Apolipoprotein E/C1 locus variants modify renal cell carcinoma risk.
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.
Moore
Lee E
LE
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20852, USA. moorele@mail.nih.gov
Brennan
Paul
P
Karami
Sara
S
Menashe
Idan
I
Berndt
Sonja I
SI
Dong
Linda M
LM
Meisner
Allison
A
Yeager
Meredith
M
Chanock
Stephen
S
Colt
Joanne
J
Schwartz
Kendra
K
Davis
Faith
F
Zaridze
David
D
Mattveev
Vsevolod
V
Janout
Vladimir
V
Kollarova
Hellena
H
Bencko
Vladimir
V
Navratilova
Marie
M
Szeszenia-Dabrowska
Neonilia
N
Mates
Dana
D
Holcatova
Ivana
I
Boffetta
Paolo
P
Chow
Wong-Ho
WH
Rosenberg
Philip S
PS
Rothman
Nathaniel
N
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
D053302:Apolipoprotein C-I; D001057:Apolipoproteins E; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II