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Genome-wide interaction analysis of genetic variants with menopausal hormone therapy for colorectal cancer risk

  • Tian, Y
  • Kim, AE
  • Bien, SA
  • Lin, Y
  • Qu, C
  • Harrison, T
  • Carreras-Torres, R
  • Díez-Obrero, V
  • Dimou, N
  • Drew, DA
  • Hidaka, A
  • Huyghe, JR
  • Jordahl, KM
  • Morrison, J
  • Murphy, N
  • Obón-Santacana, M
  • Ulrich, CM
  • Ose, J
  • Peoples, AR
  • Ruiz-Narvaez, EA
  • And 57 more
Publication Date
Apr 26, 2022
UPCommons. Portal del coneixement obert de la UPC


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 cases and 16,967 controls) from 38 studies, using logistic regression, two-step method, and 2- or 3-degree-of-freedom (d.f.) 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) with 95% confidence interval (95% CI) of 0.71 (0.64-0.78), 0.65 (0.53-0.79), and 0.73 (0.59-0.90), respectively]. The two-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was significantly reduced in women with the GG genotype [0.68 (0.64-0.72)] 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-d.f. joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing ORs of 0.78 (0.70-0.87) for TT, 0.68 (0.63-0.73) for TC, and 0.66 (0.60-0.74) for CC genotypes. In addition, five genes in rare variant analysis showed suggestive interactions with MHT (two-sided P < 1.2x10-4). 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.

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