A comprehensive analysis of common IGF1, IGFBP1 and IGFBP3 genetic variation with prospective IGF-I and IGFBP-3 blood levels and prostate cancer risk among Caucasians.
The insulin-like growth factor (IGF) pathway has been implicated in prostate development and carcinogenesis. We conducted a comprehensive analysis, utilizing a resequencing and tagging single-nucleotide polymorphism (SNP) approach, between common genetic variation in the IGF1, IGF binding protein (BP) 1, and IGFBP3 genes with IGF-I and IGFBP-3 blood levels, and prostate cancer (PCa) risk, among Caucasians in the NCI Breast and Prostate Cancer Cohort Consortium. We genotyped 14 IGF1 SNPs and 16 IGFBP1/IGFBP3 SNPs to capture common [minor allele frequency (MAF) >or= 5%] variation among Caucasians. For each SNP, we assessed the geometric mean difference in IGF blood levels (N = 5684) across genotypes and the association with PCa risk (6012 PCa cases/6641 controls). We present two-sided statistical tests and correct for multiple comparisons. A non-synonymous IGFBP3 SNP in exon 1, rs2854746 (Gly32Ala), was associated with IGFBP-3 blood levels (P(adj) = 8.8 x 10(-43)) after adjusting for the previously established IGFBP3 promoter polymorphism A-202C (rs2854744); IGFBP-3 blood levels were 6.3% higher for each minor allele. For IGF1 SNP rs4764695, the risk estimates among heterozygotes was 1.01 (99% CI: 0.90-1.14) and 1.20 (99% CI: 1.06-1.37) for variant homozygotes with overall PCa risk. The corrected allelic P-value was 8.7 x 10(-3). IGF-I levels were significantly associated with PCa risk (P(trend) = 0.02) with a 21% increase of PCa risk when compared with the highest quartile to the lowest quartile. We have identified SNPs significantly associated with IGFBP-3 blood levels, but none of these alter PCa risk; however, a novel IGF1 SNP, not associated with IGF-I blood levels, shows preliminary evidence for association with PCa risk among Caucasians.
Schumacher
Fredrick R
FR
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Cheng
Iona
I
Freedman
Matthew L
ML
Mucci
Lorelei
L
Allen
Naomi E
NE
Pollak
Michael N
MN
Hayes
Richard B
RB
Stram
Daniel O
DO
Canzian
Federico
F
Henderson
Brian E
BE
Hunter
David J
DJ
Virtamo
Jarmo
J
Manjer
Jonas
J
Gaziano
J Michael
JM
Kolonel
Laurence N
LN
Tjønneland
Anne
A
Albanes
Demetrius
D
Calle
Eugenia E
EE
Giovannucci
Edward
E
Crawford
E David
ED
Haiman
Christopher A
CA
Kraft
Peter
P
Willett
Walter C
WC
Thun
Michael J
MJ
Le Marchand
Loïc
L
Kaaks
Rudolf
R
Feigelson
Heather Spencer
HS
Bueno-de-Mesquita
H Bas
HB
Palli
Domenico
D
Riboli
Elio
E
Lund
Eiliv
E
Amiano
Pilar
P
Andriole
Gerald
G
Dunning
Alison M
AM
Trichopoulos
Dimitrios
D
Stampfer
Meir J
MJ
Key
Timothy J
TJ
Ma
Jing
J
D000368:Aged; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood* / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics*
D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I