Kronik hepatit ve sirozlu vakalarda COX-2 gen polimorfizminin fibrozis gelişimindeki önemi
Importance of COX-2 gene polymorphism to development of fibrosis in patients with cirrhosis and chronic hepatitis
Yazar: BURHAN ÖZDİL
Danışman: PROF. DR. HİKMET AKKIZ
Çukurova Üniversitesi / Tıp Fakültesi / Gastroenteroloji Ana Bilim Dalı
Derece: Tıpta Uzmanlık, 2008
Konu: Gastroenteroloji = Gastroenterology

Özet:
Kronik Hepatit ve Sirozlu Vakalarda COX-2 Gen Polimorfizminin Fibrozis Gelişimindeki ÖnemiAmaç: Kronik hepatit ve sirozlu vakalarda COX-2 geninin -765 G>C ve -8473 T>C genetik polimorfizmlerinin nekroinflamatuar aktivite ve fibrozis üzerine olan etkilerini araştırmak.Gereç ve Yöntemler: Çalışmaya HBV ve HCV'ye sekonder kronik hepatit olduğu bilinen ve karaciğer (KC) biyopsileri yapılmış 104 (51/53, K/E) hasta alındı. Hastaların yaş ortalaması (45±15) idi. Vakalardan 54 tanesi HCV, 50 tanesi HBV etiyolojili idi. COX gen polimorfizmi çalışılmak üzere 5'er cc kan örnekleri alındı. KC biyopsi örnekleri Knodell Histolojik Aktivite Skoruna (HAİ) göre değerlendirildi. Biyopsi sonuçlarına göre vakalar fibrozis 1, 3 ve 4 olarak belirlendi. Fibrozis 4 olanlar siroz safhasında olan vakalardı. Buna göre vakaların 75 tanesi kronik hepatit ve 29 tanesi sirozdu. Yine Knodell skoruna göre HAİ'leri hesaplandı. Polimorfizm saptanan olgularla saptanmayanlar arasında HAİ ve fibrosiz skorları kıyaslandı. Sonuçların değerlendirilmesi için Student' t- test (devamlı değişkenler için), X2 test (kategorik değişkenler için) ve lojistik regresyon analizi kullanıldı.Bulgular: HBV ve HCV'li gruplarda HAİ ve Fibrozis skorları arasında fark yoktu (Sırasıyla p<0,19, p<0,11). COX-2 -8473 bölgesinde TT, TC ve CC olmak üzere üç genotip mevcuttu. Bu genotipi taşıyan hastaların dağılımı TT %52,9, TC % 33,7 ve CC %13,5 idi. Fibrosiz skorları TT' de 2,9±0,9, TC'de 2,7±1,2 ve CC'de 1,8±1,2 idi (p<0,008). HAİ'leri sırasıyla 9,6±1,7, 8,4±2,7, 6,2±2,9 olarak belirlendi (p<0,0001). Fibrozis 1-3 arasında TT' nin riski 10 kat (p<0,003, OR:10,0, GA:2,2-44,9 %95), fibrsiz 1-4 arasında riski 8 kat (p<0,019, OR:8,0, GA:1,4-45,4 %95) artırdığı bulundu. COX-2 -765 bölgesinde vakaların dağılımı GG %66,3, GC:26,0 ve CC %7,7 idi. Fibrozis skorları GG'de 2,9±09, GC'de 2,6±1,3 ve CC'de 1,2±0,7 idi (p<0,0001). HAİ'leri sırasıyla 9,3±2,0, 8,5±2,7, 5,2±2,5 olarak belirlendi (0,0001). CC genotiplilerde hiç sirotik vaka yoktu. Fibrosi 1-3 grupları arasında GG'nin fibrosiz riskini 22,16 kat artırdığı bulundu (p<0,006, OR:22,16, GA:2,4-198,7 %95)Sonuç: Viral etiyolojik ajanlar arasında KC fibrozis evresi ve HAİ arasında fark yoktur. 8473 T ve 765 G allelleri nekroinflamatuar aktivite ve fibrozis riskini 8473 C ve 765 C alleli olanlara göre artırmıştır. Buna göre C allelleri nekroinflmasyon ve fibrozise göre koruyucu özellikte olabilir.Anahtar Sözcükler: COX-2 8473 T>C, 765 G>C gen polimorfizmi, karaciger fibrozis, hepatik aktivite indeksi, kronik hepatit.

