ABSTRACT
Putatively functional polymorphisms of one-carbon and xenobiotic metabolic pathways influence susceptibility for wide spectrum of diseases. The current study was aimed to explore gene-gene interactions among these two metabolic pathways in four diseases i.e. breast cancer, systemic lupus erythematosus (SLE), coronary artery disease (CAD) and Parkinson's disease (PD). Multifactor dimensionality reduction analysis was carried out on four case-control datasets. Cross-talk was observed between one-carbon and xenobiotic pathways in breast cancer (RFC 80 G>A, COMT H108L and TYMS 5'-UTR 28 bp tandem repeat) and SLE (CYP1A1 m1, MTRR 66 A>G and GSTT1). Gene-gene interactions within one-carbon metabolic pathway were observed in CAD (GCPII 1561 C>T, SHMT 1420 C>T and MTHFR 677 C>T) and PD (cSHMT 1420 C>T, MTRR 66 A>G and RFC1 80 G>A). These interaction models showed good predictability of risk for PD (The area under the receiver operating characteristic curve (C) = 0.83) and SLE (C = 0.73); and moderate predictability of risk for breast cancer (C = 0.64) and CAD (C = 0.63). Cross-talk between one-carbon and xenobiotic pathways was observed in diseases with female preponderance. Gene-gene interactions within one-carbon metabolic pathway were observed in diseases with male preponderance.
Subject(s)
Breast Neoplasms/genetics , Coronary Artery Disease/genetics , Lupus Erythematosus, Systemic/genetics , Multifactor Dimensionality Reduction , Oxidoreductases/genetics , Parkinson Disease/genetics , Transferases/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carbon/metabolism , Case-Control Studies , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Datasets as Topic , Epistasis, Genetic , Factor Analysis, Statistical , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Humans , Lupus Erythematosus, Systemic/metabolism , Lupus Erythematosus, Systemic/pathology , Male , Metabolic Networks and Pathways/genetics , Oxidoreductases/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathology , Polymorphism, Single Nucleotide , Sex Factors , Transferases/metabolism , Xenobiotics/metabolismABSTRACT
BACKGROUND: The CYP19 gene is located on chromosome 15 and it plays an important role in aromatization, which results in production of estrogen from androgens. The mutation in this gene can result in either increased or decreased aromatase activity. MATERIALS AND METHODS: A case-control study was designed to compare 250 breast cancer cases with 250 age-matched healthy controls. The frequency distribution of CYP19 polymorphism was assessed by polymerase chain reaction confronting two pair primers (PCR-CTPP). RESULTS: CYP19 polymorphism at codon 39 Trp/Arg (W39R) results in three genotypes TT, TC, and CC, but in the present study CC genotype was not found in breast cancer cases as well as in controls. The TT genotype was significantly elevated in disease (90.8%) as compared to controls (68.5%). The frequency of TC was found to be increased in premenopausal women with breast cancer (12.2%) and the frequency of TT genotype was increased in patients who were postmenopausal (94.1%). The increased frequency of heterozygotes was found in cases with familial incidences of cancer (10.8%), estrogen and progesterone receptor positive status, node positive status (9.8%), and occupied in agriculture (14.8%). Higher frequencies of both TT and TC genotype were increased in patients with high body mass index (BMI). The frequency of TT genotype was found to be increased in advanced stage of the disease. CONCLUSION: Hence, we conclude that W39 with increased aromatase activity confers greater risk to develop breast cancer especially in postmenopausal women and might also contribute to advanced stage.
