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Polymorphism in the IL18 Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women

¹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ² Department of Statistical Science, Duke University; ³ Comprehensive Cancer Center, ⁴ Department of Community and Family Medicine, and ⁵ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina; ⁶ Keck School of Medicine, University of Southern California; ⁷ Department of Urology University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California; Departments of ⁸ Health Sciences Research and ⁹ Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota; ¹⁰ Department of Epidemiology, School of Medicine, University of California, Irvine, Irvine, California; ¹¹ Queensland Institute of Medical Research, Brisbane, Queensland, Australia; ¹² Department of Virus, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society; ¹³ The Gynaecologic Clinic, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; ¹⁴ Cancer Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii; ¹⁵ Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany; Departments of ¹⁶ Cancer Genetics and ¹⁷ Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, New York; ¹⁸ Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington; ¹⁹ Genetic Epidemiology Unit and ²⁰ Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom; ²¹ Gynaecological Cancer Research Centre, University College London, EGA Institute for Women's Health, London, United Kingdom; ²² Department of Obstetrics and Gynecology, Aultman Hospital, Canton, Ohio; ²³ Women's Center, Akron General Medical Center, Akron, Ohio; ²⁴ Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Skejby, Denmark; ²⁵ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California; ²⁶ Department of Epidemiology and University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania; and ²⁷ Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany

Requests for reprints: Joellen M. Schildkraut, Department of Community and Family Medicine, Duke University Medical Center, Box 2949, Durham, NC 27710. Phone: 919-681-4761; Fax: 919-681-4766. E-mail: schil001{at}mc.duke.edu

Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a <25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3567–72)