01.20.12

Unraveling the Regulatory Mechanisms Underlying Tissue-Dependent Genetic Variation of Gene Expression

Unraveling the Regulatory Mechanisms Underlying Tissue-Dependent Genetic Variation of Gene Expression
Jingyuan Fu, Marcel G. M. Wolfs, Patrick Deelen, Harm-Jan Westra, Rudolf S. N. Fehrmann, Gerard J. te Meerman, Wim A. Buurman, Sander S. M. Rensen, Harry J. M. Groen, Rinse K. Weersma, Leonard H. van den Berg, Jan Veldink, Roel A. Ophoff, Harold Snieder, David van Heel, Ritsert C. Jansen, Marten H. Hofker, Cisca Wijmenga, Lude Franke

It is known that genetic variants can affect gene expression, but it is not yet completely clear through what mechanisms genetic variation mediate this expression. We therefore compared the cis-effect of single nucleotide polymorphisms (SNPs) on gene expression between blood samples from 1,240 human subjects and four primary non-blood tissues (liver, subcutaneous, and visceral adipose tissue and skeletal muscle) from 85 subjects. We characterized four different mechanisms for 2,072 probes that show tissue-dependent genetic regulation between blood and non-blood tissues: on average 33.2% only showed cis-regulation in non-blood tissues; 14.5% of the eQTL probes were regulated by different, independent SNPs depending on the tissue of investigation. 47.9% showed a different effect size although they were regulated by the same SNPs. Surprisingly, we observed that 4.4% were regulated by the same SNP but with opposite allelic direction. We show here that SNPs that are located in transcriptional regulatory elements are enriched for tissue-dependent regulation, including SNPs at 3′ and 5′ untranslated regions (P = 1.84×10−5 and 4.7×10−4, respectively) and SNPs that are synonymous-coding (P = 9.9×10−4). SNPs that are associated with complex traits more often exert a tissue-dependent effect on gene expression (P = 2.6×10−10). Our study yields new insights into the genetic basis of tissue-dependent expression and suggests that complex trait associated genetic variants have even more complex regulatory effects than previously anticipated.

12.7.11

Treatment with high-dose simvastatin inhibits geranylgeranylation in AML blast cells in a subset of AML patients

Treatment with high-dose simvastatin inhibits geranylgeranylation in AML blast cells in a subset of AML patients.
Karen van der Weide, Susan D.P.W.M. de Jonge-Peeters, Gerwin Huls, Rudolf S.N. Fehrmann, Jan Jacob Schuringa, Folkert Kuipers, Elisabeth G.E. de Vries, Edo Vellenga

It is currently unknown whether the in vitro effects observed with statins in acute myeloid leukemia (AML) cells, including lowering of cholesterol, inhibition of isoprenylation, and sensitization to chemotherapy also occur in vivo. Therefore, AML mononuclear cells (MNCs) were isolated from 12 patients before and after 7 days of high-dose (7.5-15 mg/kg/day) simvastatin treatment. Parallel mouse studies were performed to have besides AML cells also access to liver tissue, a major target of statins. Serum cholesterol levels were lowered by simvastatin in all patients, however, only limited changes in the mRNA expression of cholesterol metabolism genes were seen in patient and mouse MNCs compared to murine liver cells. Still, 2 out of 7 patients displayed an increased in vitro chemosensitivity of their AML cells upon simvastatin treatment. Gene set enrichment analysis on microarray data of AML patient cells and Western blot analysis for the isoprenylated proteins DnaJ and Rap1 on murine and AML patient MNCs demonstrated that in vivo simvastatin treatment resulted in inhibition of geranylgeranylation in murine MNCs and in a subset of patient AML MNCs. In summary, our data demonstrate that simvastatin treatment results in chemosensitization and inhibition of geranylgeranylation in AML cells of a subset of patients.

08.5.11

Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA.

Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA.
Rudolf S. N. Fehrmann, Ritsert C. Jansen, Jan H. Veldink, Harm-Jan Westra, Danny Arends, Marc Jan Bonder, Jingyuan Fu, Patrick Deelen, Harry J. M. Groen, Asia Smolonska, Rinse K. Weersma, Robert M. W. Hofstra, Wim A. Buurman, Sander Rensen, Marcel G. M. Wolfs, Mathieu Platteel, Alexandra Zhernakova, Clara C. Elbers, Eleanora M. Festen, Gosia Trynka, Marten H. Hofker, Christiaan G. J. Saris, Roel A. Ophoff, Leonard H. van den Berg, David A. van Heel, Cisca Wijmenga, Gerard J. te Meerman, Lude Franke

For many complex traits, genetic variants have been found associated. However, it is still mostly unclear through which downstream mechanism these variants cause these phenotypes. Knowledge of these intermediate steps is crucial to understand pathogenesis, while also providing leads for potential pharmacological intervention. Here we relied upon natural human genetic variation to identify effects of these variants on trans-gene expression (expression quantitative trait locus mapping, eQTL) in whole peripheral blood from 1,469 unrelated individuals. We looked at 1,167 published trait- or disease-associated SNPs and observed trans-eQTL effects on 113 different genes, of which we replicated 46 in monocytes of 1,490 different individuals and 18 in a smaller dataset that comprised subcutaneous adipose, visceral adipose, liver tissue, and muscle tissue. HLA single-nucleotide polymorphisms (SNPs) were 10-fold enriched for trans-eQTLs: 48% of the transacting SNPs map within the HLA, including ulcerative colitis susceptibility variants that affect plausible candidate genes AOAH and TRBV18 in trans. We identified 18 pairs of unlinked SNPs associated with the same phenotype and affecting expression of the same trans-gene (21 times more than expected, P,10216). This was particularly pronounced for mean platelet volume (MPV): Two independent SNPs significantly affect the well-known blood coagulation genes GP9 and F13A1 but also C19orf33, SAMD14, VCL, and GNG11. Several of these SNPs have a substantially higher effect on the downstream trans-genes than on the eventual phenotypes, supporting the concept that the effects of these SNPs on expression seems to be much less multifactorial. Therefore, these trans-eQTLs could well represent some of the intermediate genes that connect genetic variants with their eventual complex phenotypic outcomes. (PLoS Genetics 2011)

06.19.11

MixupMapper: correcting sample mix-ups in genome-wide datasets increases power to detect small genetic effects.

MixupMapper: correcting sample mix-ups in genome-wide datasets increases power to detect small genetic effects.
H-J Westra, R.C. Jansen, R.S.N. Fehrmann, G.J. te Meerman, D. van Heel, C. Wijmenga and L. Franke.

Motivation: Sample mix-ups can arise during sample collection, handling, genotyping or data management. It is unclear how often sample mix-ups occur in genome-wide studies, as there currently are no post-hoc methods that can identify these mix-ups in unrelated samples. We have therefore developed an algorithm (MixupMapper) that can both detect and correct sample mix-ups in genome-wide studies that study gene expression levels.

Results: We applied MixupMapper to five publicly available human genetical genomics datasets. On average, 3% of all analyzed samples had been assigned incorrect expression phenotypes: in one of the datasets 23% of the samples had incorrect expression phenotypes. The consequences of sample mix-ups are substantial: when we corrected these sample mix-ups, we identified on average 15% more significant cis-expression quantitative trait loci (cis-eQTLs). In one dataset, we identified three times as many significant cis-eQTLs after correction. Furthermore, we show through simulations that sample mix-ups can lead to an underestimation of the explained heritability of complex traits in genome-wide association datasets.

Availability and implementation: MixupMapper is freely available at http://www.genenetwork.nl/mixupmapper/

03.27.11

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL and CARD9.

