Palmieri RT, Wilson MA, Iversen ES, Clyde MA, Calingaert B, Moorman PG, Poole C, Anderson AR, Anderson S, Anton-Culver H, Beesley J, Hogdall E, Brewster W, Carney ME, Chen X, Chenevix-Trench G, Chang-Claude J, Cunningham JM, DiCioccio RA, Doherty JA, Easton DF, Edlund CK, Gayther SA, Gentry-Maharaj A, Goode EL, Goodman MT, Kjaer SK, Hogdall CK, Hopkins MP, Jenison EL, Blaakaer J, Lurie G, McGuire V, Menon U, Moysich KB, Ness RB, Pearce CL, Pharoah PDP, Pike MC, Ramus SJ, Rossing MA, Song H, Terada KY, VanDenBerg D, Vierkant RA, Wang-Gohrke S, Webb PM, Whittemore AS, Wu AH, Ziogas A, Berchuck A, Schildkraut JM. Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women. Cancer Epidemiol Biomarkers Prev. 2008 Dec 1;17(12):3567-72.

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)

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