Abstract:
Importance of COX-2 Gene Polymorphism to Development of Fibrosis in Patients with Cirrhosis and Chronic HepatitisAim: The aim of this study was to investigate impact of promoter polymorphisms of COX-2 -765 G>C and -8473 T>C on necroinflammatory activity and fibrosis.Materials and Methods: Promoter polymorphisms of COX-2 -765 G>C and -8473 T>C was studied in 104 patients (51 female, 53 male) who infected with hepatitis B or hepatitis C. Median age of patients were 45±15. 54 patients were infected with hepatitis C. 50 patients were infected with hepatitis B. Liver biopsy was evaluated according to Knodell histological activity score. According to the liver biopsy results the patients were categorized including fibrosis 1, 3 and 4. All of the patients in fibrosis 4 category was the in cirrhosis stage. In respect of this, 75 patients were in the chronic hepatitis stage and 29 patients were in the cirrhosis stage. In addition to this histological activity score was determined by Knodell score. A 5 mL sample of venous blood was collected from each subject into a test tube containing EDTA as anticoagulant. Differences in the distributions of demographic characteristics between patients were evaluated using the Student?s t-test (for continuous variables) and ?2 test (for categorical variables). The associations between COX-2 polymorphisms genotypes and the risk of fibrosis and HAI were estimated by logistic regression analyses.Results: There were not statistically significant difference in the fibrosis and histological activity scores of hepatitis B and C groups. The genotypic frequencies in the patients were TT 52.9%, TC 33.7% and CC 13.5% in -8473 COX-2 polymorphism. In -8473 TT, TC and CC genotypes group, fibrosis score were 2.9±0.9, 2.7±1.2 and 1.8±1.2 respectively. Difference of fibrosis scores of -8473 genotypes group were statistically significant (p=0.008). Histological activity scores were calculated 9,6±1,7, 8,4±2,7, 6,2±2,9 in -8473 TT, TC and CC genotypes respectively (p=0,0001). Compared with COX-2 -8473 the TC and CC genotypes, TT genotype was associated with an increased risk of fibrosis in the logistic regression analysis (p=0,003, OR=10.0, 95% CI =2,2-44,9) between fibrosis group 1 and 3. Between fibrosis group 1 and 4, COX-2 -8473 TT genotype was increased fibrosis risk 8-fold when compared with TC and CC genotypes (p=0,019, OR = 8.0, 95% CI =1,4-45,4). In the COX-2 -765 polymorphism genotypic frequencies in the patients were the following GG 66,3%, GC 26,0%, and CC 7,7%. In -8473 GG, GC and CC genotypes group fibrosis score were 2.9±0.9, 2,6±1,3 and 1,2±0,7 respectively (p=0,0001). Histological activity scores were calculated 9,3±2,0, 8,5±2,7, 5,2±2,5 in -8473 TT, TC and CC genotypes respectively (p=0,0001). We did not find CC genotype in COX-2 -765 G>C polymorphism. Compared with COX-2 -765 the C/C and GC genotypes, G/G genotype was associated with an increased risk of fibrosis in the logistic regression analysis (p=0,006, OR = 22,16 95% CI =2,4-198,7) between fibrosis group 1 and 3.Conclusion: Viral etiologic factors fibrosis score and histological activity score were not statistically different. Polymorphisms of COX-2 -8473 T and -765 G allels may increase risk of both the liver inflammation and the liver fibrosis development when compared to-8473 C and -765 C allels. In addition to this, 8473 C and -765 C allels may have protective effect on liver inflammation and the liver fibrosis development.Key Words: COX-2 8473 T>C, 765 G>C genetic polymorphism, Liver fibrosis, Hepatic activity index, chronic hepatitis