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Box FI Kuopio, Finland. We have previously shown that a tag single nucleotide polymorphism rswhich maps to the CYP3A locus 7q We further investigated the association of rs with breast cancer risk in a large case control study of 47, cases and 47, Dietmar sawyere wife sexual dysfunction from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of Dietmar sawyere wife sexual dysfunction was conducted using a custom Illumina Infinium array.

Dietmar sawyere wife sexual dysfunction analyses were conducted to determine whether this association was modified by age Dietmar sawyere wife Dietmar sawyere wife sexual dysfunction dysfunction diagnosis, ethnicity, age at menarche or tumor characteristics. We confirmed the association of rs with Dietmar sawyere wife sexual dysfunction cancer risk for women of European ancestry but found no evidence that this association differed with age at Dietmar sawyere wife sexual dysfunction. There was no evidence of effect modification by tumor characteristics.

To our knowledge rs 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 Dietmar sawyere wife sexual dysfunction menarche and a reduction in breast cancer Dietmar sawyere wife sexual dysfunction. These associations are likely mediated via Dietmar sawyere wife sexual dysfunction effect on circulating hormone levels.

Family history is a well-established risk factor for breast cancer. First-degree relatives of women with breast cancer have an approximately twofold increased risk of developing the disease relative to the general population [ 1 ]. Twin studies are consistent with this familial clustering having, at least in part, a genetic origin [ 23 ]. 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 then to test them Dietmar sawyere wife sexual dysfunction association with breast cancer risk.

This approach might also improve our understanding of the biological mechanisms involved in breast cancer pathogenesis. Endogenous sex hormones are well-established risk factors for breast cancer in postmenopausal women [ 8 ]; Dietmar sawyere wife sexual dysfunction evidence in premenopausal women Dietmar sawyere wife sexual dysfunction less consistent, with some, but not all, studies suggesting an association between higher circulating levels of estrogens and increased breast cancer risk [ 9 - 17 ].

Genetic factors influence the levels of endogenous sex hormones [ 18 ] and therefore single nucleotide polymorphisms SNPs in genes regulating these hormonal pathways are good candidates for Dietmar sawyere wife sexual dysfunction breast cancer predisposition variants. We have previously studied SNPs tagging 42 genes that might influence sex hormone levels in healthy premenopausal women of European ancestry in relation to cyclic variations in oestrogen levels during the menstrual cycle.

The aim of the present study was to further investigate an association between rs and breast cancer risk using a much larger set of subjects — the Breast Cancer Association Consortium BCAC — comprising Dietmar sawyere wife sexual dysfunction from 49 additional studies, and to assess whether there was evidence of effect modification by age at diagnosis, ethnicity, age at menarche or tumour characteristics.

The significance of tumor necrosis...

Samples for the case—control analyses were drawn from 52 studies participating in the BCAC: The majority were population-based or hospital-based case—control studies, but some studies were nested in cohorts, selected samples by age, oversampled for cases with a family history or selected samples on the basis of tumour characteristics Table S1 in Additional file 1.

Study subjects were recruited on protocols approved by the Institutional Review Boards at each participating institution, Dietmar sawyere wife sexual dysfunction all subjects provided written informed consent Additional file 2.

Full details of SNP selection, array design, genotyping and post-genotyping quality control have been published [ 5 ].

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Briefly, three categories of SNPs 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.

Samples were excluded for any of the following reasons: For these studies, no exclusions for ethnic outliers were made, but principal components analysis see below was used to adjust for inflation in these studies. Principal component analyses were carried out separately for the European, Asian and African-American subgroups, based on a subset of 37, uncorrelated SNPs. For the analyses of European subjects, we included the first six principal components as covariates, together with a seventh component derived specific to one study LMBC for which there was substantial inflation not accounted for by the components derived from the analysis of all studies.

Addition of further Dietmar sawyere wife sexual dysfunction components did not reduce inflation further. Two Dietmar sawyere wife sexual dysfunction components were included for the studies conducted in Asian populations and two principal components were included for the African-American studies.

After exclusions there Dietmar sawyere wife sexual dysfunction 47, invasive breast cancer case samples and 47, control samples from 49 studies 38 from populations of predominantly European ancestry, nine Asian and two African-American used in the analysis Tables S1 and S2 in Additional file 1.

We did not test for an association between rs and age at menarche in our hypothesis-generating study [ 19 ]. Call rates were We estimated per-allele and genotypic log odds ratios ORs for the European, Asian and African-American subgroups separately using logistic regression, adjusted for principal components and study [ 5 ].

