Association studies of the copy-number variable ß-defensin cluster on 8p23.1 in adenocarcinoma and chronic pancreatitis

BMC Research Notes

Matthias Platzer³  Christian Pilarsky⁷  Michael Krawczak⁸  Karl Werdan⁴  Karin Halina Greiser⁶  Philip Rosenstiel¹  Michael Nothnagel²  Andreas Wolf⁸  Alexander Kluttig⁵  Klaus Huse³  Robert Grützmann⁵  Marco Groth³  Oliver Kuss⁵  Gabor Gäbel⁷  Stefan Taudien³ 

[1] Institute for Clinical Molecular Biology, Christian Albrechts University Kiel, Kiel, Germany;Cologne Center for Genomics, University of Cologne, Cologne, Germany;Genome Analysis, Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstr 11, D-07745, Jena, Germany;Department of Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany;Institute for Medical Epidemiology, Biostatistics and Informatics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany;German Cancer Research Centre, Division of Cancer Epidemiology, Heidelberg, Germany;Department of Visceral, Thoracic and Vascular Surgery, University Hospital, Technical University of Dresden, Dresden, Germany;Institute for Medical Informatics and Statistics, Christian Albrechts University Kiel, Kiel, Germany

关键词: Pancreatic ductal adenocarcinoma;    Chronic pancreatitis;    Copy number variation;    Single nucleotide variants;    Defensins;   

Others  :  1165243
DOI  :  10.1186/1756-0500-5-629

 received in 2012-06-29, accepted in 2012-11-07,  发布年份 2012

【 摘 要 】

Background

Human ß-defensins are a family of antimicrobial peptides located at the mucosal surface. Both sequence multi-site variations (MSV) and copy-number variants (CNV) of the defensin-encoding genes are associated with increased risk for various diseases, including cancer and inflammatory conditions such as psoriasis and acute pancreatitis. In a case–control study, we investigated the association between MSV in DEFB104 as well as defensin gene (DEF) cluster copy number (CN), and pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP).

Results

Two groups of PDAC (N=70) and CP (N=60) patients were compared to matched healthy control groups CARLA1 (N=232) and CARLA2 (N=160), respectively. Four DEFB104 MSV were haplotyped by PCR, cloning and sequencing. DEF cluster CN was determined by multiplex ligation-dependent probe amplification.

Neither the PDAC nor the CP cohorts show significant differences in the DEFB104 haplotype distribution compared to the respective control groups CARLA1 and CARLA2, respectively.

The diploid DEF cluster CN exhibit a significantly different distribution between PDAC and CARLA1 (Fisher’s exact test P=0.027), but not between CP and CARLA2 (P=0.867).

Conclusion

Different DEF cluster b CN distribution between PDAC patients and healthy controls indicate a potential protective effect of higher CNs against the disease.

