Association between IGF1 CA microsatellites and mammographic density, anthropometric measures, and circulating IGF-I levels in premenopausal Caucasian women
ABSTRACT 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.
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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.Breast Cancer Research and Treatment 03/2009; 118(2):415-24. DOI:10.1007/s10549-009-0336-y · 4.20 Impact Factor
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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.Journal of Human Genetics 03/2010; 55(4):255-8. DOI:10.1038/jhg.2010.17 · 2.53 Impact Factor
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ABSTRACT: Systemic insulin-like growth factor 1 (IGF1) level is an important risk factor for various diseases. The inter-individual variation of serum IGF1 is determined by environmental and genetic factors, which are attributed to a microsatellite in IGF1 promoter. However, the exact nature of the underlying regulatory elements accounting for this association has not been characterized. Here, we defined the haplotype patterns, including both SNPs and the microsatellite, in the Chinese population, and investigated their regulatory effect on serum IGF1 level. This is the first study in which haplotype patterns of the microsatellite and SNPs in the IGF1 promoter are examined together. The linkage disequilibrium (LD) patterns of IGF1 were examined using tagSNPs of the IGF1 regulatory region. The microsatellite, three tagSNPs and haplotypes were correlated with serum IGF1 concentration in 450 normal premenopausal Chinese women. Common alleles of the microsatellite were in strong LD with the three tagSNPs and were associated with particular haplotypes composed of SNPs. Neither the CA repeat number nor SNPs alone showed a robust association with serum IGF1 concentration. On the other hand, the haplotype T-19-A-T was significantly associated with serum IGF1 level. No association was found between SNPs and microsatellite alone. However, the haplotype showed better correlation with serum IGF1 level. The results indicate that the previously observed correlation with microsatellite was because of a haplotype effect in the IGF1 promoter. Microsatellite or tagSNPs alone are not the primary regulatory elements of IGF1 expression. The exact regulatory genetic variant needs to be defined by functional genetic studies.Clinical Endocrinology 12/2010; 74(4):520-7. DOI:10.1111/j.1365-2265.2010.03962.x · 3.35 Impact Factor