title: 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.
abstract: 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.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.forename: Iona
authors.initials: I
authors.lastname: Cheng
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Freedman
authors.forename: Lorelei
authors.initials: L
authors.lastname: Mucci
authors.forename: Naomi E
authors.initials: NE
authors.lastname: Allen
authors.forename: Michael N
authors.initials: MN
authors.lastname: Pollak
authors.forename: Richard B
authors.initials: RB
authors.lastname: Hayes
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Jarmo
authors.initials: J
authors.lastname: Virtamo
authors.forename: Jonas
authors.initials: J
authors.lastname: Manjer
authors.forename: J Michael
authors.initials: JM
authors.lastname: Gaziano
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Demetrius
authors.initials: D
authors.lastname: Albanes
authors.forename: Eugenia E
authors.initials: EE
authors.lastname: Calle
authors.forename: Edward
authors.initials: E
authors.lastname: Giovannucci
authors.forename: E David
authors.initials: ED
authors.lastname: Crawford
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Walter C
authors.initials: WC
authors.lastname: Willett
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thun
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Heather Spencer
authors.initials: HS
authors.lastname: Feigelson
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Pilar
authors.initials: P
authors.lastname: Amiano
authors.forename: Gerald
authors.initials: G
authors.lastname: Andriole
authors.forename: Alison M
authors.initials: AM
authors.lastname: Dunning
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Key
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
mesh_terms: 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*
chemical_list: D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I