title: Mutation screening of apical sodium-dependent bile acid transporter (SLC10A2): novel haplotype block including six newly identified variants linked to reduced expression.
abstract: 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 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.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Auerbachstr. 112, 70376, Stuttgart, Germany. Olga.renner@ikp-stuttgart.de
authors.forename: Olga
authors.initials: O
authors.lastname: Renner
authors.forename: Simone
authors.initials: S
authors.lastname: Harsch
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Dietmar M
authors.initials: DM
authors.lastname: Klass
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kratzer
authors.forename: Eduard F
authors.initials: EF
authors.lastname: Stange
mesh_terms: D000328:Adult; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007082:Ileum / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009154:Mutation; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D017931:DNA Primers; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; D014280:Triglycerides; C071908:sodium-bile acid cotransporter; D002784:Cholesterol