Abstract
The aim of this study was to investigate association between copy number variation of the defensin beta 4 gene (DEFB4) and susceptibility to cervical cancer in a population at high risk of persistent oncogenic human papillomavirus (HPV) infection. The study subjects comprised 204 women with cervical cancer, a population having a high risk of persistent oncogenic HPV infection (cervical cancer group), and 200 healthy women from the general population (control group). Copy number variation of DEFB4 in each test sample was determined by relative quantitation using the comparative CT (ΔΔCT) method. Differences between the two groups were evaluated. The median DEFB4 copy number in the cervical cancer group was four and in the control group was five (P=2.77e–4, t-test). The odds ratio of cervical cancer in individuals with four DEFB4 copies or less was higher (odds ratio 2.02; 95% confidence interval odds ratio 1.36–3.02), compared with that in individuals with five or more copies (odds ratio 0.49; 95% confidence interval odds ratio 0.33–0.74). We found copy number variation of DEFB4 was a host genetic factor conferring susceptibility to cervical cancer. A lower DEFB4 copy number was associated with susceptibility to cervical cancer.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Accession codes
References
Ganz, T. Defensins: antimicrobial peptides of innate immunity. Nat. Rev. Immunol. 3, 710–720 (2003).
Schutte, B. C. & McCray, P. B. [Beta]-defensins in lung host defense. Annu. Rev. Physiol. 64, 709–748 (2002).
Horne, A. W., Stock, S. J. & King, A. E. Innate immunity and disorders of the female reproductive tract. Reproduction 135, 739–749 (2008).
Hollox, E. J., Armour, J. A. L. & Barber, J. C. K. Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster. Am. J. Hum. Genet. 73, 591–600 (2003).
Groth, M., Wiegand, C., Szafranski, K., Huse, K., Kramer, M., Rosenstile, P. et al. Both copy number and sequence variations affect expression of human DEFB4. Genes Immun. 11, 458–466 (2010).
Janssens, W., Nuytten, H., Dupont, L. J., Van Eldere, J., Vermeire, S., Lambrechts, D. et al. Genomic copy number determines functional expression of {beta}-defensin 2 in airway epithelial cells and associates with chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 182, 163–169 (2010).
Milanese, M., Segat, L., Arraes, L. C., Garzino-Demo, A. & Crovella, S. Copy number variation of defensin genes and HIV infection in Brazilian children. J. Acquir. Immune Defic. Syndr. 50, 331–333 (2009).
Sun, L., Finnegan, C. M., Kish-Catalone, T., Blumenthal, R., Garzino-Demo, P., La Terra Maggiore, G. M. et al. Human beta-defensins suppress human immunodeficiency virus infection: potential role in mucosal protection. J. Virol. 79, 14318–14329 (2005).
Schiffman, M., Castle, P. E., Jeronimo, J., Rodriguez, A. C. & Wacholder, S. Human papillomavirus and cervical cancer. Lancet 370, 890–907 (2007).
Shimada, T., Miyashita, M., Miura, S., Nakayama, D., Miura, K., Fukuda, M. et al. Genital human papilloma virus infection in mentally-institutionalized virgins. Gynecol. Oncol. 106, 488–489 (2007).
Doorbar, J. Molecular biology of human papillomavirus infection and cervical cancer. Clin. Sci. 110, 525–541 (2006).
Moscicki, A. B., Palefsky, J., Smith, G., Siboshski, S. & Schoolnik, G. Variability of human papillomavirus DNA testing in a longitudinal cohort of young women. Obstet. Gynecol. 82 (Pt 1), 578–585 (1993).
Woodman, C. B., Collins, S., Winter, H., Bailey, A., Ellis, J., Prior, P. et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 357, 1831–1836 (2001).
Ho, G. Y., Bierman, R., Beardsley, L., Chang, C. J. & Burk, R. D. Natural history of cervicovaginal papillomavirus infection in young women. N. Engl. J. Med. 338, 423–428 (1998).
Castellsague, X. & Munoz, N. Cofactors in human papillomavirus carcinogenesis–role of parity, oral contraceptives, and tobacco smoking. J. Natl. Cancer Inst. Monogr. 31, 20–28 (2003).
