Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk.
Journal
Journal of the National Cancer Institute
ISSN: 1460-2105
Titre abrégé: J Natl Cancer Inst
Pays: United States
ID NLM: 7503089
Informations de publication
Date de publication:
08 08 2022
08 08 2022
Historique:
received:
31
08
2021
revised:
17
02
2022
accepted:
26
04
2022
pubmed:
6
5
2022
medline:
11
8
2022
entrez:
5
5
2022
Statut:
ppublish
Résumé
The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 35512400
pii: 6581085
doi: 10.1093/jnci/djac094
pmc: PMC9360460
doi:
Substances chimiques
Estrogens
0
Progestins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1135-1148Subventions
Organisme : NCI NIH HHS
ID : P30 CA015704
Pays : United States
Organisme : NIH HHS
ID : S10 OD028685
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA137088
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA189184
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA206110
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008C
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207371
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196569
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201200008I
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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