Mutation screening of apical sodium-dependent bile acid transporter (SLC10A2): novel haplotype block including six newly identified variants linked to reduced expression

被引:18
作者
Renner, Olga [2 ,3 ]
Harsch, Simone [2 ,3 ]
Schaeffeler, Elke [2 ,3 ]
Schwab, Matthias [2 ,3 ]
Klass, Dietmar M. [4 ]
Kratzer, Wolfgang [4 ]
Stange, Eduard F. [1 ]
机构
[1] Robert Bosch Krankenhaus, Dept Internal Med 1, D-70376 Stuttgart, Germany
[2] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany
[3] Univ Tubingen, D-70376 Stuttgart, Germany
[4] Univ Hosp Ulm, Dept Med 1, D-89081 Ulm, Germany
关键词
GALLSTONE DISEASE; TRANSCRIPTIONAL REGULATION; GENE-EXPRESSION; ILEAL; CHOLESTEROL; COTRANSPORTER; MALABSORPTION; HYPERTRIGLYCERIDEMIA; HOMEOSTASIS; ABSORPTION;
D O I
10.1007/s00439-009-0630-0
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The apical sodium-dependent bile acid transporter (SLC10A2) plays a key role in the reabsorption of luminal bile acids into the enterohepatic circulation. Rare variations in SLC10A2 have been reported to be associated with Crohn's disease, primary bile acid malabsorption and familial hypertriglyceridemia; however, variants associated with reduced SLC10A2 expression have not been reported to date. In this study, we have performed a sequence analysis of SLC10A2 using genomic DNA of 93 individuals. A new haplotype structure was identified including ten variants with complete linkage disequilibrium (LD' = 1.0, r (2) = 1.0) of which six polymorphisms were novel. The sequence variants were confirmed in three independent cohorts (n = 1,290) by a recently established MALDI-TOF MS iPLEX (TM) assay. Remarkably, haplotype carriers with the minor allele exhibited significant reduced ileal SLC10A2 expression on mRNA levels (2.6-fold, P = 0.0009) and protein levels (2.4-fold, P = 0.0157). In future studies a single tag SNP selected of this haplotype block will provide reliable genetic testing to investigate systemically the influence of the SLC10A2 haplotype for disease susceptibility and/or drug response.
引用
收藏
页码:381 / 391
页数:11
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