Olga Renner

Publications of Olga Renner

• MALDI-TOF mass spectrometry screening of cholelithiasis risk markers in the gene of HNF1alpha.

  Authors: Dominique Richter, Simone Harsch, André Strohmeyer, Satoko Hirobe-Jahn, Silke Schimmel, Olga Renner, Oliver Müller, Elke Schäffeler, Wolfgang Kratzer, Matthias Schwab, Eduard F Stange

  Journal of proteomics. 05/2012;

  In recent years MALDI-TOF MS gained in importance for high-throughput DNA analysis. In the present study this technique was used for the pathogenetic analysis of gallstone disease. The intestinalIn recent years MALDI-TOF MS gained in importance for high-throughput DNA analysis. In the present study this technique was used for the pathogenetic analysis of gallstone disease. The intestinal apical sodium-dependent bile acid transporter (ASBT) shows a genetic association with gallstone disease. ASBT has 3 binding sites in its 5'UTR for hepatocyte nuclear factor 1alpha (HNF1alpha). We hypothesized that genetic alterations in the HNF1alpha gene could influence ASBT expression. The gene HNF1alpha was sequenced in 46 Stuttgart random samples, composed of 16 controls and 30 gallstone patients. Subsequently, two independent cohorts (Stuttgart: 67 gallstones carriers, 109 controls, Leutkirch: 112 gallstone carriers, 99 controls) were screened by MALDI-TOF MS. The subjects were further divided to gender and weight. 24 known polymorphisms and two novel SNPs in the 3'UTR of HNF1alpha were detected (c.*220G>A and c.*1151G>A). After gender-specific sub-division of the pooled cohorts, 4 SNPs result in significant differences between male gallstone carriers and male controls (Stuttgart/Leutkirch: rs2255531 OR=2.78; p=0.006, rs1169288 OR=2.13; p=0.032 rs7310409 OR=2.34; p=0.025 and rs1169294 OR=2.13; p=0.031). Two novel variants in the 3'UTR of HNF1alpha were detected and four SNPs of HNF1alpha show a significant association to cholelithiasis in male gallstone patients. This article is part of a Special Issue entitled: Genome regulation.

• Effects of SLC10A2 variant rs9514089 on gallstone risk and serum cholesterol levels- meta-analysis of three independent cohorts.

  Authors: Anke Tönjes, Henning Wittenburg, Jan Halbritter, Olga Renner, Simone Harsch, Eduard F Stange, Frank Lammert, Michael Stumvoll, Peter Kovacs

  BMC medical genetics. 11/2011; 12:149.

  Recently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis inRecently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis in humans. Here we assessed the effects of rs9514089 on gallstone risk and related phenotypes of the metabolic syndrome in the self-contained population of Sorbs (183 cases with gallstones/826 controls). Furthermore, we performed a meta-analysis for effects of rs9514089 on susceptibility for cholelithiasis in three independent cohorts (Stuttgart: 56 cases/71 controls, Aachen: 184 cases/184 controls and Sorbs). There was no significant association of rs9514089 with gallstone risk, serum lipid parameters and BMI in the Sorbs and in the meta-analysis of all three cohorts (p > 0.05). There was an effect trend in the subgroup of lean subjects but based on different effect directions in the three cohorts there was no significant association in the meta-analysis. We were not able to replicate the effect of rs9514089 on gallstone risk in the Sorbs. Further analyses in larger cohorts are required to finally assess the role of genetic variants in SLC10A2 in human gallstone development and lipid metabolism.

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

  Authors: Olga Renner, Simone Harsch, Elke Schaeffeler, Matthias Schwab, Dietmar Klass, Wolfgang Kratzer, Eduard Stange

  Human genetics. 02/2009;

  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 beenThe 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 iPLEXtrade mark 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.

• A Variant of the SLC10A2 Gene Encoding the Apical Sodium-Dependent Bile Acid Transporter Is a Risk Factor for Gallstone Disease.