【 授权许可】

   
2012 Taudien et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Skipworth JR, Shankar A, Pereira SP: Managing acute and chronic pancreatitis. Practitioner 2010, 254:23-27. 22
• [2]Kloppel G, Maillet B: Development of chronic pancreatitis from acute pancreatitis: a pathogenetic concept. Zentralbl Chir 1995, 120:274-277.
• [3]Ahmed SA, Wray C, Rilo HL, Choe KA, Gelrud A, Howington JA, Lowy AM, Matthews JB: Chronic pancreatitis: recent advances and ongoing challenges. Curr Probl Surg 2006, 43:127-238.
• [4]Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R: Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol 2010, 24:349-358.
• [5]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [6]Raptis DA, Fessas C, Belasyse-Smith P, Kurzawinski TR: Clinical presentation and waiting time targets do not affect prognosis in patients with pancreatic cancer. Surgeon 2010, 8:239-246.
• [7]Lehrer RI: Immunology: Peptide gets in shape for self-defence. Nature 2011, 469:309-310.
• [8]Beisswenger C, Bals R: Antimicrobial peptides in lung inflammation. Chem Immunol Allergy 2005, 86:55-71.
• [9]Diamond G, Ryan L: Beta-defensins: what are they REALLY doing in the oral cavity? Oral Dis 2011, 17(7):628-635.
• [10]Guani-Guerra E, Santos-Mendoza T, Lugo-Reyes SO, Teran LM: Antimicrobial peptides: general overview and clinical implications in human health and disease. Clin Immunol 2010, 135:1-11.
• [11]Herr C, Shaykhiev R, Bals R: The role of cathelicidin and defensins in pulmonary inflammatory diseases. Expert Opin Biol Ther 2007, 7:1449-1461.
• [12]Hollox EJ: Copy number variation of beta-defensins and relevance to disease. Cytogenet Genome Res 2008, 123:148-155.
• [13]Paris S, Wolgin M, Kielbassa AM, Pries A, Zakrzewicz A: Gene expression of human beta-defensins in healthy and inflamed human dental pulps. J Endod 2009, 35:520-523.
• [14]Hollox EJ, Armour JA, Barber JC: Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. Am J Hum Genet 2003, 73:591-600.
• [15]Taudien S, Galgoczy P, Huse K, Reichwald K, Schilhabel M, Szafranski K, Shimizu A, Asakawa S, Frankish A, Loncarevic IF, et al.: Polymorphic segmental duplications at 8p23.1 challenge the determination of individual defensin gene repertoires and the assembly of a contiguous human reference sequence. BMC Genomics 2004, 5:92. BioMed Central Full Text
• [16]Groth M, Szafranski K, Taudien S, Huse K, Mueller O, Rosenstiel P, Nygren AO, Schreiber S, Birkenmeier G, Platzer M: High-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes. Hum Mutat 2008, 29:1247-1254.
• [17]Groth M, Wiegand C, Szafranski K, Huse K, Kramer M, Rosenstiel P, Schreiber S, Norgauer J, Platzer M: Both copy number and sequence variations affect expression of human DEFB4. Genes Immun 2010, 11:458-466.
• [18]Hardwick RJ, Machado LR, Zuccherato LW, Antolinos S, Xue Y, Shawa N, Gilman RH, Cabrera L, Berg DE, Tyler-Smith C, et al.: A worldwide analysis of beta-defensin copy number variation suggests recent selection of a high-expressing DEFB103 gene copy in East Asia. Hum Mutat 2011, 32:743-750.
• [19]Taudien S, Groth M, Huse K, Petzold A, Szafranski K, Hampe J, Rosenstiel P, Schreiber S, Platzer M: Haplotyping and copy number estimation of the highly polymorphic human beta-defensin locus on 8p23 by 454 amplicon sequencing. BMC Genomics 2010, 11:252. BioMed Central Full Text
• [20]Taudien S, Szafranski K, Felder M, Groth M, Huse K, Raffaelli F, Petzold A, Zhang X, Rosenstiel P, Hampe J, et al.: Comprehensive assessment of sequence variation within the copy number variable defensin cluster on 8p23 by target enriched in-depth 454 sequencing. BMC Genomics 2011, 12:243. BioMed Central Full Text
• [21]Hollox EJ, Huffmeier U, Zeeuwen PL, Palla R, Lascorz J, Rodijk-Olthuis D, van de Kerkhof PC, Traupe H, de Jongh G, den Heijer M, et al.: Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet 2008, 40:23-25.
• [22]Fredman D, White SJ, Potter S, Eichler EE, Den Dunnen JT, Brookes AJ: Complex SNP-related sequence variation in segmental genome duplications. Nat Genet 2004, 36:861-866.