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL and CARD9.
Janse M, Lamberts LE, Franke L, Raychaudhuri S, Ellinghaus E, Boberg KM, Melum E, Folseraas T, Schrumpf E, Bergquist A, Björnsson E, Fu J, Westra HJ, Groen HJ, Fehrmann RS, Smolonska J, van den Berg LH, Ophoff RA, Porte RJ, Weismüller TJ, Wedemeyer J, Schramm C, Sterneck M, Günther R, Braun F, Vermeire S, Henckaerts L, Wijmenga C, Ponsioen CY, Schreiber S, Karlsen TH, Franke A, Weersma RK.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1186 PSC patients and 1748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1491 controls from the Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls) and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (p value 4.12×10(-4) ), 4q27 (p value 4.10×10(-5) ) and 9q34 (p value 8.41×10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (p <0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify non-random, evidence-based links we used GRAIL analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9 and REL as novel candidates. Conclusion: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2 and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors. (Hepatology 2011.).

03.8.11

Involvement of the TGF-β and β-Catenin Pathways in Pelvic Lymph Node Metastasis in Early-Stage Cervical Cancer

Involvement of the TGF-β and β-Catenin Pathways in Pelvic Lymph Node Metastasis in Early-Stage Cervical Cancer.
Maartje G. Noordhuis, Rudolf S.N. Fehrmann, G. Bea A. Wisman, Esther R. Nijhuis, Jelmer J. van Zanden, Perry D. Moerland, Emiel Ver Loren van Themaat, Haukeline H. Volders, Mirjam Kok, Klaske A. ten Hoor, Harry Hollema, Elisabeth G.E. de Vries, Geertruida H. de Bock, Ate G.J. van der Zee, and Ed Schuuring

Purpose: Presence of pelvic lymph node metastases is the main prognostic factor in early-stage cervical cancer patients, primarily treated with surgery. Aim of this study was to identify cellular tumor pathways associated with pelvic lymph node metastasis in early-stage cervical cancer.

Experimental Design: Gene expression profiles (Affymetrix U133 plus 2.0) of 20 patients with negative (N0) and 19 with positive lymph nodes (N+), were compared with gene sets that represent all 285 presently available pathway signatures. Validation immunostaining of tumors of 274 consecutive early-stage cervical cancer patients was performed for representatives of the identified pathways.

Results: Analysis of 285 pathways resulted in identification of five pathways (TGF-β, NFAT, ALK, BAD, and PAR1) that were dysregulated in the N0, and two pathways (β-catenin and Glycosphingolipid Biosynthesis Neo Lactoseries) in the N+ group. Class comparison analysis revealed that five of 149 genes that were most significantly differentially expressed between N0 and N+ tumors (P < 0.001) were involved in β-catenin signaling (TCF4, CTNNAL1, CTNND1/p120, DKK3, and WNT5a). Immunohistochemical validation of two well-known cellular tumor pathways (TGF-β and β-catenin) confirmed that the TGF-β pathway (positivity of Smad4) was related to N0 (OR: 0.20, 95% CI: 0.06–0.66) and the β-catenin pathway (p120 positivity) to N+ (OR: 1.79, 95%CI: 1.05–3.05).

Conclusions: Our study provides new, validated insights in the molecular mechanism of lymph node metastasis in cervical cancer. Pathway analysis of the microarray expression profile suggested that the TGF-β and p120-associated noncanonical β-catenin pathways are important in pelvic lymph node metastasis in early-stage cervical cancer.

