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A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density.

Rudolph A, Fasching PA, Behrens S, Eilber U, Bolla MK, Wang Q, Thompson D, Czene K, Brand JS, Li J, Scott C, Pankratz VS, Brandt K, Hallberg E, Olson JE, Lee A, Beckmann MW, Ekici AB, Haeberle L, Maskarinec G, Le Marchand L, Schumacher F, Milne RL, Knight JA, Apicella C, Southey MC, Kapuscinski MK, Hopper JL, Andrulis IL, Giles GG, Haiman CA, Khaw KT, Luben R, Hall P, Pharoah PD, Couch FJ, Easton DF, Dos-Santos-Silva I, Vachon C, Chang-Claude J - Breast Cancer Res. (2015)

Bottom Line: No significant interactions were identified after adjustment for multiple testing.The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL.Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02).

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120, Heidelberg, Germany. a.rudolph@dkfz.de.

ABSTRACT

Introduction: Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density.

Methods: The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (P int) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density.

Results: No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02).

Conclusions: The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.

No MeSH data available.


Related in: MedlinePlus

Meta-analyses of study estimates for association of current use of menopausal hormone therapy with square-root-transformed percent mammographic density analyzing all study subjects (a), non-cases (b) and cases (c). ABCFS Australian breast cancer family study, BBCC Bavarian breast cancer cases and controls, EPIC European prospective investigation into cancer and nutrition, MCBS Mayo clinic breast cancer study, MCCS Melbourne collaborative cohort study, MEC Multi-ethnic cohort, MMHS Mayo mammography health study, OFBCR Ontario familial breast cancer registry, SASBAC Singapore and Sweden breast cancer study, SIBS Sisters in breast screening study
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Fig1: Meta-analyses of study estimates for association of current use of menopausal hormone therapy with square-root-transformed percent mammographic density analyzing all study subjects (a), non-cases (b) and cases (c). ABCFS Australian breast cancer family study, BBCC Bavarian breast cancer cases and controls, EPIC European prospective investigation into cancer and nutrition, MCBS Mayo clinic breast cancer study, MCCS Melbourne collaborative cohort study, MEC Multi-ethnic cohort, MMHS Mayo mammography health study, OFBCR Ontario familial breast cancer registry, SASBAC Singapore and Sweden breast cancer study, SIBS Sisters in breast screening study

Mentions: The beta value from fixed effect meta-analysis of the association between current use of MHT and square-root-transformed percent density was 0.43 (95 % CI 0.34, 0.53). There was some indication of between-study heterogeneity (P value for heterogeneity = 0.12, I2= 35.4 %), which was attributable to one study (OFBCR). The beta value for current use of MHT was very similar when analyzing solely cases (beta = 0.42, 95 % CI 0.26, 0.58) or non-cases (beta = 0.42, 95 % CI 0.30, 0.54). The forest plots for the whole study sample, non-cases and cases, respectively are displayed in Fig. 1.Fig. 1


A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density.

Rudolph A, Fasching PA, Behrens S, Eilber U, Bolla MK, Wang Q, Thompson D, Czene K, Brand JS, Li J, Scott C, Pankratz VS, Brandt K, Hallberg E, Olson JE, Lee A, Beckmann MW, Ekici AB, Haeberle L, Maskarinec G, Le Marchand L, Schumacher F, Milne RL, Knight JA, Apicella C, Southey MC, Kapuscinski MK, Hopper JL, Andrulis IL, Giles GG, Haiman CA, Khaw KT, Luben R, Hall P, Pharoah PD, Couch FJ, Easton DF, Dos-Santos-Silva I, Vachon C, Chang-Claude J - Breast Cancer Res. (2015)

Meta-analyses of study estimates for association of current use of menopausal hormone therapy with square-root-transformed percent mammographic density analyzing all study subjects (a), non-cases (b) and cases (c). ABCFS Australian breast cancer family study, BBCC Bavarian breast cancer cases and controls, EPIC European prospective investigation into cancer and nutrition, MCBS Mayo clinic breast cancer study, MCCS Melbourne collaborative cohort study, MEC Multi-ethnic cohort, MMHS Mayo mammography health study, OFBCR Ontario familial breast cancer registry, SASBAC Singapore and Sweden breast cancer study, SIBS Sisters in breast screening study
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4537547&req=5

Fig1: Meta-analyses of study estimates for association of current use of menopausal hormone therapy with square-root-transformed percent mammographic density analyzing all study subjects (a), non-cases (b) and cases (c). ABCFS Australian breast cancer family study, BBCC Bavarian breast cancer cases and controls, EPIC European prospective investigation into cancer and nutrition, MCBS Mayo clinic breast cancer study, MCCS Melbourne collaborative cohort study, MEC Multi-ethnic cohort, MMHS Mayo mammography health study, OFBCR Ontario familial breast cancer registry, SASBAC Singapore and Sweden breast cancer study, SIBS Sisters in breast screening study
Mentions: The beta value from fixed effect meta-analysis of the association between current use of MHT and square-root-transformed percent density was 0.43 (95 % CI 0.34, 0.53). There was some indication of between-study heterogeneity (P value for heterogeneity = 0.12, I2= 35.4 %), which was attributable to one study (OFBCR). The beta value for current use of MHT was very similar when analyzing solely cases (beta = 0.42, 95 % CI 0.26, 0.58) or non-cases (beta = 0.42, 95 % CI 0.30, 0.54). The forest plots for the whole study sample, non-cases and cases, respectively are displayed in Fig. 1.Fig. 1

Bottom Line: No significant interactions were identified after adjustment for multiple testing.The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL.Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02).

View Article: PubMed Central - PubMed

Affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, D-69120, Heidelberg, Germany. a.rudolph@dkfz.de.

ABSTRACT

Introduction: Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density.

Methods: The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (P int) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density.

Results: No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02).

Conclusions: The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.

No MeSH data available.


Related in: MedlinePlus