Abstract
BackgroundIncreased mammographic density is one of the strongest independent risk factors for breast cancer. It is believed that one third of breast cancers are derived from breasts with more than 50% density. Mammographic density is affected by age, BMI, parity, and genetic predisposition. It is also greatly influenced by hormonal and growth factor changes in a woman's life cycle, spanning from puberty through adult to menopause. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are therefore of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here.MethodsSamples from 964 postmenopausal Norwegian women aged 55-71 years were collected as a part of the Tromsø Mammography and Breast Cancer Study. All samples were genotyped for 25 SNPs in IGF1, IGF2, IGF1R, IGF2R, IGFALS and IGFBP3 using Taqman (ABI). The main statistical analyses were conducted with the PROC HAPLOTYPE procedure within SAS/GENETICS™ (SAS 9.1.3).ResultsThe haplotype analysis revealed six haploblocks within the studied genes. Of those, four had significant associations with circulating levels of IGF1 or IGFBP3 and/or mammographic density. One haplotype variant in the IGF1 gene was found to be associated with mammographic density. Within the IGF2 gene one haplotype variant was associated with levels of both IGF1 and IGFBP3. Two haplotype variants in the IGF2R were associated with the level of IGF1. Both variants of the IGFBP3 haplotype were associated with the IGFBP3 level and indicate regulation in cis.ConclusionPolymorphisms within the IGF1 gene and related genes were associated with plasma levels of IGF1, IGFBP3 and mammographic density in this study of postmenopausal women.
Highlights
Increased mammographic density is one of the strongest independent risk factors for breast cancer
Since variation in specific genes affects the levels of IGF1 and IGFBP3 and may influence mammographic density as well as breast cancer susceptibility, we set out to analyze 24 Single Nucleotide Polymorphism (SNP) in IGF1, IGF1 receptor (IGF1R), IGF2, IGF2 receptor (IGF2R), IGFBP3 and IGFALS and their association with mammographic density and plasma levels of IGF1 and IGFBP3 among 964 postmenopausal women
Stratified analysis by age and body mass index (BMI) We examined if the significant association found between IGF1 haplotype 4 and absolute mammographic density was specific to groups of age or BMI, and stratified the analysis by tertiles of age and tertiles of BMI
Summary
Increased mammographic density is one of the strongest independent risk factors for breast cancer. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here. Exposure to endogenous and exogenous steroid hormones and growth factors has been linked to both increased mammographic density and breast cancer risk. It has been estimated from twin studies that as much as 65% of the variation in mammographic density may be due to hereditary factors[12,13]. Since variation in specific genes affects the levels of IGF1 and IGFBP3 and may influence mammographic density as well as breast cancer susceptibility, we set out to analyze 24 SNPs in IGF1, IGF1R, IGF2, IGF2R, IGFBP3 and IGFALS and their association with mammographic density and plasma levels of IGF1 and IGFBP3 among 964 postmenopausal women
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