02.7.11

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.
Carl A Anderson, Gabrielle Boucher, Charlie W Lees, Andre Franke, Mauro D’Amato, Kent D Taylor, James C Lee, Philippe Goyette, Marcin Imielinski, Anna Latiano, Caroline Lagacé, Regan Scott, Leila Amininejad, Suzannah Bumpstead, Leonard Baidoo, Robert N Baldassano, Murray Barclay, Theodore M Bayless, Stephan Brand, Carsten Büning, Jean-Frédéric Colombel, Lee A Denson, Martine De Vos, Marla Dubinsky, Cathryn Edwards, David Ellinghaus, Rudolf S N Fehrmann, James A B Floyd, Timothy Florin, Denis Franchimont, Lude Franke, Michel Georges, Jürgen Glas, Nicole L Glazer, Stephen L Guthery, Talin Haritunians, Nicholas K Hayward, Jean-Pierre Hugot, Gilles Jobin, Debby Laukens, Ian Lawrance, Marc Lémann, Arie Levine, Cecile Libioulle, Edouard Louis, Dermot P McGovern, Monica Milla, Grant W Montgomery, Katherine I Morley, Craig Mowat, Aylwin Ng, William Newman, Roel A Ophoff, Laura Papi, Orazio Palmieri, Laurent Peyrin-Biroulet, Julián Panés, Anne Phillips, Natalie J Prescott, Deborah D Proctor, Rebecca Roberts, Richard Russell, Paul Rutgeerts, Jeremy Sanderson, Miquel Sans, Philip Schumm, Frank Seibold, Yashoda Sharma, Lisa A Simms, Mark Seielstad, A Hillary Steinhart, Stephan R Targan, Leonard H van den Berg, Morten Vatn, Hein Verspaget, Thomas Walters, Cisca Wijmenga, David C Wilson, Harm-Jan Westra, Ramnik J Xavier, Zhen Z Zhao, Cyriel Y Ponsioen, Vibeke Andersen, Leif Torkvist, Maria Gazouli, Nicholas P Anagnou, Tom H Karlsen, Limas Kupcinskas, Jurgita Sventoraityte, John C Mansfield, Subra Kugathasan, Mark S Silverberg, Jonas Halfvarson, Jerome I Rotter, Christopher G Mathew, Anne M Griffiths, Richard Gearry, Tariq Ahmad, Steven R Brant, Mathias Chamaillard, Jack Satsangi, Judy H Cho, Stefan Schreiber, Mark J Daly, Jeffrey C Barrett, Miles Parkes, Vito Annese, Hakon Hakonarson, Graham Radford-Smith, Richard H Duerr, Séverine Vermeire, Rinse K Weersma & John D Rioux

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10−8), increasing the number of ulcerative colitis–associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn’s disease and ulcerative colitis.

01.11.11

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer.
D M Heijink, R S N Fehrmann, E G E de Vries, J J Koornstra, D Oosterhuis, A G J van der Zee, J H Kleibeuker and S de Jong.

Comparing normal colorectal mucosa and adenomas focusing on deregulated pathways obtains insight into the biological processes of early colorectal carcinogenesis. Publicly available microarray expression data from 26 normal mucosa and 47 adenoma samples were analyzed. Biological pathways enriched in adenomas were identified with Gene Set Enrichment Analysis (GSEA). The analysis revealed 10, 11 and 16 gene sets distinguishing adenomas from normal mucosa according to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Map Annotator and Pathway Profiler (GenMAPP) and Biocarta databases, respectively. Biological pathways known to be involved in colon carcinogenesis such as cell cycle (P=0.002) and Wnt signaling (P=0.007) were enriched in adenomas. In addition, we found enrichment of novel pathways such as retinoblastoma (Rb) pathway (P=0.002), Src pathway (P=0.004), folate biosynthesis (P=0.019) and Hedgehog signaling (P=0.037) in adenomas. Microarray results for Rb and Src pathway genes were validated by quantitative reverse transcriptase–polymerase chain reaction (qRT–PCR) on mRNA isolated from an independent set of adenoma and normal colon samples. A high correlation between microarray data and qRT–PCR expression data was found. The relevance of targeting of identified pathways was shown using the Rb pathway inhibitors roscovitine and PD-0332991 and the Src pathway inhibitor dasatinib. All inhibitors used induced cell growth reduction in adenoma cells. This study shows a bioinformatical and functional approach leading to potentially new options for chemoprevention of colorectal cancer.

