Dataset Information

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

ABSTRACT:

Introduction

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.

Methods

We 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.

Results

We 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 (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 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 (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29).

Conclusions

To 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.

SUBMITTER: Johnson N

PROVIDER: S-EPMC4522594 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Publications

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

Johnson Nichola N Dudbridge Frank F Orr Nick N Gibson Lorna L Jones Michael E ME Schoemaker Minouk J MJ Folkerd Elizabeth J EJ Haynes Ben P BP Hopper John L JL Southey Melissa C MC Dite Gillian S GS Apicella Carmel C Schmidt Marjanka K MK Broeks Annegien A Van't Veer Laura J LJ Atsma Femke F Muir Kenneth K Lophatananon Artitaya A Fasching Peter A PA Beckmann Matthias W MW Ekici Arif B AB Renner Stefan P SP Sawyer Elinor E Tomlinson Ian I Kerin Michael M Miller Nicola N Burwinkel Barbara B Marme Frederik F Schneeweiss Andreas A Sohn Christof C Guénel Pascal P Truong Therese T Cordina Emilie E Menegaux Florence F Bojesen Stig E SE Nordestgaard Børge G BG Flyger Henrik H Milne Roger R Zamora M Pilar MP Arias Perez Jose Ignacio JI Benitez Javier J Bernstein Leslie L Anton-Culver Hoda H Ziogas Argyrios A Clarke Dur Christina C Brenner Hermann H Müller Heiko H Arndt Volker V Dieffenbach Aida Karina AK Meindl Alfons A Heil Joerg J Bartram Claus R CR Schmutzler Rita K RK Brauch Hiltrud H Justenhoven Christina C Ko Yon-Dschun YD Nevanlinna Heli H Muranen Taru A TA Aittomäki Kristiina K Blomqvist Carl C Matsuo Keitaro K Dörk Thilo T Bogdanova Natalia V NV Antonenkova Natalia N NN Lindblom Annika A Mannermaa Arto A Kataja Vesa V Kosma Veli-Matti VM Hartikainen Jaana M JM Chenevix-Trench Georgia G Beesley Jonathan J Wu Anna H AH Van den Berg David D Tseng Chiu-Chen CC Lambrechts Diether D Smeets Dominiek D Neven Patrick P Wildiers Hans H Chang-Claude Jenny J Rudolph Anja A Nickels Stefan S Flesch-Janys Dieter D Radice Paolo P Peterlongo Paolo P Bonanni Bernardo B Pensotti Valeria V Couch Fergus J FJ Olson Janet E JE Wang Xianshu X Fredericksen Zachary Z Pankratz Vernon S VS Giles Graham G GG Severi Gianluca G Baglietto Laura L Haiman Chris C Simard Jacques J Goldberg Mark S MS Labrèche France F Dumont Martine M Soucy Penny P Teo Soo S Yip Cheng Har CH Phuah Sze Yee SY Cornes Belinda K BK Kristensen Vessela N VN Grenaker Alnæs Grethe G Børresen-Dale Anne-Lise AL Zheng Wei W Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Andrulis Irene L IL Knight Julia A JA Glendon Gord G Mulligan Anna Marie AM Devillee Peter P Figueroa Jonine J Chanock Stephen J SJ Lissowska Jolanta J Sherman Mark E ME Hall Per P Schoof Nils N Hooning Maartje M Hollestelle Antoinette A Oldenburg Rogier A RA Tilanus-Linthorst Madeleine M Liu Jianjun J Cox Angie A Brock Ian W IW Reed Malcolm W R MW Cross Simon S SS Blot William W Signorello Lisa B LB Pharoah Paul D P PD Dunning Alison M AM Shah Mitul M Kang Daehee D Noh Dong-Young DY Park Sue K SK Choi Ji-Yeob JY Hartman Mikael M Miao Hui H Lim Wei Yen WY Tang Anthony A Hamann Ute U Försti Asta A Rüdiger Thomas T Ulmer Hans Ulrich HU Jakubowska Anna A Lubinski Jan J Jaworska-Bieniek Katarzyna K Durda Katarzyna K Sangrajrang Suleeporn S Gaborieau Valerie V Brennan Paul P McKay James J Slager Susan S Toland Amanda E AE Vachon Celine C Yannoukakos Drakoulis D Shen Chen-Yang CY Yu Jyh-Cherng JC Huang Chiun-Sheng CS Hou Ming-Feng MF González-Neira Anna A Tessier Daniel C DC Vincent Daniel D Bacot Francois F Luccarini Craig C Dennis Joe J Michailidou Kyriaki K Bolla Manjeet K MK Wang Jean J Easton Douglas F DF García-Closas Montserrat M Dowsett Mitch M Ashworth Alan A Swerdlow Anthony J AJ Peto Julian J dos Santos Silva Isabel I Fletcher Olivia O

