Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study
Authors: Johnson Nichola , Dudbridge Frank , Orr Nick , Gibson Lorna , Jones Michael E , Schoemaker Minouk J , Folkerd Elizabeth J , Haynes Ben P , Hopper John L , Southey Melissa C , Dite Gillian S , Apicella Carmel , Schmidt Marjanka K , Broeks Annegien , Van’t Veer Laura J , Atsma Femke , Muir Kenneth , Lophatananon Artitaya , Fasching Peter A , Beckmann Matthias W , Ekici Arif B , Renner Stefan P , Sawyer Elinor , Tomlinson Ian , Kerin Michael , Miller Nicola , Burwinkel Barbara , Marme Frederik , Schneeweiss Andreas , Sohn Christof , Guénel Pascal , Truong Therese , Cordina Emilie , Menegaux Florence , Bojesen Stig E , Nordestgaard Børge G , Flyger Henrik , Milne Roger , Zamora M Pilar , Arias Perez Jose Ignacio , Benitez Javier , Bernstein Leslie , Anton-Culver Hoda , Ziogas Argyrios , Clarke Dur Christina , Brenner Hermann , Müller Heiko , Arndt Volker , Dieffenbach Aida Karina , Meindl Alfons , Heil Joerg , Bartram Claus R , Schmutzler Rita K , Brauch Hiltrud , Justenhoven Christina , Ko Yon-Dschun ,   The GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Nevanlinna Heli , Muranen Taru A , Aittomäki Kristiina , Blomqvist Carl , Matsuo Keitaro , Dörk Thilo , Bogdanova Natalia V , Antonenkova Natalia N , Lindblom Annika , Mannermaa Arto , Kataja Vesa , Kosma Veli-Matti , Hartikainen Jaana M , Chenevix-Trench Georgia , Beesley Jonathan ,   kConFab Investigators,   Australian Ovarian Cancer Study Group, Wu Anna H , Van den Berg David , Tseng Chiu-Chen , Lambrechts Diether , Smeets Dominiek , Neven Patrick , Wildiers Hans , Chang-Claude Jenny , Rudolph Anja , Nickels Stefan , Flesch-Janys Dieter , Radice Paolo , Peterlongo Paolo , Bonanni Bernardo , Pensotti Valeria , Couch Fergus J , Olson Janet E , Wang Xianshu , Fredericksen Zachary , Pankratz Vernon S , Giles Graham G , Severi Gianluca , Baglietto Laura , Haiman Chris , Simard Jacques , Goldberg Mark S , Labrèche France , Dumont Martine , Soucy Penny , Teo Soo , Yip Cheng Har , Phuah Sze Yee , Cornes Belinda K , Kristensen Vessela N , Grenaker Alnæs Grethe , Børresen-Dale Anne-Lise , Zheng Wei , Winqvist Robert , Pylkäs Katri , Jukkola-Vuorinen Arja , Grip Mervi , Andrulis Irene L , Knight Julia A , Glendon Gord , Mulligan Anna Marie , Devillee Peter , Figueroa Jonine , Chanock Stephen J , Lissowska Jolanta , Sherman Mark E , Hall Per , Schoof Nils , Hooning Maartje , Hollestelle Antoinette , Oldenburg Rogier A , Tilanus-Linthorst Madeleine , Liu Jianjun , Cox Angie , Brock Ian W , Reed Malcolm WR , Cross Simon S , Blot William , Signorello Lisa B , Pharoah Paul DP , Dunning Alison M , Shah Mitul , Kang Daehee , Noh Dong-Young , Park Sue K , Choi Ji-Yeob , Hartman Mikael , Miao Hui , Lim Wei Yen , Tang Anthony , Hamann Ute , Försti Asta , Rüdiger Thomas , Ulmer Hans Ulrich , Jakubowska Anna , Lubinski Jan , Jaworska-Bieniek Katarzyna , Durda Katarzyna , Sangrajrang Suleeporn , Gaborieau Valerie , Brennan Paul , McKay James , Slager Susan , Toland Amanda E , Vachon Celine , Yannoukakos Drakoulis , Shen Chen-Yang , Yu Jyh-Cherng , Huang Chiun-Sheng , Hou Ming-Feng , González-Neira Anna , Tessier Daniel C , Vincent Daniel , Bacot Francois , Luccarini Craig , Dennis Joe , Michailidou Kyriaki , Bolla Manjeet K , Wang Jean , Easton Douglas F , García-Closas Montserrat , Dowsett Mitch , Ashworth Alan , Swerdlow Anthony J , Peto Julian , dos Santos Silva Isabel , Fletcher Olivia 
Published: May 2014

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 (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).

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.