Fehringer, G., Ozcelik, H., Knight, J. A., Paterson, A. D. & Boyd, N. F. Association between IGF1 CA microsatellites and mammographic density, anthropometric measures, and circulating IGF-I levels in premenopausal Caucasian women. Breast Cancer Res. Treat. 116, 413-423
Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. Breast Cancer Research and Treatment
(Impact Factor: 3.94).
10/2008; 116(2):413-23. DOI: 10.1007/s10549-008-0146-7
Results from several studies indicate that mammographic density, a strong risk factor for breast cancer, is greater in premenopausal women with higher circulating IGF-I levels. Both mammographic density and circulating IGF-I levels appear to be partly heritable traits. We hypothesized that in premenopausal women, IGF1 variants are associated with circulating IGF-I concentration, which in turn influences variation in breast density. Therefore, we examined the association of IGF1 polymorphisms with circulating IGF-I levels and mammographic density.
Percentage density, amounts of dense and non-dense (fat) tissue, IGF-I levels, and BMI were measured in 163 premenopausal women. Three CA repeat polymorphisms were genotyped, one each at the 5' and 3' ends of IGF1 and one in intron 2.
The number of 19 alleles at the 5' polymorphism was associated with lower circulating levels of IGF-I (P = 0.02), whereas the number of 185 alleles at the 3' polymorphism was associated with higher percentage density (P = 0.03) and a smaller amount of non-dense tissue (P = 0.02). The strength of the effect of the 185 allele at 3' on percentage density was greatly reduced and statistical significance lost when BMI was included in regression models.
Our results suggest an association between the number of 185 alleles at 3' with percentage density. This association appears to be mediated by body composition and particularly body fat, as indicated by the association of 3' IGF1 genotype with non-dense (fat) tissue and the mediating effect of BMI on the association of 3' genotype with percentage density.
Available from: ncbi.nlm.nih.gov
- "An important limitation of this study is that we did not genotype the IGF-1 promoter microsatellite polymorphism, which has been associated with circulating IGF-1 levels [6,10]. However, most previous studies have not observed this polymorphism to be associated with childhood body size. "
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Early life body size and circulating levels of IGF-1 and IGFBP-3 have been linked to increased risks of breast and other cancers, but it is unclear whether these exposures act through a common mechanism. Previous studies have examined the role of IGF-1 and IGFBP-3 genetic variation in relation to adult height and body size, but few studies have examined associations with birthweight and childhood size.
We examined whether htSNPs in IGF-1 and the IGFBP-1/IGFBP-3 gene region are associated with the self-reported outcomes of birthweight, body fatness at ages 5 and 10, and body mass index (BMI) at age 18 among healthy women from the Nurses’ Health Study (NHS) and NHSII. We used ordinal logistic regression to model odds ratios (ORs) and 95% confidence intervals (CI) of a one category increase for birthweight and somatotypes at ages 5 and 10. We used linear regression to model associations with BMI at age 18.
Among 4567 healthy women in NHS and NHSII, we observed no association between common IGF-1 or IGFBP-1/IGFBP-3 SNPs and birthweight, body fatness at ages 5 and 10, or BMI at age 18.
Common IGF-1 and IGFBP-1/IGFBP-3 SNPs are not associated with body size in early life.
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ABSTRACT: Several studies suggest that higher circulating insulin-like growth factor I (IGF-I) levels are associated with premenopausal breast cancer risk. Breast cancer risk and circulating IGF-I concentration appear to be partly heritable, thus genetic variation at IGF1 could influence IGF-I levels and breast cancer risk. We investigated the association of IGF1 CA repeat variants with premenopausal breast cancer risk using a family-based design. The study sample included 840 families from the Ontario Familial Breast Cancer Registry (OFBCR) and the Australian Breast Cancer Family Registry (ABCFR). Three CA repeat variants, at 5', 3', and in intron 2 were genotyped (5'CA, 3'CA, In2CA). We found several nominally significant associations. The 5'CA-21 allele (P = 0.03) and In2CA-212 allele (P = 0.04) were associated with lower risk, and the In2CA-216 allele with higher risk (P = 0.04) for the combined ABCFR-OFBCR. These associations were not significant after taking into account multiple comparisons. In2CA-216 was more strongly associated with risk when we used a recessive instead of an additive model (P = 0.01). 5'CA alleles of repeat length 18-20 were associated with higher risk (P = 0.02), and 5'CA alleles of >20 repeats were associated with lower risk (P = 0.01). These associations were significant in the OFBCR (In2CA-216 recessive, P = 0.02; 5'CA 18-20 and >20 allele grouping, P = 0.01) but not strongly supported by the ABCFR (In2CA-216 recessive, P = 0.14; 5'CA 18-20, P = 0.25; 5'CA >20, P = 0.20). The associations we found could be due to chance as many comparisons were made. Our results do not strongly support an association between these IGF1 variants and breast cancer risk.
Available from: Graham G Giles
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ABSTRACT: Height, weight, and body mass index (BMI) are partly heritable, known to be associated with chronic diseases, and are linked to circulating insulin-like growth factor I (IGF-I) concentrations. IGF-I concentrations are also partly heritable and thus genetic variation at IGF1 could influence height, weight, BMI and the risk of developing chronic diseases. Our objective was to examine the association of genetic variation at IGF1 with height, weight and BMI using a sample of premenopausal women. A family-based study design was used to investigate the association of three IGF1 CA repeat variants at 5' (5'CA), intron 2 (In2CA) and 3' (3'CA) with these anthropometric measures. We analyzed the data for 827 families of different sizes and configurations, which included 1520 premenopausal women. Nominally significant associations (P<or=0.05) were found for a rare 3' variant allele (3'CA-193) and BMI (P=0.05), and for the more common 3'CA-187 allele and weight (P=0.04). These associations did not remain significant when adjusted for multiple comparisons. Haplotype analysis did not support an association between these variants and anthropometric measures. This study does not support an association between IGF1 and these anthropometric measures. Study limitations, including sample size and capturing genetic variation at IGF1 with these markers, could mean associations were missed.
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