  Authors: Olga Renner, Simone Harsch, Elke Schaeffeler, Stefan Winter, Matthias Schwab, Marcin Krawczyk, Jonas Rosendahl, Henning Wittenburg, Frank Lammert, Eduard F Stange

  PloS one. 01/2009; 4(10):e7321.

  BACKGROUND: Cholelithiasis is a multifactorial process and several mechanisms of gallstone formation have been postulated. As one of these mechanisms, a decreased expression of the ileal apicalBACKGROUND: Cholelithiasis is a multifactorial process and several mechanisms of gallstone formation have been postulated. As one of these mechanisms, a decreased expression of the ileal apical sodium-dependent bile acid transporter gene SLC10A2 in gallstone carriers was described previously. In this study the SLC10A2 gene was investigated to identify novel genetic variants and their association with gallstone formation. METHODOLOGY/PRINCIPAL FINDINGS: Study subjects were selected with the presence or absence of gallstones confirmed by ultrasound and medical history. Genomic DNA was obtained from blood leukocytes. Sequence analysis was performed of all six exonic and flanking regions as well as of 2,400 base pairs of the SLC10A2 promoter in a cohort of gallstone carriers and control subjects from Stuttgart, Germany. Genotype frequencies of newly identified genetic variants (n = 6) and known single nucleotide polymorphisms (n = 24) were established using MALDI-TOF mass spectrometry. Six new genetic variants were found within the SLC10A2 gene. Although none of the variants was linked to gallstone disease in the Stuttgart cohort overall, the minor allele of SNP rs9514089 was more prevalent in male non-obese gallstone carriers (p = 0.06680, OR = 11.00). In a separate population from Aachen, Germany, the occurrence of rs9514089 was two-fold higher in gallstone patients (22%) than in corresponding controls (11%) (p = 0.00995, OR = 2.19). In the pooled Aachen/Stuttgart cohort rs9514089 was highly significantly linked to cholelithiasis (p = 0.00767, OR = 2.04). A more frequent occurrence was observed for male gallstone carriers (22%) compared to controls (9%) (p = 0.01017, OR = 2.99), for the total normal weight group (p = 0.00754, OR = 2.90), and for male non-obese gallstone patients (p = 0.01410, OR = 6.85). Moreover, for the minor allele of rs9514089 an association with low plasma cholesterol levels was found especially in gallstone carriers (p = 0.05). CONCLUSIONS/SIGNIFICANCE: We have identified SLC10A2 as a novel susceptibility gene for cholelithiasis in humans. Comprehensive statistical analysis provides strong evidence that rs9514089 is a genetic determinant especially in male non-obese gallstone carriers. The minor allele of rs9514089 is related to differences in plasma cholesterol levels among the subjects.

• Diminished Expression of Apical Sodium-Dependent Bile Acid Transporter in Gallstone Disease Is Independent of Ileal Inflammation.

  Authors: Arthur Holzer, Simone Harsch, Olga Renner, André Strohmeyer, Silke Schimmel, Jan Wehkamp, Peter Fritz, Eduard F Stange

  Digestion. 11/2008; 78(1):52-59.

  Background: Non-obese gallstone patients exhibit a diminished expression of apical sodium-dependent bile acid transporter (ASBT) in terminal ileum. Crohn's ileitis demonstrates a significantBackground: Non-obese gallstone patients exhibit a diminished expression of apical sodium-dependent bile acid transporter (ASBT) in terminal ileum. Crohn's ileitis demonstrates a significant downregulation of this transporter. Aim: To test whether subclinical ileal inflammation contributes to gallstone disease. Methods: Biopsies from terminal ileum of female subjects with gallstone disease (n = 7), active Crohn's disease (n = 17) and controls (n = 22) were investigated. mRNA expression of ASBT, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-8, c-jun and c-fos was measured. c-jun and c-fos protein levels were determined and hematoxylin and eosin staining was applied for ileal histology. Results: ASBT expression was comparably low both in gallstone (47% of controls, p = 0.0093) and Crohn's disease (42% of controls, p = 0.0008). In gallstone disease there was a non-significant trend towards elevated TNF-alpha and IL-1beta, but all cytokines were increased in active Crohn's disease. c-jun and c-fos were slightly diminished in patients with gallstones. Neither cytokines nor transcription factors correlated significantly with ASBT. The gallstone-associated ileal biopsies exhibited no histological inflammation. Conclusion: Although the expression of ASBT was similarly diminished in both gallstone and Crohn's disease, subclinical ileal inflammation does not appear to be relevant in gallstone patients. The mechanisms of transcriptional repression of ASBT in both diseases are apparently different.