To test for departure from a multiplicative model we compared multiplicative and unconstrained models using a one degree of freedom likelihood ratio Dietmar sawyere wife sexual dysfunction. Heterogeneity in ORs between studies within each subgroup European, Asian and African-Americanand between subgroups, was assessed using the Cochrane Q statistic and quantified using the I 2 measure [ 20 ].

Availability of data for each of the stratifying variables in each study is shown in Table S3 in Additional file 1. To assess the relationship between each of the stratifying variables and genotype, stratum-specific ORs were calculated using logistic regression. Cases Dietmar sawyere wife sexual dysfunction each stratum were compared with all control subjects, adjusted for study and principal components.

Case-only logistic Dietmar sawyere wife sexual dysfunction was used to test for heterogeneity Dietmar sawyere wife sexual dysfunction strata binary stratifying variables or across strata stratifying variables with three or more strata. P values were estimated using likelihood ratio tests with one degree of freedom. We assessed whether rs was associated with age at menarche in cases and controls separately.

The two groups did not...

Studies that had not collected data on age at menarche in both cases and controls were excluded Table S4 in Additional file 1. We used linear regression, adjusted for principal components and study, to estimate the relationship between age at menarche years and rs genotype 0, 1, 2 rare alleles and logistic regression adjusted for principal Dietmar sawyere wife sexual dysfunction and study to estimate the association between age at menarche Dietmar sawyere wife sexual dysfunction breast cancer risk.

May 26, Genetic factors influence...

We considered four models: Nested models were compared using Dietmar sawyere wife sexual dysfunction Dietmar sawyere wife sexual dysfunction tests. All P values reported are two-sided.

The case—control analysis comprised genotype data for 47, invasive breast cancer cases and 47, controls from 49 studies, including 80, The overall MAF for European control women was 0.

The case—control analysis was consistent with a modest association between rs and breast cancer risk for women of European ancestry, with an estimated per-allele OR of 0. Genotype-specific ORs were 0. Association of rs with breast cancer risk for women of European ancestry. Forest plots of the association of the rs AG heterozygote genotype A and GG homozygote genotype B with breast cancer risk for women of European ancestry.

Data for rs in women of Asian or African-American ancestry were more limited, with just two African-American studies 1, cases and controls and nine Asian studies 5, cases and 6, controls.

Association of rs with risk of breast Dietmar sawyere wife sexual dysfunction for women of European ancestry: Association of rs with risk of breast cancer for women of European ancestry stratified by oestrogen Dietmar sawyere Dietmar sawyere wife sexual dysfunction sexual dysfunction ER status, progesterone receptor PR status, morphology, grade and nodal status.

OR hetodds ratio comparing rs AG genotype versus AA genotype; H 0null hypothesis; NK, not known; OR homodds ratio comparing rs GG genotype versus AA genotype; P 1test Dietmar sawyere wife sexual dysfunction H 0 no association between rs and breast cancer risk; P hettest of H 0 no difference between stratum specific estimates for variables with two strata or test of H Dietmar sawyere wife sexual dysfunction no linear trend in stratum specific estimates for variables with three strata.

The SNP rs maps to a locus CYP3A that has been considered Dietmar sawyere wife sexual dysfunction a priori candidate for involvement in determining age at menopause and age at menarche [ 2122 ].

There was a 1. H 0null hypothesis; NK, not known; OR hetodds ratio comparing rs AG genotype versus AA genotype; Dietmar sawyere wife sexual dysfunction homodds ratio comparing rs GG genotype versus AA genotype; P 1test of H 0 no association between rs and breast cancer risk; P hettest of H 0 no difference between stratum specific estimates.

Dietmar sawyere wife sexual dysfunction of rs with age at menarche for women of European ancestry by case-control status. H 0null hypothesis; P trendtest of H 0 no linear trend in age at menarche according to rs genotype.

H 0null hypothesis; OR hetodds ratio comparing rs AG genotype versus AA genotype; OR homodds ratio comparing rs GG genotype versus AA genotype; P 1test of H 0 no association between rs and breast cancer risk; P hettest of H 0 no linear trend in stratum specific estimates.

This study of more than 47, breast cancer cases and 47, controls has confirmed that rs, mapping to 7q Previously, our hypothesis-generating study of 10, breast cancer cases and 17, controls found a per-allele OR estimate of 0. In this considerably larger study, we found a heterozygote OR estimate of 0. To our knowledge, rs is the first SNP 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 [ 23 ].

