生物谷報道：德國波恩大學(xué)的研究人員與來自羅馬尼亞的演劇人員共同研究發(fā)現(xiàn)一種基因變異體能顯著增加患膽石的風(fēng)險,。這項研究的相關(guān)文章表發(fā)在7月11日的Hepatology雜志上（Hepatology No. 46, 11 July 2007, DOI 10.1002/hep.21847）。
據(jù)估計,，每10個歐洲人中就有一個人攜帶這種變異體,。對那些受影響者，其一生中發(fā)生膽石的可能性比其他人高出2到3倍,。這種相關(guān)基因攜帶構(gòu)建一種將膽固醇從肝臟運送到膽管的分子泵,。膽固醇石大多數(shù)膽石的形成原料。遺傳的改變似乎能導(dǎo)致這種泵高速,、持久地工作,。
這種突變發(fā)生的基因就是ABCG8基因。它編碼的分子泵將血脂膽固醇從肝臟輸送到膽管,。
研究人員希望他們的發(fā)現(xiàn)將能夠有助于膽石的預(yù)防和治療,。Lammert教授認(rèn)為，這個發(fā)現(xiàn)可能有助于將來對特定患者進(jìn)行藥物治療,，從而避免動手術(shù),。當(dāng)然，這項研究還沒有弄清該基因與膽石的常見問題的關(guān)系,。研究人員推測至少還存在3到4個能增加膽石患病風(fēng)險的基因變異體,。
原始出處:
Hepatology
Early View (Articles online in advance of print)
Published Online: 11 Jul 2007
Original Article
Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol
Frank Grünhage 1§, Monica Acalovschi 2§, Simona Tirziu 2, Maja Walier 3, Thomas F. Wienker 3, Anca Ciocan 2, Ofelia Mosteanu 2, Tilman Sauerbruch 1, Frank Lammert 1 *¶
1Department of Internal Medicine I, University Hospital Bonn, Bonner Forum Biomedizin and University of Bonn, Bonn, Germany
2Department of Medicine III, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
3Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
email: Frank Lammert ([email protected])
*Correspondence to Frank Lammert, Department of Medicine I, University Hospital Bonn, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
The linkage results were presented at the ECHO Meeting, Paris, France, in December 2006 and will be presented at the Annual Meeting of the German Gastroenterological Association (DGVS), Bochum, Germany, in September 2007.
Potential conflict of interest: Nothing to report.
§These authors contributed equally to the study.
¶fax: (49) 228 287 14698
Funded by:
Romanian National Council of Scientific Research in Universities; Grant Number: CNCSIS 1263/2005
German Research Council (Deutsche Forschungsgemeinschaft [DFG]); Grant Number: LA 997/3-1
Deutsche Forschungsgemeinschaft (DFG) Research Group 423 Genetic Epidemiology and Medical Genetics of Complex Diseases
University of Bonn; Grant Number: BONFOR O-107.0083
Ministry of Innovation, Science, Research and Technology (MIWFT) of North-Rhine Westphalia
Federal Ministry of Education and Research
European Cholestasis Study Group (ECHO)
Abstract
Genomewide scans of inbred strains of mice have linked the genes encoding the hepatocanalicular cholesterol transporter ABCG5/G8 to gallstone formation. Five nonsynonymous coding single-nucleotide polymorphisms (SNPs) in the orthologous human genes are associated with differences in serum cholesterol and plant sterol levels. We now tested these ABCG5/G8 SNPs for linkage and association with gallstone susceptibility in humans. Prospectively, we collected data from 178 white individuals with gallbladder stones or history of cholecystectomy in 84 families and from 70 stone-free controls, as confirmed by abdominal ultrasound. We performed nonparametric linkage (NPL) analysis of affected sib pairs (ASPs) and association tests of cases and controls. In ASPs, gallstones were strongly linked to the D19H variant of the ABCG8 gene (NPL score = 7.1; P = 4.6 ?10-13). The risk of gallstones in carriers of the 19H allele was significantly increased in randomly selected cases from the ASP cohort compared to the stone-free controls (OR = 3.018; P = 0.017). Consistent with the mouse model, heterozygosity for the lithogenic ABCG8 allele was associated with gallstones in humans; 21.4% of gallstone patients carried the heterozygous D19H genotype, compared with 8.6% of controls (OR = 2.954; P = 0.026). Conclusion: The linkage and association studies identified the cholesterol transporter ABCG5/G8 as a genetic determinant of gallstone formation, or LITH gene, in humans. The function of this transporter and the results of the genetic study taken together indicate that in gallstone-susceptible carriers of the ABCG8 19H allele, cholesterol cholelithiasis is secondary to increased hepatobiliary cholesterol secretion. (HEPATOLOGY 2007.)
