Polymorphism in theIL18Gene and Epithelial Ovarian Cancer in Non-Hispanic White Women

Abstract

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 lowpenetrance 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)

RETRACTED ARTICLE: Targeted immune therapy of ovarian cancer

“…Apart from typical epidemiologic approaches, the ability to examine the impact of genetic variation in disease processes over the past decade represents a significant advance in understanding the role of the immune system in disease risk. While genome wide association studies to date have found significant associations with ovarian cancer and single nucleotide polymorphisms (SNPs) in genes that are not directly immune-related [29-31], several groups have conducted candidate gene studies that evaluated SNPs in immune-related genes, including NFKB1 [32], NOD2 [33], NFKBIA [34], CASP8 [35, 36], MBL2 [37], PTGS2 [38], ALOX5 [39], IL1A [39], IL1R1 [40], TNFS10 [41] and IL18 [42]. While this is not an all-inclusive list of studies that have assessed immune related SNPs in relation to ovarian cancer risk, it does start to provide insight into contribution of immune genes in this disease.…”

Role of inflammasome genetics in susceptibility to HPV infection and cervical cancer development

“…Twelve single‐SNPs in seven inflammasome genes (rs12150220 and rs11651270 in NLRP1 , rs35829419 and rs10754558 in NLRP3 , rs2043211 and rs6509365 in CARD8 , rs1143643 and rs1143629 in IL1B , rs5744256 and rs1834481 in IL18 , rs4758635 in NLRP6 , rs6920220 in TNFAIP3 ) were selected based on previously reported association with viral diseases [Pontillo et al, , ; Motavaf et al, ; Kamada et al, ] or cancer development [Verma et al, ; Palmieri et al, ; Chen et al, ; Ungerbäck et al, ].…”

“…This intronic variant is known to affect IL‐18 plasma level and it was previously associated with the progression toward several types of cancer [Palmieri et al, ; Haghshenas et al, ; Khalili‐Azad et al, ].…”

The Immune System in the Pathogenesis of Ovarian Cancer

“…However, when they assessed this SNP in a larger ovarian cancer consortium, the Ovarian Cancer Association Consortium, the significance was attenuated (OR per-allele =0.99, 95% CI: 0.9–1.05). 54 Interestingly, in a genome-wide association study that assessed 704,409 SNPs for association with IL-18 levels in a cohort of 1523 women (with and without type 2 diabetes) from the Women’s Health Study and 435 women (with no history of chronic disease) from the Women’s Genome Health Study, rs1834481 was significantly associated with plasma IL-18 levels. 55 It should be noted that a number of SNPs in other immune-related genes assessed for association with ovarian cancer risk were not found to be significantly associated.…”