Genome-wide association studies have identified more than 70 breast cancer risk variants [ 56 ] and more than 30 variants associated with age at menarche [ 22 ], none of which map to the CYP3A locus.

In this current analysis, rs accounted for only 0. Our analysis shows some inconsistency with a recent genome-wide study of circulating oestradiol, testosterone Dietmar sawyere wife sexual dysfunction sex hormone-binding globulin in postmenopausal women [ 24 ]. In that study there was no genome-wide significant association observed with plasma oestradiol levels in either the primary analysis of approximately 1, postmenopausal women who were not taking postmenopausal hormones at blood draw or the secondary analysis that included approximately current postmenopausal hormone users.

One possible explanation for the apparent effect modification of the rs—breast cancer risk association by age at menarche is that this is a function of genotyping a marker SNP rather Dietmar sawyere wife sexual dysfunction the true causal variant.

Only chromosomes carrying the rare allele of rs and the rare protective allele of SNP X type iii would be enriched in controls. Genotyping the marker Dietmar sawyere wife sexual dysfunction rather than the causal variant Dietmar sawyere wife sexual dysfunction to misclassification.

As Dietmar sawyere wife sexual dysfunction causal variant is associated with a protective effect on breast cancer risk, the proportion of chromosomes carrying both the rare allele of the causal variant and the marker type iii compared with the common allele of the causal variant and the rare allele of the marker type ii will be greater in controls than in cases such that the Dietmar sawyere wife sexual dysfunction of misclassification will be greater for cases than controls.

This will attenuate the association between genotype and age at menarche to a greater extent in cases than in controls creating an apparent effect modification. Fine mapping and functional studies will be required to identify the causal variant and to determine the true relationship between the causal variant, age at menarche and breast cancer Dietmar sawyere wife sexual dysfunction. Despite our original finding of a strong association between rs Dietmar sawyere wife sexual dysfunction hormone levels, we found no evidence that the association between this SNP and breast cancer risk differed by the hormone receptor status of the tumour, and nor did we find any evidence that the association differed by stage, grade or lymph node involvement.

Given the number of stratified analyses that we carried out six stratifying variables and given that there is no biological basis to support an interaction between rs and morphology, this is probably a chance observation. We used age at diagnosis as a proxy for menopausal status at diagnosis because menopausal status at diagnosis is difficult to determine by questionnaire, especially given the use of hormone replacement therapies; while information on age at diagnosis was available for all but 1.

The strengths of our study include the large size of this combined analysis, and the availability of information on tumour characteristics for the majority of cases and on age at menarche for the majority of cases and controls. Limitations include low power of the study to examine an association between genotype and breast cancer risk for non-Europeans.

In summary, we have confirmed that rs is associated with breast cancer, Dietmar sawyere wife sexual dysfunction shown for the first time that rs is associated Dietmar sawyere wife sexual dysfunction age at menarche in controls and have suggested a potential mechanism for these associations. P value for linear trend; SNP: Dietmar sawyere wife sexual dysfunction authors take responsibility for the work and read and approved the final version of the manuscript.

Contains Table S1 presenting details of participating BCAC studies; Table S2 presenting rs genotypes for breast cancer cases and controls from 49 BCAC studies; Table S3 presenting availability of data on age at diagnosis, hormone receptor status, morphology, Dietmar sawyere wife sexual dysfunction and nodal status for breast cancer cases from 38 European BCAC studies; Table S4 presenting availability of data on age at menarche for breast cancer cases and controls from 40 European BCAC studies; and Figure S1 showing association of the rsAG genotype with breast cancer risk for women of Asian and African-American ancestry.

The authors thank all of the individuals who took part in these studies and all of the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. NBHS thanks study participants and research staff for their contributions and commitment to the study. SBCGS thanks study participants and research staff for their contributions and commitment to the study. SKKDKFZS are grateful to all of the patients for their participation and thank the physicians and other hospital staff, scientists, research assistants and study staff who contributed to the patient recruitment, data collection and sample preparation.

UKBGS thanks Breakthrough Breast Cancer and the Institute of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors, nurses and other healthcare providers and health information sources who have contributed to the study.

The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, Dietmar sawyere wife sexual dysfunction does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.

Collection of cancer incidence data used in this study was supported by the California Department of Public Health as part of the statewide cancer reporting program mandated by California Health and Safety Code Section The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the CDC or the Mississippi Cancer Registry.

National Center for Biotechnology InformationU. Journal List Breast Cancer Res v. Published online May Hiltrud Brauch 39 Dietmar sawyere wife sexual dysfunction. Christina Justenhoven 39 Dr.

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