Breast cancer research : BCR 20140526 3

<h4>Introduction</h4>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.<h4>Methods</h4>We 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 ...[more]

PMID: 24887515

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Project description:BackgroundEarlier age of pubertal maturation in females is associated with increased risk for mental health problems in adolescence, compared with on-time or later maturation. However, most investigations of pubertal timing and mental health consider risk for individual disorders and fail to account for comorbidity. A latent-modeling approach using a large, nationally representative sample could better explain the transdiagnostic nature of the consequences of early-onset puberty.MethodsData on age of menarche and mental disorders were drawn from a population-representative sample of adolescents (n=4925), ages 13-17. Confirmatory factor analysis was used to fit four latent disorder categories: distress, eating, and externalizing, and fear disorders. Timing of menarche included those with earlier (age≤10, age 11) and later age of onset (age 13, 14+), relative to those with average timing of menarche (age 12). Associations between timing of menarche and latent disorders were estimated in a structural equation model (SEM), adjusted for age, income, race, parent marital status, BMI, and childhood adversity.ResultsThe measurement model evidenced acceptable fit (CFI=0.91; RMSEA=0.02). Onset of menarche before age 11 was significantly associated with distress disorders (coefficient=0.096; p<0.0001), fear disorders (coefficient=0.09; p<0.0001), and externalizing disorders (coefficient=0.039; p=0.049) as compared to on-time or late menarche. No residual associations of early menarche with individual disorders over and above the latent disorders were observed.ConclusionThe latent modeling approach illuminated meaningful transdiagnostic psychiatric associations with early timing of menarche. Biological processes initiated at puberty can influence cognitive and affective processes as well as social relationships for adolescents. Under developmentally normative conditions, these changes may be adaptive. However, for those out of sync with their peers, researchers and clinicians should recognize the potential for these processes to influence liability to a broad array of psychopathological consequences in adolescence.

Project description:INTRODUCTION:The stroma is the supportive framework of biologic tissue in the breast, consisting of various proteins such as the proteoglycans, decorin and lumican. Altered expression of decorin and lumican is associated with breast tumors. We hypothesized that genetic variation in the decorin (DCN) and lumican (LUM) genes may contribute to breast cancer. METHODS:We investigated associations of 14 common polymorphisms in the DCN and LUM genes with 798 breast cancer cases and 843 controls from Mayo Clinic, MN, USA. One polymorphism per gene with the strongest risk association in the Mayo Clinic sample was genotyped in 4,470 breast cancer cases and 4,560 controls from East Anglia, England (Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH)). RESULTS:In the Mayo Clinic sample, six polymorphisms were associated with breast cancer risk (P trend <or= 0.05). The association with LUM rs2268578, evaluated further in SEARCH, was positive, although the odds ratios (OR) were weaker and not statistically significant. ORs were 1.4 (95% confidence interval [CI], 1.1 to 1.8) for heterozygotes and 2.2 (95% CI, 1.1 to 4.3; P2 df = 0.002) for homozygotes in the Mayo Clinic sample, and were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.4 (95% CI, 1.0 to 2.1; P2 df = 0.13) for homozygotes in the SEARCH sample. In combined analyses, the ORs were 1.1 (95% CI, 1.0 to 1.2) for heterozygotes and 1.6 (95% CI, 1.2 to 2.3; P2 df = 0.005) for homozygotes. Positive associations for this polymorphism were observed for estrogen receptor-positive tumors in both the Mayo Clinic sample (OR for heterozygotes = 1.5, 1.1 to 1.9 and OR for homozygotes = 2.5, 1.2 to 5.3;P2 df = 0.001) and the SEARCH sample (OR for heterozygotes = 1.0, 0.9 to 1.1 and OR for homozygotes = 1.6, 1.0 to 2.5; P2 df = 0.10). In combined analyses, the ORs were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.9 (95% CI, 1.3 to 2.8; P2 df = 0.001) for homozygotes. CONCLUSIONS:Although LUM rs2268578 was associated with breast cancer in the Mayo Clinic study, particularly estrogen receptor-positive breast cancer, weaker and modest associations were observed in the SEARCH sample. These modest associations will require larger samples to adequately assess the importance of this polymorphism in breast cancer.

Dataset Information

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

Introduction

Methods

Results

Conclusions

Publications

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

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