Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad 500082, Andhra Pradesh, India.
Mol Biol Rep. 2011 Nov;38(8):4893-901. doi: 10.1007/s11033-010-0631-z. Epub 2010 Dec 14.
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.
鉴于越来越多的证据证实一碳代谢异常在乳腺癌发病机制中的作用，以及缺乏对基因-基因相互作用的研究，我们调查了膳食微量营养素和一碳代谢中 8 个功能多态性在调节 244 对印度女性病例对照的乳腺癌风险中的作用，并使用多因子维度缩减分析（MDR）探索了可能的基因-基因相互作用。膳食微量营养素状况使用经过验证的食物频率问卷进行评估。使用 PCR-RFLP/AFLP 方法对谷氨酸羧肽酶 II (GCPII) C1561T、还原叶酸载体 (RFC)1 G80A、细胞质丝氨酸羟甲基转移酶 (cSHMT) C1420T、胸苷酸合成酶 (TYMS) 5'-UTR 串联重复、TYMS 3'-UTR ins6/del6、亚甲基四氢叶酸还原酶 (MTHFR) C677T、甲基四氢叶酸-同型半胱氨酸甲基转移酶 (MTR) A2756G、甲基四氢叶酸-同型半胱氨酸甲基转移酶还原酶 (MTRR) A66G 进行基因分型。低膳食叶酸摄入（P < 0.001）、RFC1 G80A（OR：1.38，95%CI 1.06-1.81）和 MTHFR C677T（OR：1.74（1.11-2.73））与乳腺癌风险独立相关，而 cSHMT C1420T 提供保护（OR：0.72，95%CI 0.55-0.94）。MDR 分析表明，RFC1 80、MTHFR 677 和 TYMS 5'-UTR 基因座之间存在显著的三变量相互作用（P（趋势）<0.02），高危基因型组合显示乳腺癌风险增加（OR 4.65，95%CI 1.77-12.24）。总之，发现膳食和遗传因素都会影响乳腺癌的易感性。此外，本研究强调了多基因座分析相对于单基因座分析在建立一碳代谢基因座之间的上位性相互作用以调节乳腺癌易感性方面的重要性。