Apple, R. J., Erlich, H. A., Klitz, W., Manos, M. M., Becker, T. M. & Wheeler, C. M. HLA DR-DQ associations with cervical carcinoma show papillomavirus-type specificity. Nat. Genet. 6, 157–162 (1994).
Beskow, A. H., Josefsson, A. M. & Gyllensten, U. B. HLA class II alleles associated with infection by HPV16 in cervical cancer in situ. Int. J. Cancer 93, 817–822 (2001).
Hildesheim, A. & Wang, S. S. Host and viral genetics and risk of cervical cancer: a review. Virus Res. 89, 229–240 (2002).
Wang, S. S. & Hildesheim, A. Viral and host factors in human papillomavirus persistence and progression. J. Natl. Cancer Inst. Monogr. 31, 35–40 (2003).
Matsumoto, K., Maeda, H., Oki, A., Takatsuka, N., Yasugi, T., Furuta, R. et al. HLA class II DRB1*1302 allele protects against progression to cervical intraepithelial neoplasia grade 3: a multicenter prospective cohort study. Int. J. Gynecol. Cancer 22, 471–478 (2012).
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 47, 1023–1028 (2009).
Chen, Q., Book, M., Fang, X., Hoeft, A. & Stuber, F. Screening of copy number polymorphisms in human beta-defensin genes using modified real-time quantitative PCR. J. Immunol. Methods 308, 231–240 (2006).
Magnusson, P. K., Lichtenstein, P. & Gyllensten, U. B. Heritability of cervical tumours. Int. J. Cancer 88, 698–701 (2000).
Wang, S. S., Bratti, M. C., Rodriguez, A. C., Herrero, R., Burk, R. D., Porras, C. et al. Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer. J. Infect. Dis. 199, 20–30 (2009).
Wang, S. S., Gonzalez, P., Yu, K., Porras, C., Li, Q., Safaeian, M. et al. Common genetic variants and risk for HPV persistence and progression to cervical cancer. PLoS One 5, e8667 (2010).
Safaeian, M., Hildesheim, A., Gonzalez, P., Yu, K., Porras, C., Li, Q. et al. Single nucleotide polymorphisms in the PRDX3 and RPS19 and risk of HPV persistence and cervical precancer/cancer. PLoS One 7, e33619 (2012).
Buck, C. B., Day, P. M., Thompson, C. D., Lubkowski, J., Lu, W., Lowy, D. R. et al. Human alpha-defensins block papillomavirus infection. Proc. Natl Acad. Sci. 103, 1516–1521 (2006).
Hardwick, R. J., Machado, L. R., Zuccherato, L. W., Antolinos, S., Xue, Y., Shawa, N. 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. 32, 743–750 (2011).
Acknowledgements
We thank Miss Yasuko Noguchi for her technical assistance. This work was supported by the Japan Society for the Promotion of Science KAKENHI grant numbers nos. 23592406, 24791712 and 22591827.
Author contributions: All authors must see and approve the final version of the manuscript. Conceived and designed the experiment: KM, KiY and HM. Performed the experiments: SA, KM, AK, HM, SM and KY. Analyzed the data: SA, KM, YH and KS. Contributed materials and analysis tools: AH, OJ, KS and AY. Wrote the paper: SA and KM.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Abe, S., Miura, K., Kinoshita, A. et al. Copy number variation of the antimicrobial-gene, defensin beta 4, is associated with susceptibility to cervical cancer. J Hum Genet 58, 250–253 (2013). https://doi.org/10.1038/jhg.2013.7
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2013.7
Keywords
This article is cited by
-
Convergent evolution of defensin sequence, structure and function
Cellular and Molecular Life Sciences (2017)
-
Low DEFB4 Copy Number and High Systemic hBD-2 and IL-22 Levels Are Associated with Dermatophytosis
Journal of Investigative Dermatology (2015)
-
A novel method for sex determination by detecting the number of X chromosomes
International Journal of Legal Medicine (2015)
-
Single human papillomavirus 16 or 52 infection and later cytological findings in Japanese women with NILM or ASC-US
Journal of Human Genetics (2014)
