title: Apolipoprotein E/C1 locus variants modify renal cell carcinoma risk.
abstract: Lipid peroxidation is considered a unifying mechanistic pathway through which known risk factors induce renal cell carcinoma (RCC). We hypothesized that genes selected a priori for their role in lipid peroxidation would modify cancer risk. We genotyped 635 single nucleotide polymorphisms (SNP) in 38candidate genes in 777 Caucasian RCC cases and 1,035 controls enrolled in a large European case-control study. Top candidate SNPs were confirmed among 718 Caucasian cases and 615 controls in a second study in the United States. Two of the three SNPs (rs8106822 and rs405509) that replicated in the U.S. study were within a regulatory region of the APOE promoter. The OR for rs8106822 A>G variant was 1.22(AG) and 1.41(GG) (P(trend) = 0.01) in the European study, 1.05(AG) and 1.51(GG) (P(trend) = 0.03) in the U.S. study, and 1.15(AG) and 1.44(GG) (P(trend) = 0.001) among 1,485 cases and 1,639 controls combined. The rs405509 G>T variant was associated with risk in the European (OR, 0.87(TG); OR, 0.71(TT); P(trend) = 0.02), the U.S. (OR, 0.68(TG); OR, 0.71(TT); P(trend) = 0.02), and both studies combined (OR(TG), 0.79; OR(TT), 0.71; P(trend) = 0.001), as was the G-G haplotype (r(2) = 0.64; P= 4.7 x 10(-4)). This association is biologically plausible as SNP rs405509 was shown to modify protein binding and transcriptional activity of the APOE protein in vitro and is in linkage disequilibrium with key known variants defining the e2, e3, and e4 alleles that modify risk of atherosclerosis, Alzheimer's disease risk, and progression to AIDS. In two large case-control studies, our findings further define a functional region of interest at the APOE locus that increases RCC susceptibility.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20852, USA. moorele@mail.nih.gov
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Sara
authors.initials: S
authors.lastname: Karami
authors.forename: Idan
authors.initials: I
authors.lastname: Menashe
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Linda M
authors.initials: LM
authors.lastname: Dong
authors.forename: Allison
authors.initials: A
authors.lastname: Meisner
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Joanne
authors.initials: J
authors.lastname: Colt
authors.forename: Kendra
authors.initials: K
authors.lastname: Schwartz
authors.forename: Faith
authors.initials: F
authors.lastname: Davis
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Mattveev
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.forename: Hellena
authors.initials: H
authors.lastname: Kollarova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bencko
authors.forename: Marie
authors.initials: M
authors.lastname: Navratilova
authors.forename: Neonilia
authors.initials: N
authors.lastname: Szeszenia-Dabrowska
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.forename: Ivana
authors.initials: I
authors.lastname: Holcatova
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rosenberg
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D053302:Apolipoprotein C-I / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007680:Kidney Neoplasms / Q000453:epidemiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D015227:Lipid Peroxidation; D008297:Male; D008875:Middle Aged; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D053302:Apolipoprotein C-I; D001057:Apolipoproteins E; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II