Περίληψη:
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) ≥ 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 (Padj = 8.8 × 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 × 10-3. IGF-I levels were significantly associated with PCa risk (Ptrend = 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. © The Author 2010. Published by Oxford University Press. All rights reserved.
Συγγραφείς:
Schumacher, F.R.
Cheng, I.
Freedman, M.L.
Mucci, L.
Allen, N.E.
Pollak, M.N.
Hayes, R.B.
Stram, D.O.
Canzian, F.
Henderson, B.E.
Hunter, D.J.
Virtamo, J.
Manjer, J.
Gaziano, J.M.
Kolone, L.N.
Tjønneland, A.
Albanes, D.
Calle, E.E.
Giovannucci, E.
David Crawford, E.
Haiman, C.A.
Kraft, P.
Willett, W.C.
Thun, M.J.
Le Marchand, L.
Kaaks, R.
Feigelson, H.S.
Bueno-de-Mesquita, H.B.
Palli, D.
Riboli, E.
Lund, E.
Amiano, P.
Andriole, G.
Dunning, A.M.
Trichopoulos, D.
Stampfer, M.J.
Key, T.J.
Ma, J.
Λέξεις-κλειδιά:
somatomedin binding protein 1; somatomedin binding protein 3; somatomedin C; somatomedin binding protein 1; somatomedin binding protein 3; somatomedin C, adult; article; blood analysis; cancer risk; carcinogenesis; Caucasian; gene frequency; gene identification; gene sequence; genetic association; genetic polymorphism; genetic risk; genetic variability; genotype; heterozygote; homozygote; human; human tissue; major clinical study; male; priority journal; promoter region; prostate cancer; single nucleotide polymorphism; statistical analysis; aged; blood; breast tumor; Caucasian; cohort analysis; female; gene linkage disequilibrium; genetic predisposition; genetic variability; genetics; metabolism; middle aged; prostate tumor; risk factor, Aged; Breast Neoplasms; Cohort Studies; European Continental Ancestry Group; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Risk Factors
