生物谷报道：德国波恩大学的研究人员与来自罗马尼亚的演剧人员共同研究发现一种基因变异体能显著增加患胆石的风险。这项研究的相关文章表发在7月11日的Hepatology杂志上（Hepatology No. 46, 11 July 2007, DOI 10.1002/hep.21847）。
据估计，每10个欧洲人中就有一个人携带这种变异体。对那些受影响者，其一生中发生胆石的可能性比其他人高出2到3倍。这种相关基因携带构建一种将胆固醇从肝脏运送到胆管的分子泵。胆固醇石大多数胆石的形成原料。遗传的改变似乎能导致这种泵高速、持久地工作。
这种突变发生的基因就是ABCG8基因。它编码的分子泵将血脂胆固醇从肝脏输送到胆管。
研究人员希望他们的发现将能够有助于胆石的预防和治疗。Lammert教授认为，这个发现可能有助于将来对特定患者进行药物治疗，从而避免动手术。当然，这项研究还没有弄清该基因与胆石的常见问题的关系。研究人员推测至少还存在3到4个能增加胆石患病风险的基因变异体。
原始出处:
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 (frank.lammert@ukb.uni-bonn.de)
*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.)
