Promoter variants of the gene for uridine-diphosphate-glucuronosyltransferase 1A1 as modulators of biochemical phenotype and population pharmacogenetic markers.

amil ija en zi ma u ridin -dif osfat -glu kuronoziltransferaza (U GT ) kat a lizuj e glukuronidaciju širokog spektra endobiotika i ksenobiotika. UGT1 familija je kodirana genskim kompleksom UGT1, koji se sastoji od 13 proksimalnih varijabilnih egzona i od 4 zajednička distalna egzona. Alternativnom obradom nastaje više transkripata, među kojima je posebno značajan onaj čiji je produkt UGT1A1 enzim, koji učestvuje u metabolizmu bilirubina i mnogih lekova. Više od 60 varijanti je detektovano u UGT1A1 genu, koje su povezane sa patološkim stanjima. Varijante u TATA boksu promotora UGT1A gena se razlikuje po broju TA ponovaka. Wild type UGT1A1*1 sadrži 6 TA ponovaka (TA6), dok su varijante koje sadrže 5, 7 ili 8 TA ponovaka označene kao UGT1A1*36 (TA5), UGT1A1*28 (TA7) i UGT1A1*37 (TA8). Transkripciona aktivnost promotora je manja što je veći broj ponovaka u odnosu na TA6. Žilberov sindrom (ŽS) je često kliničko stanje koje karakteriše hiperbilirubinemija i ikterus. Uzrokovan je smanjenom aktivnošću UGT1A1 enzima. Najčešće detektovana varijanta koja se nalazi u osnovi ŽS je UGT1A1*28. Njena učestalost varira u različitim populacijama, a kod belaca je prisutna sa 26% do 31%. ŽS je blago oboljenje, ali kao komorbiditet može dovesti do pogrešne dijagnoze bolesti jetre ili hemolitičkih procesa. U tim slučajevima je neophodno potvrditi ili isključiti dijagnozu ŽS molekularnom analizom UGT1A1 gena. Malo se zna o uticaju varijanti promotora UGT1A1 gena na scenario kod oboljenja jetre. Samo u nekoliko slučajeva je kod pacijenata sa hepatitisom C sprovedeno genetičko testiranje na UGT1A1*28, i pošto je dokazana pozitivnost objasnila detektovan nivo bilirubina, pacijenti su lečeni po standardnom protokolu i postigli su kontinuiran virusološki odgovor. Kod hemolitičkih anemija, kao što je talasemija, takođe je pokazano da je nivo bilirubina povezan sa pojavom komplikacija. Stoga se varijante u UGT1A1 genu tretiraju kao tercijarni modifikatori kod beta- talasemijskih sindroma...The uridine-diphosphate-glucuronosyltransferase enzyme family (UGT) catalyse the glucuronidation of a wide range of endobiotics and xenobiotics. The UGT1 family is encoded by the UGT1 gene complex consisting of 13 proximal variable exons and 4 common distal exons. Alternative splicing gives multiple transcripts, among which the UGT1A1 enzyme product, which is involved in the metabolism of bilirubin and many drugs, is particularly important. More than 60 variantshave been detected in the UGT1A1 gene, which are associated with pathological conditions. Variants in the TATA box of the UGT1A gene promoter differ in the number of TA repeats. Wild type UGT1A1 contains 6 TA repeats (TA6), while variants with 5, 7 or 8 TA repeats are designated UGT 1A1*36 (TA5), UGT1A1*28 (TA7) and UGT1A1*37 (TA8). The transcription activity of the promoter decreased accordingly to higher number of repeats compared to TA6. Gilbert's syndrome (GS) is often a clinical condition characterized by hyperbilirubinaemia and icterus. It is caused by a reduced activity of UGT1A1 enzymes. The most commonly detected variant found in the basis of GS is UGT1A1*28. Its frequency varies in different populations, and whites are present from 26% to 31%. GS is a mild illness, but as a comorbidity it can lead to a wrong diagnosis of liver disease or hemolytic processes. In these cases, it is necessary to confirm or exclude the diagnosis of GS by molecular analysis of the UGT1A1 gene. The effect of variants of UGT1A1 gene on the development in liver disease is poorly known. In only a few cases, genetic testing for UGT1A1*28 was performed in patients with hepatitis C, and since the confirmed positivity explained the detected level of bilirubin, patients were treated by standard protocol and achieved a continious viral response. In hemolytic anemia, such as thalassemia, it has also been shown that the level of bilirubin is associated with the numerous of complications. Therefore, the TA promoter variants in the UGT1A1 gene are treated as tertiary modifiers in beta-talasemia syndromes..