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Implications for Prostate Cancer of Insulin-Like Growth Factor-I (IGF-I) Genetic Variation and Circulating IGF-I Levels

Departments of Surgical and Perioperative Sciences (M.J., P.S.), Urology and Andrology, and Public Health and Clinical Medicine (G.H.), Umeå University Hospital, 901 85 Umeå, Sweden; International Agency for Research on Cancer (J.D.M., S.R.), 69372 Lyon, France; Department of Medical Epidemiology and Biostatistics (F.W., K.B., H.-O.A., H.G.), Karolinska Institutet, 17177 Stockholm, Sweden; Julius Center for Health Sciences and Primary Care (M.V., C.H.v.G.), University Medical Center Utrecht, 85500 Utrecht, The Netherlands; Department of Epidemiology (H.-O.A.), Harvard University, Boston, Massachusetts 02215; and Division of Cancer Epidemiology (R.K.), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

Address all correspondence and requests for reprints to: Mattias Johansson, Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, 901 85 Umeå, Sweden. E-mail: Mattias.Johansson{at}oc.umu.se.

Background: Elevated levels of circulating IGF-I have consistently been associated with increased prostate cancer risk. We recently found a haplotype in the 3' region of the IGF-I gene associated with increased risk of prostate cancer, and we hypothesized that the observed association is mediated by circulating IGF-I.

Materials and Methods: We analyzed haplotypes and three haplotype-tagging single nucleotide polymorphisms (htSNPs) in the 3' region of the IGF-I gene in relation to circulating levels IGF-I in 698 control subjects from the CAncer Prostate in Sweden (CAPS) study and 575 cases and controls from the prospective Northern Sweden Health and Disease Cohort (NSHDC) study. We also performed a meta-analysis of these two and four other association studies on genetic variation in the 3' region of the IGF-I gene in relation to circulating IGF-I levels.

Results: The IGF-I haplotype previously associated with prostate cancer risk, labeled "TCC," was associated with elevated levels of IGF-I in the CAPS study (P = 0.02), but not in the NSHDC study. In contrast, two of the three IGF-I htSNPs tagging this haplotype, rs6220 and rs7136446, were associated with elevated levels of IGF-I in the NSHDC (P = 0.03 and P = 0.04, respectively), but not in the CAPS study. In the meta-analysis, the TCC haplotype and the rs6220 SNP were associated with elevated levels of circulating IGF-I (P = 0.001 and P < 0.0001, respectively).

Conclusions: Genetic variation in the 3' region of the IGF-I gene seems to influence circulating levels of IGF-I. This observation is consistent with the hypothesis that variation in the IGF-I gene plays a role in prostate cancer susceptibility by influencing circulating levels of IGF-I.

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