Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density.
BACKGROUND
High breast density is one of the strongest known risk factors for developing breast cancer. Insulin-like growth factor I (IGF-I) is a strong mitogen and has been suggested to increase breast cancer risk by increasing the amount of dense tissue in the female breast.


OBJECTIVE
We wanted to investigate the effect of common variation in the IGF-1 gene on serum IGF-I levels and on breast density.


METHODS
Mammograms and blood samples of 1,928 premenopausal participants of the Dutch Prospect-EPIC cohort were collected at baseline. Using a haplotype tagging approach, 16 single nucleotide polymorphisms (SNP) from three blocks covering the IGF-1 gene were genotyped in all study participants. Breast density was assessed using a quantitative computer-assisted method. For a subgroup of women, who went through menopause within 5 years after recruitment (n=656), premenopausal IGF-I levels and additionally postmenopausal breast density were determined. False positive report probabilities (FPRP) for statistically significant relations were calculated using the Wacholder method.


RESULTS
The minor alleles of five SNPs in block 3 were significantly associated with elevated levels of IGF-I (rs9989002, rs2033178, rs7136446, rs978458, rs6220; P-values: 0.01-0.04). The same SNPs were related with modestly higher percent breast density before menopause and-in the subgroup of women that became postmenopausal during follow-up-with a modestly higher percent breast density after menopause. The most significant result, i.e. the relation between rs6220 and IGF-I levels, had an FPRP<0.5 assuming prior probabilities of 0.01 and higher.


CONCLUSIONS
Common genetic variation in the IGF-1 gene is related to circulating levels of IGF-I, but the relationship with breast density is indecisive.
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands. mverheus@umcutrecht.nl
Martijn
M
Verheus
James D
JD
McKay
Rudolf
R
Kaaks
Federico
F
Canzian
Carine
C
Biessy
Mattias
M
Johansson
Diederick E
DE
Grobbee
Petra H M
PH
Peeters
Carla H
CH
van Gils
D001940:Breast / Q000033:anatomy & histology / Q000502:physiology*; D001943:Breast Neoplasms / Q000097:blood* / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism*; D008327:Mammography; D008593:Menopause; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies
D007334:Insulin-Like Growth Factor I