• [23]Armour JA, Palla R, Zeeuwen PL, den Heijer M, Schalkwijk J, Hollox EJ: Accurate, high-throughput typing of copy number variation using paralogue ratios from dispersed repeats. Nucleic Acids Res 2007, 35:e19.
• [24]Deutsch S, Choudhury U, Merla G, Howald C, Sylvan A, Antonarakis SE: Detection of aneuploidies by paralogous sequence quantification. J Med Genet 2004, 41:908-915.
• [25]Lee HH, Chang JG, Lin SP, Chao HT, Yang ML, Ng HT: Rapid detection of trisomy 21 by homologous gene quantitative PCR (HGQ-PCR). Hum Genet 1997, 99:364-367.
• [26]Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002, 30:e57.
• [27]Aldhous MC, Abu Bakar S, Prescott NJ, Palla R, Soo K, Mansfield JC, Mathew CG, Satsangi J, Armour JA: Measurement methods and accuracy in copy number variation: failure to replicate associations of beta-defensin copy number with Crohn's disease. Hum Mol Genet 2010, 19:4930-4938.
• [28]Perne A, Zhang X, Lehmann L, Groth M, Stuber F, Book M: Comparison of multiplex ligation-dependent probe amplification and real-time PCR accuracy for gene copy number quantification using the beta-defensin locus. Biotechniques 2009, 47:1023-1028.
• [29]Chen Q, Hakimi M, Wu S, Jin Y, Cheng B, Wang H, Xie G, Ganz T, Linzmeier RM, Fang X: Increased genomic copy number of DEFA1/DEFA3 is associated with susceptibility to severe sepsis in Chinese Han population. Anesthesiology 2010, 112:1428-1434.
• [30]Aldhous MC, Noble CL, Satsangi J: Dysregulation of human beta-defensin-2 protein in inflammatory bowel disease. PLoS One 2009, 4:e6285.
• [31]Bentley RW, Pearson J, Gearry RB, Barclay ML, McKinney C, Merriman TR, Roberts RL: Association of Higher DEFB4 Genomic Copy Number With Crohn's Disease. Am J Gastroenterol 2009, 105(2):354-359.
• [32]Fellermann K, Stange DE, Schaeffeler E, Schmalzl H, Wehkamp J, Bevins CL, Reinisch W, Teml A, Schwab M, Lichter P, et al.: A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am J Hum Genet 2006, 79:439-448.
• [33]Huse K, Taudien S, Groth M, Rosenstiel P, Szafranski K, Hiller M, Hampe J, Junker K, Schubert J, Schreiber S, et al.: Genetic variants of the copy number polymorphic beta-defensin locus are associated with sporadic prostate cancer. Tumour Biol 2008, 29:83-92.
• [34]Greiser KH, Kluttig A, Schumann B, Kors JA, Swenne CA, Kuss O, Werdan K, Haerting J: Cardiovascular disease, risk factors and heart rate variability in the elderly general population: design and objectives of the CARdiovascular disease, Living and Ageing in Halle (CARLA) Study. BMC Cardiovasc Disord 2005, 5:33. BioMed Central Full Text
• [35]Gronborg M, Bunkenborg J, Kristiansen TZ, Jensen ON, Yeo CJ, Hruban RH, Maitra A, Goggins MG, Pandey A: Comprehensive proteomic analysis of human pancreatic juice. J Proteome Res 2004, 3:1042-1055.
• [36]Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L: Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993, 328:1433-1437.
• [37]Raimondi S, Maisonneuve P, Lowenfels AB: Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol 2009, 6:699-708.
• [38]Pitchumoni CS, Rubin A, Das K: Pancreatitis in inflammatory bowel diseases. J Clin Gastroenterol 2010, 44:246-253.
• [39]Hollox EJ: Beta-defensins and Crohn's disease: confusion from counting copies. Am J Gastroenterol 2010, 105:360-362.
• [40]Jerrells TR, Vidlak D, Strachota JM: Alcoholic pancreatitis: mechanisms of viral infections as cofactors in the development of acute and chronic pancreatitis and fibrosis. J Leukoc Biol 2007, 81:430-439.
• [41]Tiszlavicz Z, Szabolcs A, Takacs T, Farkas G, Kovacs-Nagy R, Szantai E, Sasvari-Szekely M, Mandi Y: Polymorphisms of beta defensins are associated with the risk of severe acute pancreatitis. Pancreatology 2010, 10:483-490.
• [42]Farrow B, Sugiyama Y, Chen A, Uffort E, Nealon W, Mark Evers B: Inflammatory mechanisms contributing to pancreatic cancer development. Ann Surg 2004, 239:763-769. discussion 769–771
• [43]Coussens LM, Werb Z: Inflammation and cancer. Nature 2002, 420:860-867.
• [44]Kohlgraf KG, Pingel LC, Dietrich DE, Brogden KA: Defensins as anti-inflammatory compounds and mucosal adjuvants. Future Microbiol 2010, 5:99-113.
• [45]Ganz T: Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003, 3:710-720.