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

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.

Links between age at menarche, antral follicle count, and body mass index in African American and European American women

“…Additionally, many large genome-wide studies have found links between LIN28B and menarche (6-8, 10, 15, 64). Importantly, genetic loci that influence the age of menarche and age of thelarche often also impact breast cancer risk in women (15,(33)(34)(35)(36). These studies underscore the tremendous complexity of the regulation of puberty timing and the pleiotropy and environmental interactions that likely exist between menarche, body fat, and several diseases.…”

“…Not only does the reproductive lifespan's timing and length relate to female fertility, but the lifespan itself is closely associated with risks for various diseases and cancers. Notably, many genetic and epidemiologic studies have found that earlier menarche is linked with great risks for obesity (11,(20)(21)(22)(23)(24)(25)(26)(27), type 2 diabetes mellitus or insulin resistance (2,28,29), cardiovascular disease and mortality (2,29,30), and various cancers, including endometrial cancer (14,31) and breast cancer (14,15,(32)(33)(34)(35)(36). Conversely, later age of menarche is linked with increased risk for osteoporosis, decreased fertility, and decreased risk for breast and endometrial cancer, type 2 diabetes, and obesity (2,29,37).…”

Gene-Environment Dependence Creates Spurious Gene-Environment Interaction

“…We thank the Breast Cancer Association Consortium (BCAC) for access to the data published in Johnson et al 15 …”

Association of breast cancer risk with polymorphisms in genes involved in the metabolism of xenobiotics and interaction with tobacco smoking: A gene‐set analysis

“…Out of the 182 genetic loci associated with breast cancer in GWAS, 11 no one was located in XM genes. Breast cancer risk in relation to XM gene polymorphisms has been investigated in NATs, 12 CYPs, [13][14][15] GSTs, 16 UGTs, 17,18 SULTs, 19,20 but in these studies breast cancer risk was investigated in relation to individual SNPs without consideration of their possible joint effects. Studies on NAT1 and NAT2 genes have assessed breast cancer risk in relation to specific combinations of SNPs to characterize the acetylator phenotype (slow, intermediate or rapid).…”