Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women.
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).
Palmieri
Rachel T
RT
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Wilson
Melanie A
MA
Iversen
Edwin S
ES
Clyde
Merlise A
MA
Calingaert
Brian
B
Moorman
Patricia G
PG
Poole
Charles
C
Anderson
A Rebecca
AR
Anderson
Stephanie
S
Anton-Culver
Hoda
H
Beesley
Jonathan
J
Hogdall
Estrid
E
Brewster
Wendy
W
Carney
Michael E
ME
Chen
Xiaoqing
X
Chenevix-Trench
Georgia
G
Chang-Claude
Jenny
J
Cunningham
Julie M
JM
Dicioccio
Richard A
RA
Doherty
Jennifer A
JA
Easton
Douglas F
DF
Edlund
Christopher K
CK
Gayther
Simon A
SA
Gentry-Maharaj
Aleksandra
A
Goode
Ellen L
EL
Goodman
Marc T
MT
Kjaer
Susanne Kruger
SK
Hogdall
Claus K
CK
Hopkins
Michael P
MP
Jenison
Eric L
EL
Blaakaer
Jan
J
Lurie
Galina
G
McGuire
Valerie
V
Menon
Usha
U
Moysich
Kirsten B
KB
Ness
Roberta B
RB
Pearce
Celeste Leigh
CL
Pharoah
Paul D P
PD
Pike
Malcolm C
MC
Ramus
Susan J
SJ
Rossing
Mary Anne
MA
Song
Honglin
H
Terada
Keith Y
KY
Vandenberg
David
D
Vierkant
Robert A
RA
Wang-Gohrke
Shan
S
Webb
Penelope M
PM
Whittemore
Alice S
AS
Wu
Anna H
AH
Ziogas
Argyrios
A
Berchuck
Andrew
A
Schildkraut
Joellen M
JM
D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics*; D016015:Logistic Models; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics*; D009657:North Carolina; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D020382:Interleukin-18