Abstract
IntroductionWe have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.MethodsWe further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.ResultsWe confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29).ConclusionsTo our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
Highlights
We have previously shown that a tag single nucleotide polymorphism, which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years
Three categories of single nucleotide polymorphism (SNP) were chosen for inclusion in the array: SNPs selected on the basis of pooled genome-wide association study data; SNPs selected for the fine-mapping of published risk loci; and candidate SNPs selected on the basis of previous analyses or specific hypotheses. rs10235235 was a candidate SNP selected on the basis of our previous analyses [19]
The overall minor allele frequency (MAF) for European control women was 0.089, but with strong evidence of between-study heterogeneity (Phet = 1 × 10−22) that was accounted for by the three Finnish studies (HEBCS, MAF = 0.15; KBCP, MAF = 0.21; and OBCS, MAF = 0.15; P for heterogeneity (Phet) = 0.01); no evidence of heterogeneity remained after taking account of these studies (MAF = 0.087; Phet = 0.23)
Summary
We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Genome-wide association studies [5,6] have identified more than 70 common variants that are associated with breast cancer susceptibility but they account for only another approximately 15% of the excess familial risk. A statistically efficient alternative is to increase power by trying to identify variants associated with known quantitative phenotypic markers of susceptibility to breast cancer [7], and to test them for association with breast cancer risk. This approach might improve our understanding of the biological mechanisms involved in breast cancer pathogenesis
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