title: Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer.
abstract: In view of growing body of evidence substantiating the role of aberrations in one-carbon metabolism in the pathophysiology of breast cancer and lack of studies on gene-gene interactions, we investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating the breast cancer risk in 244 case-control pairs of Indian women and explored possible gene-gene interactions using Multifactor dimensionality reduction analysis (MDR). Dietary micronutrient status was assessed using the validated Food Frequency Questionnaire. Genotyping was done for glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier (RFC)1 G80A, cytosolic serine hydroxymethyltransferase (cSHMT) C1420T, thymidylate synthase (TYMS) 5'-UTR tandem repeat, TYMS 3'-UTR ins6/del6, methylenetetrahydrofolate reductase (MTHFR) C677T, methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G, methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) A66G polymorphisms by using the PCR-RFLP/AFLP methods. Low dietary folate intake (P < 0.001), RFC1 G80A (OR: 1.38, 95% CI 1.06-1.81) and MTHFR C677T (OR: 1.74 (1.11-2.73) were independently associated with the breast cancer risk whereas cSHMT C1420T conferred protection (OR: 0.72, 95% CI 0.55-0.94). MDR analysis demonstrated a significant tri-variate interaction among RFC1 80, MTHFR 677 and TYMS 5'-UTR loci (P (trend) < 0.02) with high-risk genotype combination showing inflated risk for breast cancer (OR 4.65, 95% CI 1.77-12.24). To conclude, dietary as well as genetic factors were found to influence susceptibility to breast cancer. Further, the current study highlighted the importance of multi-loci analyses over the single-locus analysis towards establishing the epistatic interactions between loci of one-carbon metabolism modulate susceptibility to the breast cancer.
authors.affiliation: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad 500082, Andhra Pradesh, India.
authors.forename: Shaik Mohammad
authors.initials: SM
authors.lastname: Naushad
authors.forename: Addepalli
authors.initials: A
authors.lastname: Pavani
authors.forename: Raghunadha Rao
authors.initials: RR
authors.lastname: Digumarti
authors.forename: Suryanarayana Raju
authors.initials: SR
authors.lastname: Gottumukkala
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics*; D002244:Carbon / Q000378:metabolism*; D016022:Case-Control Studies; D003710:Demography; D004843:Epistasis, Genetic; D005260:Female; D005492:Folic Acid / Q000097:blood; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D002244:Carbon; D005492:Folic Acid