje olarak desteklenmi tir.

Abstract:
ABSTRACTErgen, HA. Investigation of Mevalonate Kinase V377I and ABC1 Gene Polymorphisms inHypercholesterolemic Subjects, Istanbul University Institute of Health Sciences, PhD Tesis ofDepartment of Molecular Medicine, stanbul, 2006.One of the members of Adenosine Triphosphate Binding Cassette transporter (ABC)gene family, ABC1 (ABCAI) gene, has an important role on maturation of HDL, which picksup the cholesterol from the peripheral tissues and takes it to the Liver, by transferring thecholesterol from the cell to the HDL. Mevalonate Kinase (MVK) is an enzyme, which hasan important role in isoprenoid/cholesterol biosynthesis process and it has been indicatedthat it is also active in the regulation of cholesterol biosynthesis process. In this study, weinvestigated the role of ABCA1 C6730T, C2665T, T3212C, (E.D)1833,1834, C69T,G191C and MVK V377I gene polymorphisms on the plasma lipid levels of patients withhypercholesterolemia, who have MI and diabetes mellitus, and Turkish population. Plasmatriglyceride and VLDL levels were higher in patients with hypercholestreolemia and MIpatients with ABCA1 C69T CC genotype compared to patients with CT genotype (P<0,05).Also in the total group with CC genotype VLDL levels were found to be higher than theVLDL levels of the subjects carrying the CT genotype (P<0,05). We observed that incomparison to the control group the G191C B allele had a significantly higher prevalence inthe group consisting of diabetic patients (P<0,05). In diabetic patients, the risk of carryingG191C AA genotype was increased compared to patients with MI (P<0,023) and control(P<0,001)subjects. Our investigation on the total group showed that individuals carryingG191C AA genotype had higher plasma total-cholesterol, LDL and VLDL levels than thecarries of BB (P:0,017, P:0,036, P:0,004) and AB (P:0,027, P:0,034, P:0,007) genotypes. Thefrequencies of G191C B allele were found to be higher in men compared to the women inboth patients with hypercholesterolemia as well as in the total group (p:0,05). All patientswith LVH who had MI were found to be carriers of the G191C B allele and 75% of them hadC69T T allele and %83 of them had C69T C allele. Also all MI patients with DLA were foundto be carriers of the G191C B allele and C69T CT genotype. Four of the patients in the MIgroup have had coronary angiography. All these patients carried G191C A and C69T Calleles. In our study we neither found any relationship between MVK V377I genotypes andplasma lipoprotein levels, nor did we encounter any mutation of the V377I gene in our studygroups. The results of our study, which is the first of its kind on the Turkish populationsuggest that mutations of G191C and C69T genes may be associated with plasma lipoproteinlevels in hypercholesterolemic patiens and Turkish population in contrast to the MVK V377Imutation.Key words: Lipoprotein, Hypercholesterolemia, ABCA1, MVK, PolymorphismThis study was supported by The Research Support Unit of stanbul University as the projectno T-380/08032004.