title: Functional variants in CYP1B1, KRAS and MTHFR genes are associated with shorter telomere length in postmenopausal women.
abstract: Estrogens and antioxidants indirectly alleviate telomere attrition. However, available clinical data on the association between hormone exposure and telomere length are inconclusive. In the present study, we examined the effects of exogenous estrogen use and of some genetic factors implicated in estrogen metabolism and oxidative stress response on mean leukocyte telomere length. We studied 259 postmenopausal women. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695), MnSOD (rs4880), KRAS (rs61764370), and MTHFR (rs1801133 and rs1801131) polymorphisms. Mean leukocyte telomere length was measured using a quantitative real-time PCR assay. In multivariate analysis we found no association between oral contraceptives or hormone replacement therapy (HRT) and mean leukocyte telomere length. The presence of variant alleles in CYP1B1, KRAS and MTHFR genes was statistically significantly associated with shorter mean leukocyte telomere length. Further, the data provided evidence for the effect modification of the association between HRT and mean leukocyte telomere length by the CYP1B1, KRAS and MTHFR genotypes. Our findings suggest that functionally relevant genetic variants within estrogen and folate metabolic pathways may influence telomere length. We propose these genetic factors should be taken into consideration when interpreting associations between hormone exposure and telomere length.
authors.affiliation: Clinical Institute of Medical Genetics, Department of Obstetrics and Gynecology, University Medical Center Ljubljana, Zaloska 2, Ljubljana, Slovenia.
authors.forename: Jasmina Z
authors.initials: JZ
authors.lastname: Cerne
authors.affiliation: Institute for Biostatistics and Medical Informatics, Faculty of Medicine Ljubljana, Korytkova 2, Ljubljana, Slovenia.
authors.forename: Maja
authors.initials: M
authors.lastname: Pohar-Perme
authors.affiliation: Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Zaloska 2, Ljubljana, Slovenia.
authors.forename: Petra
authors.initials: P
authors.lastname: Cerkovnik
authors.affiliation: Clinical Institute of Medical Genetics, Department of Obstetrics and Gynecology, University Medical Center Ljubljana, Zaloska 2, Ljubljana, Slovenia.
authors.forename: Ksenija
authors.initials: K
authors.lastname: Gersak
authors.affiliation: Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Zaloska 2, Ljubljana, Slovenia.
authors.forename: Srdjan
authors.initials: S
authors.lastname: Novakovic
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D004967:Estrogens / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D005492:Folic Acid / Q000737:chemistry; D011905:Genes, ras; D014644:Genetic Variation; D005838:Genotype; D020249:Hormone Replacement Therapy; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D017698:Postmenopause; D060888:Real-Time Polymerase Chain Reaction; D016615:Telomere / Q000648:ultrastructure*
chemical_list: D004967:Estrogens; D005492:Folic Acid; D065633:Cytochrome P-450 CYP1B1; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: Estrogen metabolism; Hormone replacement therapy; Oxidative stress; Polymorphism; Postmenopause; Telomere length