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

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Johnson N, Dudbridge F, Orr N, Gibson L, Jones ME, Schoemaker MJ, Folkerd EJ, Haynes BP, Hopper JL, Southey MC, Dite GS, Apicella C, Schmidt MK, Broeks A, Van TVLJ, Atsma F, Muir K, Lophatananon A, Fasching PA, Beckmann MW, Ekici AB, Renner SP, Sawyer E, Tomlinson I, Kerin M, Miller N, Burwinkel B, Marme F, Schneeweiss A, Sohn C, Guenel P, Truong T, Cordina E, Menegaux F, Bojesen SE, Nordestgaard BG, Flyger H, Milne R, Zamora MP, Arias Perez JI, Benitez J, Bernstein L, Anton-Culver H, Ziogas A, Clarke Dur C, Brenner H, Muller H, Arndt V, Dieffenbach AK, Meindl A, Heil J, Bartram CR, Schmutzler RK, Brauch H, Justenhoven C, Ko YD, Nevanlinna H, Muranen TA, Aittomaki K, Blomqvist C, Matsuo K, Dork T, Bogdanova NV, Antonenkova NN, Lindblom A, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Chenevix-Trench G, Beesley J, Wu AH, Van den Berg D, Tseng CC, Lambrechts D, Smeets D, Neven P, Wildiers H, Chang-Claude J, Rudolph A, Nickels S, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Pensotti V, Couch FJ, Olson JE, Wang X, Fredericksen Z, Pankratz VS, Giles GG, Severi G, Baglietto L, Haiman C, Simard J, Goldberg MS, Labreche F, Dumont M, Soucy P, Teo S, Yip CH, Phuah SY, Cornes BK, Kristensen VN, Grenaker Alnaes G, Borresen-Dale AL, Zheng W, Winqvist R, Pylkas K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Devillee P, Figueroa J, Chanock SJ, Lissowska J, Sherman ME, Hall P, Schoof N, Hooning M, Hollestelle A, Oldenburg RA, Tilanus-Linthorst M, Liu J, Cox A, Brock IW, Reed MW, Cross SS, Blot W, Signorello LB, Pharoah PD, Dunning AM, Shah M, Kang D, Noh DY, Park SK, Choi JY, Hartman M, Miao H, Lim WY, Tang A, Hamann U, Forsti A, Rudiger T, Ulmer HU, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Slager S, Toland AE, Vachon C, Yannoukakos D, Shen CY, Yu JC, Huang CS, Hou MF, Gonzalez-Neira A, Tessier DC, Vincent D, Bacot F, Luccarini C, Dennis J, Michailidou K, Bolla MK, Wang J, Easton DF, Garcia-Closas M, Dowsett M, Ashworth A, Swerdlow AJ, Peto J, Dos Santos Silva I, Fletcher O (2014) Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study. Breast Cancer Res 16:


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="">

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