The synergistic effect between adult weight changes and CYP24A1 polymorphisms is associated with pre- and postmenopausal breast cancer risk
Vitamin D (VD) metabolism regulates adipose tissue, lipogenesis inflammation, and tumor growth. CYP24A1 is the key enzyme for metabolic inactivation of active VD (1,25(OH)2D3). We examined whether common germline single nucleotide polymorphisms (SNPs) in the CYP24A1 gene could affect the association between adult weight gain and breast cancer (BC) risk.
The population-based case–control study included 818 patients with primary BC and 935 residence and age matched healthy controls. We studied the relationships between CYP24A1 gene SNPs (rs2209314, rs2585428, rs2762941, rs3787555, rs4809959, rs73913757, rs912505, and rs927a650), adult weight change and BC risk. Gene–weight change interactions were analyzed.
Neither of CYP24A1 gene SNPs was associated with BC risk in the study participants. However, we found consistent gene–weight interactions with increasing adult weight gain for CYP24A1–rs2762941 (P-interaction = 0.0089) and CYP24A1–rs927650 (P-interaction = 0.0283). Adult weight gain has a higher premenopausal BC risk with double variant T alleles of rs927650 compared to women carrying at least one wild-type C allele (OR for TT = 1.82, 95% CI 1.10–3.01; for CT = 0.93, 95% CI 0.76–1.14; for CC = 1.12 95% CI 0.93–1.35). Women with double wild-type A alleles were at a higher postmenopausal BC risk compared to those carrying at least one variant-type G allele (OR for AA = 1.51, 95% CI 1.29–1.76; for AG = 1.13, 95% CI 0.98–1.30; for GG = 1.22 95% CI 0.95–1.57). When stratified by CYP24A1 SNPs genotypes, weight gain in adulthood increased postmenopausal BC risk of women with homozygous allele compared to women with heterozygotes allele.
Significant interactions of weight change with CYP24A1 polymorphisms suggest CYP24A1 as a potential link between weight change and BC risk and the possibility that the impact of adult weight gain on postmenopausal BC risk may be enhanced by homozygous alleles of CYP24A1 SNPs.
KeywordsBreast cancer Weight change CYP24A1 Single nucleotide polymorphisms
We appreciate all study participants for their contributions. We thank the entire data collection team. Incident breast cancer cases and controls for this study were collected by Wuxi Center for Disease Control, Jiangsu Center for Disease Control.
This study was supported by World Cancer Research Fund (2011/RFA/473).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was approved by the ethical committee of the Jiangsu Center for Disease Control and Prevention (Jiangsu, China).
All participants signed a written informed consent.
- 2.Lahmann PH, Hoffmann K, Allen N, van Gils CH, Khaw KT, Tehard B, Berrino F, Tjonneland A, Bigaard J, Olsen A et al (2004) Body size and breast cancer risk: findings from the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 111(5):762–771PubMedCrossRefPubMedCentralGoogle Scholar
- 3.Lahmann PH, Schulz M, Hoffmann K, Boeing H, Tjonneland A, Olsen A, Overvad K, Key TJ, Allen NE, Khaw KT et al (2005) Long-term weight change and breast cancer risk: the European prospective investigation into cancer and nutrition (EPIC). Br J Cancer 93(5):582–589PubMedPubMedCentralCrossRefGoogle Scholar
- 4.Neuhouser ML, Aragaki AK, Prentice RL, Manson JE, Chlebowski R, Carty CL, Ochs-Balcom HM, Thomson CA, Caan BJ, Tinker LF et al (2015) Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the women’s health initiative randomized clinical trials. JAMA Oncol 1(5):611–621PubMedPubMedCentralCrossRefGoogle Scholar
- 7.Imperial College London (2008) WCRF/AICR systematic literature review continuous update report. The associations between food, nutrition and physical activity and the risk of breast cancerGoogle Scholar
- 11.Vimaleswaran KS, Berry DJ, Lu C, Tikkanen E, Pilz S, Hiraki LT, Cooper JD, Dastani Z, Li R, Houston DK et al (2013) Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS MED 10(2):e1001383PubMedPubMedCentralCrossRefGoogle Scholar
- 16.Lopes N, Sousa B, Martins D, Gomes M, Vieira D, Veronese LA, Milanezi F, Paredes J, Costa JL, Schmitt F (2010) Alterations in vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions. BMC Cancer 10:483PubMedPubMedCentralCrossRefGoogle Scholar
- 19.Lu S, Qian Y, Huang X, Yu H, Yang J, Han R, Su J, Du W, Zhou J, Dong M et al (2017) The association of dietary pattern and breast cancer in Jiangsu, China: a population-based case–control study. PLoS ONE 12(9):e184453Google Scholar
- 21.Yao S, Zirpoli G, Bovbjerg DH, Jandorf L, Hong CC, Zhao H, Sucheston LE, Tang L, Roberts M, Ciupak G et al (2012) Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women: a case-control study. Breast Cancer Res 14(2):R58PubMedPubMedCentralCrossRefGoogle Scholar
- 25.Penna-Martinez M, Ramos-Lopez E, Stern J, Kahles H, Hinsch N, Hansmann ML, Selkinski I, Grunwald F, Vorlander C, Bechstein WO et al (2012) Impaired vitamin D activation and association with CYP24A1 haplotypes in differentiated thyroid carcinoma. Thyroid 22(7):709–716PubMedPubMedCentralCrossRefGoogle Scholar
- 26.Von Schuckmann LA, Law MH, Montgomery GW, Green AC, van der Pols JC (2016) Vitamin D pathway gene polymorphisms and keratinocyte cancers: a nested case–control study and meta-analysis. Anticancer Res 36(5):2145–2152Google Scholar
- 33.Malmberg P, Karlsson T, Svensson H, Lonn M, Carlsson NG, Sandberg AS, Jennische E, Osmancevic A, Holmang A (2014) A new approach to measuring vitamin D in human adipose tissue using time-of-flight secondary ion mass spectrometry: a pilot study. J Photochem Photobiol B 138:295–301PubMedCrossRefPubMedCentralGoogle Scholar
- 35.Domingues-Faria C, Chanet A, Salles J, Berry A, Giraudet C, Patrac V, Denis P, Bouton K, Goncalves-Mendes N, Vasson MP et al (2014) Vitamin D deficiency down-regulates Notch pathway contributing to skeletal muscle atrophy in old wistar rats. Nutr Metab (Lond) 11(1):47PubMedCentralCrossRefGoogle Scholar
- 40.Barry EL, Rees JR, Peacock JL, Mott LA, Amos CI, Bostick RM, Figueiredo JC, Ahnen DJ, Bresalier RS, Burke CA et al (2014) Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. J Clin Endocrinol Metab 99(10):E2133–E2137PubMedPubMedCentralCrossRefGoogle Scholar
- 42.Batai K, Murphy AB, Shah E, Ruden M, Newsome J, Agate S, Dixon MA, Chen HY, Deane LA, Hollowell CM et al (2014) Common vitamin D pathway gene variants reveal contrasting effects on serum vitamin D levels in African Americans and European Americans. Hum Genet 133(11):1395–1405PubMedPubMedCentralCrossRefGoogle Scholar