Cancer Epidemiol Biomarkers Prev. , 2019., Feb 1. doi: 10.1158/1055-9965.EPI-18-0826.

Genetic Variation in Steroid and Xenobiotic Metabolizing Pathways and Enterolactone Excretion Before and After Flaxseed Intervention in African American and European American Women.

Chang H Yao S Tritchler D et al.


Background: Metabolism and excretion of the phytoestrogen enterolactone (ENL), which has been associated with breast cancer risk, may be affected by variation in steroid hormone and xenobiotic-metabolizing genes.Methods: We conducted a randomized, crossover flaxseed intervention study in 252 healthy, postmenopausal women [137 European ancestry (EA) and 115 African ancestry (AA)] from western New York. Participants were randomly assigned to maintain usual diet or consume 10 g/day ground flaxseed for 6 weeks. After a 2-month washout period, participants crossed over to the other diet condition for an additional 6 weeks. Urinary ENL excretion was measured by gas chromatography-mass spectrometry and 70 polymorphisms in 29 genes related to steroid hormone and xenobiotic metabolism were genotyped. Mixed additive genetic models were constructed to examine association of genetic variation with urinary ENL excretion at baseline and after the flaxseed intervention.Results: SNPs in several genes were nominally (P < 0.05) associated with ENL excretion at baseline and/or after intervention: ESR1, CYP1B1, COMT, CYP3A5, ARPC1A, BCL2L11, SHBG, SLCO1B1, and ZKSCAN5 A greater number of SNPs were associated among AA women than among EA women, and no SNPs were associated in both races. No SNP-ENL associations were statistically significant after correction for multiple comparisons. Conclusions: Variation in several genes related to steroid hormone metabolism was associated with lignan excretion at baseline and/or after flaxseed intervention among postmenopausal women. Impact: These findings may contribute to our understanding of the differences observed in urinary ENL excretion among AA and EA women and thus hormone-related breast cancer risk.

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Key Points

Not all studies support a positive association between lignan exposure and optimal health effects, which may be a result of individual variation in metabolism. Variation in steroid hormone–metabolizing genes may also impact the effects of dietary lignan exposure. Limited research describing associations between lignans and other phytoestrogens and genetic variation support that phytoestrogen biomarker levels may be dependent upon variation in genes related to steroid hormone metabolism. Most of the previous genetic studies have been conducted in populations of European ancestry (EA), and those from populations of African ancestry (AA) are lacking. Here a dietary flaxseed intervention study  healthy postmenopausal women of both African and European descent, which aimed to examine associations of single nucleotide polymorphisms (SNPs) in genes important in steroid hormone metabolism with enterolignan excretion at baseline and in response to the flaxseed intervention was conducted.

This study has several notable strengths including the use of a crossover design where each participant serves as her own control, and thus the influence of confounding covariates is reduced. A relatively large number of SNPs in related genes, and involved both AA and EA populations were used. Although none of the selected SNPs were significantly associated with ENL excretion after correction for multiple comparisons, the results of this study nevertheless may shed light on the potential impact of genetic variation on lignan metabolism of postmenopausal women and stimulate further research.

It was concluded that variation in a number of genes related to steroid hormone metabolism were associated with lignan excretion at baseline and after flaxseed intervention among postmenopausal women, which may help explain the difference in urinary ENL levels among AAs and EAs. To our knowledge, this is the first report suggesting potential explanations related to genetic variation for racial disparities in lignan metabolism among AA and EA postmenopausal women. Future chemoprevention and diet intervention strategies to reduce breast cancer incidence and mortality may benefit by incorporation of genetic variation and examination by race.