Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Hum Mol Genet. 2010 Aug 1;19(15):3089-101. doi: 10.1093/hmg/ddq210. Epub 2010 May 19.
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.
胰岛素样生长因子（IGF）途径与前列腺发育和癌变有关。我们利用重测序和标记单核苷酸多态性（SNP）方法，对 IGF1、IGF 结合蛋白（BP）1 和 IGFBP3 基因中的常见遗传变异与 IGF-I 和 IGFBP-3 血液水平以及白种人前列腺癌（PCa）风险之间进行了综合分析，这些数据来自 NCI 乳腺癌和前列腺癌队列联盟。我们对 14 个 IGF1 SNP 和 16 个 IGFBP1/IGFBP3 SNP 进行了基因分型，以捕获白种人中常见的（MAF≥5%）变异。对于每个 SNP，我们评估了基因型之间 IGF 血液水平的几何平均值差异（N=5684）和与 PCa 风险的相关性（6012 例 PCa 病例/6641 例对照）。我们给出了双侧统计检验结果，并对多重比较进行了校正。IGFBP3 外显子 1 中的一个非同义 SNP（rs2854746，Gly32Ala）与 IGFBP-3 血液水平相关（调整先前建立的 IGFBP3 启动子多态性 A-202C（rs2854744）后，P（adj）=8.8×10（-43））；每一个 minor 等位基因都会使 IGFBP-3 血液水平升高 6.3%。对于 IGF1 SNP rs4764695，杂合子的风险估计值为 1.01（99%CI：0.90-1.14），变体纯合子的风险估计值为 1.20（99%CI：1.06-1.37），总体 PCa 风险。校正后的等位基因 P 值为 8.7×10（-3）。IGF-I 水平与 PCa 风险显著相关（P（趋势）=0.02），与 IGF-I 血液水平最高四分位与最低四分位相比，PCa 风险增加 21%。我们已经确定了与 IGFBP-3 血液水平显著相关的 SNP，但没有一个 SNP 改变 PCa 风险；然而，一个新的 IGF1 SNP 与 IGF-I 血液水平无关，初步显示与白种人 PCa 风险相关。
