Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer

Abstract

Insulin-like growth factor-I (IGF1) stimulates cell proliferation, decreases apoptosis, and has been implicated in cancer development. Epidemiological studies have shown elevated levels of circulating IGF1 to be associated with increased risk of prostate cancer. To what extent genetic variation in the IGF1 gene is related to prostate cancer risk is largely unknown. We performed a comprehensive haplotype tagging (HT) assessment of single nucleotide polymorphisms (SNPs) representing the common haplotype variation in the IGF1 gene. We genotyped 10 SNPs (9 haplotype tagging SNPs (htSNPs)) within Cancer Prostate in Sweden (CAPS), a case-control study of 2,863 cases and 1,737 controls, in order to investigate if genetic variation in the IGF1 gene is associated with prostate cancer risk. Three haplotype blocks were identified across the IGF1 gene and 9 SNPs were selected as haplotype tagging SNPs. Common haplotypes in the block covering the 3 0 region of the IGF1 gene showed significant global association with prostate cancer risk (p = 0.004), with one particular haplotype giving an odds ratio of 1.46 (95% CI 5 1.15-1.84, p = 0.002). This haplotype had a prevalence of 5% in the study population. Our results indicate that common variation in the IGF1 gene, particularly in the 3 0 region, may affect prostate cancer risk. Further studies on genetic variations in the IGF1 gene in relation to prostate cancer risk as well as to circulating levels of IGF1 are needed to confirm this novel finding. ' 2006 Wiley-Liss, Inc.

Haplotype-Based Analysis of Common Variation in the Growth Hormone Receptor Gene and Prostate Cancer Risk

“…Prospective studies have shown elevated levels of circulating IGF-I to be associated with several cancer types, including prostate cancer (4)(5)(6). Genetic variation in the IGF1 gene seems to play a role in determining circulating levels (7,8,9) and may also influence prostate cancer risk (10,11).…”

Genetic Variation in the SST Gene and its Receptors in Relation to Circulating Levels of Insulin-Like Growth Factor-I, IGFBP3, and Prostate Cancer Risk

“…In the latter study, increasing circulating levels of IGFI conferred a clear trend toward increased risk of prostate cancer. In addition, we recently identified several variants in the 3 ¶ region of the IGF1 gene associated with both increased prostate risk as well as elevated circulating IGFI levels, a finding supporting the role of IGFI in prostate cancer etiology along the lines of Mendelian randomization (12). SST seems to result in suppressed levels of both IGFI and GH1 (13).…”

“…Although the IGF1 and IGFBP3 genes are the most obvious candidates to account for this variability (12,21), other members of the growth hormone/IGFI axis are also candidates to influence circulating IGFI and IGFBP3 hormone levels. In the present study, we report a missense SNP in the SSTR5 gene associated with a decrease in plasma levels of IGFBP3 by 11% per rare allele as confirmed in an independent study population.…”

“…Cancer Prostate in Sweden (CAPS) is a population-based case-control study that has been extensively described previously (12,14). In brief, after notification from regional oncological centers 2,975 case patients donated a blood sample and filled out a questionnaire concerning demographic, medical, and life-style data.…”

“…Single nucleotide polymorphisms (SNP) were selected using a haplotype tagging approach as described previously (12,15). Genotype data on SNPs genotyped by the HapMap consortium across the SST and SSTR1-5 loci were obtained.…”