Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels.
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.


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.
Johansson
Mattias
M
Department of Surgical and Perioperative Sciences, Umeå University Hospital, 901 85 Umeå, Sweden. Mattias.Johansson@oc.umu.se
McKay
James D
JD
Wiklund
Fredrik
F
Rinaldi
Sabina
S
Verheus
Martijn
M
van Gils
Carla H
CH
Hallmans
Göran
G
Bälter
Katarina
K
Adami
Hans-Olov
HO
Grönberg
Henrik
H
Stattin
Pär
P
Kaaks
Rudolf
R
D015331:Cohort Studies; D018628:Gene Dosage; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism*; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics*; D013548:Sweden / Q000453:epidemiology
D007334:Insulin-Like Growth Factor I