• Reduced ileal expression of organic solute transporter alpha and beta (OSTalpha -OSTbeta ) in non-obese gallstone disease.

  Authors: Olga Renner, Simone Harsch, André Strohmeyer, Silke Schimmel, Eduard F Stange

  Journal of lipid research. 06/2008;

  Cholelithiasis is a multifactorial process and several mechanisms have been postulated. A decreased expression of the ileal apical sodium-dependent bile acid transporter (ASBT) and of the cytosolicCholelithiasis is a multifactorial process and several mechanisms have been postulated. A decreased expression of the ileal apical sodium-dependent bile acid transporter (ASBT) and of the cytosolic ileal lipid binding protein (ILBP) was recently described in female non-obese patients. The role of the recently identified organic solute transporter (OSTa-OSTss) in gallstone pathogenesis remains still unclear. Therefore we performed analysis of OSTa-OSTss in gallstone patients, regarding body weight. Ileal mucosal biopsies were collected during routinely colonoscopy from female gallstone carriers (n=19) and controls (n=34). OSTa-OSTss mRNA expression was measured using the LightCycler sequence detection system; protein was analyzed by immunohistochemistry and Western blot. The mRNA expression of OSTa-OSTss was significantly (OSTa: 3.3-fold, p=0.006; OSTss: 2.6-fold, p=0.03) reduced in normal weight but not overweight gallstone carriers compared to controls. OSTa-OSTss protein levels also showed a reduction by 40-67%. The expression of OSTa-OSTss correlated positively with ASBT (r=0.65; 0.58, respectively), ILBP (r=0.77; 0.67), the farnesoid X receptor (FXR) (r=0.58; 0.50). Fibroblast growth factor-19 (FGF-19) showed a 2.8-fold (p=0.06) and liver receptor homolog-1 (LRH-1) a 2.0-fold reduction (p=0.04) in non-obese patients. In conclusion, an impaired function of all three ileal bile acid transporters may lead to low ileal bile acid reabsorption, an altered bile acid pool composition and therefore contribute to the formation of gallstones in non-obese.

• Increased association with detergent-resistant membranes/lipid rafts of apically targeted mutants of the interleukin-6 receptor gp80.

  Authors: Deborah M Buk, Olga Renner, Lutz Graeve

  European journal of cell biology. 11/2005; 84(10):819-31.

  Interleukin (IL)-6 is an important cytokine in inflammatory processes, differentiation and growth. The IL-6 receptor complex comprises the specific IL-6 receptor (gp80) and two molecules of theInterleukin (IL)-6 is an important cytokine in inflammatory processes, differentiation and growth. The IL-6 receptor complex comprises the specific IL-6 receptor (gp80) and two molecules of the signal tranducing component gp130 which transduces the signal into the nucleus via the Jak-STAT pathway. Both, gp80 and gp130 are sorted preferentially to the basolateral membrane of polarised Madin-Darby canine kidney (MDCK) cells. Previously, we have shown that gp130 partially localises to detergent-resistant membranes (DRMs)/lipid rafts and that lipid raft integrity is crucial for signalling to occur. Here we now demonstrate that wild-type gp80 is associated with DRMs only to a minor extent. However, gp80 mutants which lack parts of the cytoplasmic domain and therefore are more apically expressed than the wild type show an increased affinity for the liquid-ordered membrane domain. Studies with non-polarised MDCK cells suggest that the lipid raft association of the different mutants of gp80 precedes the establishment of cell polarity. Our findings suggest that lipid rafts play a role in the sorting of apically targeted gp80.