11.19.10

Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction

Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction.
Sotoodehnia N, Isaacs A, de Bakker PI, Dörr M, Newton-Cheh C, Nolte IM, van der Harst P, Müller M, Eijgelsheim M, Alonso A, Hicks AA, Padmanabhan S, Hayward C, Smith AV, Polasek O, Giovannone S, Fu J, Magnani JW, Marciante KD, Pfeufer A, Gharib SA, Teumer A, Li M, Bis JC, Rivadeneira F, Aspelund T, Köttgen A, Johnson T, Rice K, Sie MP, Wang YA, Klopp N, Fuchsberger C, Wild SH, Leach IM, Estrada K, Völker U, Wright AF, Asselbergs FW, Qu J, Chakravarti A, Sinner MF, Kors JA, Petersmann A, Harris TB, Soliman EZ, Munroe PB, Psaty BM, Oostra BA, Cupples LA, Perz S, de Boer RA, Uitterlinden AG, Völzke H, Spector TD, Liu FY, Boerwinkle E, Dominiczak AF, Rotter JI, van Herpen G, Levy D, Wichmann HE, van Gilst WH, Witteman JC, Kroemer HK, Kao WH, Heckbert SR, Meitinger T, Hofman A, Campbell H, Folsom AR, van Veldhuisen DJ, Schwienbacher C, O’Donnell CJ, Volpato CB, Caulfield MJ, Connell JM, Launer L, Lu X, Franke L, Fehrmann RS, Te Meerman G, Groen HJ, Weersma RK, van den Berg LH, Wijmenga C, Ophoff RA, Navis G, Rudan I, Snieder H, Wilson JF, Pramstaller PP, Siscovick DS, Wang TJ, Gudnason V, van Duijn CM, Felix SB, Fishman GI, Jamshidi Y, Ch Stricker BH, Samani NJ, Kääb S, Arking DE.

The QRS interval, from the beginning of the Q wave to the end of the S wave on an electrocardiogram, reflects ventricular depolarization and conduction time and is a risk factor for mortality, sudden death and heart failure. We performed a genome-wide association meta-analysis in 40,407 individuals of European descent from 14 studies, with further genotyping in 7,170 additional Europeans, and we identified 22 loci associated with QRS duration (P < 5 × 10(-8)). These loci map in or near genes in pathways with established roles in ventricular conduction such as sodium channels, transcription factors and calcium-handling proteins, but also point to previously unidentified biologic processes, such as kinase inhibitors and genes related to tumorigenesis. We demonstrate that SCN10A, a candidate gene at the most significantly associated locus in this study, is expressed in the mouse ventricular conduction system, and treatment with a selective SCN10A blocker prolongs QRS duration. These findings extend our current knowledge of ventricular depolarization and conduction.

09.29.10

A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit.

A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit.
Brunetto AT, Sarker D, Papadatos-Pastos D, Fehrmann R, Kaye SB, Johnston S, Allen M, De Bono JS, Swanton C.

BACKGROUND AND METHODS: Novel approaches to treat chemo-refractory metastatic breast cancer (MBC) are currently under investigation. This retrospective series reviews the outcome of 70 MBC patients who have participated in 30 phase I trials at the Royal Marsden Hospital from 2002 to 2009.

RESULTS: The median treatment lines before phase I trial entry for MBC was 5 (range: 1-12 lines). The overall response rate was 11.4% (95% CI: 4.0-18.9%) and the clinical benefit rate at 4 months was 20% (95% CI: 10.6-29.3). The median time to progression was 7.0 weeks (95% CI: 6.4-7.5) and median overall survival was 8.7 months (95% CI: 7.6-9.8) from start of first phase I treatment. No patients discontinued trial because of treatment-related toxicities. Abnormal lactate dehydrogenase, serum albuminor=5 previous treatment lines, liver metastases and Eastern Cooperative Group performance status >or=2 at study entry were significantly associated with poor overall survival in multivariate analysis.

CONCLUSION: This retrospective analysis provides evidence that patients with MBC tolerate phase I clinical trials and a significant proportion of patients with chemo-refractory disease, particularly those with triple-negative or Her2-positive breast cancer, may benefit from treatment.

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• Unraveling the Regulatory Mechanisms Underlying Tissue-Dependent Genetic Variation of Gene Expression
• Treatment with high-dose simvastatin inhibits geranylgeranylation in AML blast cells in a subset of AML patients
• Trans-eQTLs Reveal That Independent Genetic Variants Associated with a Complex Phenotype Converge on Intermediate Genes, with a Major Role for the HLA.
• MixupMapper: correcting sample mix-ups in genome-wide datasets increases power to detect small genetic effects.
• Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL and CARD9.

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