Dataset Information

Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.

ABSTRACT:

Background

The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.

Methods

We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.

Results

The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4).

Conclusion

Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

SUBMITTER: Tian Y

PROVIDER: S-EPMC9360460 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.

Tian Yu Y Kim Andre E AE Bien Stephanie A SA Lin Yi Y Qu Conghui C Harrison Tabitha A TA Carreras-Torres Robert R Díez-Obrero Virginia V Dimou Niki N Drew David A DA Hidaka Akihisa A Huyghe Jeroen R JR Jordahl Kristina M KM Morrison John J Murphy Neil N Obón-Santacana Mireia M Ulrich Cornelia M CM Ose Jennifer J Peoples Anita R AR Ruiz-Narvaez Edward A EA Shcherbina Anna A Stern Mariana C MC Su Yu-Ru YR van Duijnhoven Franzel J B FJB Arndt Volker V Baurley James W JW Berndt Sonja I SI Bishop D Timothy DT Brenner Hermann H Buchanan Daniel D DD Chan Andrew T AT Figueiredo Jane C JC Gallinger Steven S Gruber Stephen B SB Harlid Sophia S Hoffmeister Michael M Jenkins Mark A MA Joshi Amit D AD Keku Temitope O TO Larsson Susanna C SC Le Marchand Loic L Li Li L Giles Graham G GG Milne Roger L RL Nan Hongmei H Nassir Rami R Ogino Shuji S Budiarto Arif A Platz Elizabeth A EA Potter John D JD Prentice Ross L RL Rennert Gad G Sakoda Lori C LC Schoen Robert E RE Slattery Martha L ML Thibodeau Stephen N SN Van Guelpen Bethany B Visvanathan Kala K White Emily E Wolk Alicja A Woods Michael O MO Wu Anna H AH Campbell Peter T PT Casey Graham G Conti David V DV Gunter Marc J MJ Kundaje Anshul A Lewinger Juan Pablo JP Moreno Victor V Newcomb Polly A PA Pardamean Bens B Thomas Duncan C DC Tsilidis Konstantinos K KK Peters Ulrike U Gauderman W James WJ Hsu Li L Chang-Claude Jenny J

Journal of the National Cancer Institute 20220801 8

<h4>Background</h4>The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.<h4>Methods</h4>We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, ...[more]

PMID: 35512400

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Project description:IntroductionMammographic 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.MethodsThe 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.ResultsNo 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).ConclusionsThe 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.

Project description:BackgroundEpidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC.ObjectivesOur aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.MethodsWe applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO).ResultsInverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate.ConclusionsVariation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

Dataset Information

Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.

Background

Methods

Results

Conclusion

Publications

Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.

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