亚甲基四氢叶酸还原酶（MTHFR）基因 C677T、A1298C 和 G1793A 多态性：与男性透明细胞肾细胞癌风险和肿瘤行为的关联。

Methylenetetrahydrofolate reductase (MTHFR) gene C677T, A1298C and G1793A polymorphisms: association with risk for clear cell renal cell carcinoma and tumour behaviour in men.

机构信息

Private Practice of Urology and Andrology, Tehran, Iran.

出版信息

Clin Oncol (R Coll Radiol). 2012 May;24(4):269-81. doi: 10.1016/j.clon.2011.03.005. Epub 2011 Apr 13.

DOI:10.1016/j.clon.2011.03.005

PMID:21489764

Abstract

AIMS

Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated whether MTHFR C677T, A1298C and G1793A polymorphisms modified clear cell renal cell carcinoma (CCRCC) risk independently as well as in combination with serum total homocysteine (Hcy) and folate levels.

MATERIALS AND METHODS

A case-control study of 152 cases (men) and 304 age-matched healthy controls was conducted in one geographical area of Iran. Genotyping of MTHFR gene polymorphisms was carried out using a polymerase chain reaction restriction fragment length polymorphism technique. Serum levels of total Hcy, folate and vitamin B12 were also determined.

RESULTS

The MTHFR 677T and 1298C allele frequencies were 42.8 and 47.4% in cases, compared with 33.7 and 33.1% in controls. After controlling for confounding factors, a significant increase in CCRCC risk was found among carriers of the 677CT genotype compared with those with the 677CC genotype (odds ratio 2.21, 95% confidence interval 1.31-3.76), with a significant trend (P=0.014). Statistically significant odds ratios were also found in patients homozygous for MTHFR C677T, who have a 1.58-fold higher risk of developing CCRCC (95% confidence interval=1.21-2.44; P=0.024). Compared with the MTHFR 677CC genotype, the odds ratio (95% confidence interval) for the MTHFR 677TT genotype was 6.18 (95% confidence interval=4.75-8.34) for stage IV cancer and 4.68 (95% confidence interval=2.72-6.54) for grade 3 CCRCC (both P=0.0001). After adjustment for selected variants, the MTHFR 1298AC genotype showed a significantly increased risk of CCRCC compared with the wild-type (odds ratio=3.71, 95% confidence interval=2.22-5.33; P=0.001), and the 1298C allele carrier showed a positive association with the risk of CCRCC compared with the wild-type (odds ratio=3.9, 95% confidence interval=2.55-6.02; P=0.001). Furthermore, subjects carrying at least one copy of the variant allele showed a 4.4 times increased risk of developing CCRCC than their control counterparts (odds ratio=4.40, 95% confidence interval=2.41-6.72; P=0.0001). There was not a significant interaction between MTHFR polymorphisms and serum levels of total Hcy and folate in increasing the risk of CCRCC.

CONCLUSIONS

Our results provide evidence that the MTHFR polymorphisms might contribute to increased CCRCC risk in men.

摘要

目的

亚甲基四氢叶酸还原酶（MTHFR）在调节叶酸代谢中起着至关重要的作用，叶酸代谢影响 DNA 合成和甲基化。本研究旨在探讨 MTHFR C677T、A1298C 和 G1793A 多态性是否独立以及与血清总同型半胱氨酸（Hcy）和叶酸水平相结合，对透明细胞肾细胞癌（CCRCC）风险有影响。

材料和方法

在伊朗的一个地理区域进行了一项病例对照研究，共纳入 152 例（男性）病例和 304 例年龄匹配的健康对照者。采用聚合酶链反应限制性片段长度多态性技术检测 MTHFR 基因多态性。还测定了血清总 Hcy、叶酸和维生素 B12 水平。

结果

病例组中 MTHFR 677T 和 1298C 等位基因频率分别为 42.8%和 47.4%，对照组分别为 33.7%和 33.1%。在控制混杂因素后，与 677CC 基因型携带者相比，677CT 基因型携带者的 CCRCC 风险显著增加（比值比 2.21，95%置信区间 1.31-3.76），且存在显著趋势（P=0.014）。在 MTHFR C677T 纯合子患者中也发现了有统计学意义的比值比，他们患 CCRCC 的风险增加了 1.58 倍（95%置信区间=1.21-2.44；P=0.024）。与 MTHFR 677CC 基因型相比，MTHFR 677TT 基因型的比值比（95%置信区间）为 4.75-8.34）和 2.72-6.54），差异均有统计学意义（均 P=0.0001）。在选择变异体后进行调整，MTHFR 1298AC 基因型与野生型相比，CCRCC 的风险显著增加（比值比=3.71，95%置信区间=2.22-5.33；P=0.001），1298C 等位基因携带者与野生型相比，CCRCC 的风险呈阳性关联（比值比=3.9，95%置信区间=2.55-6.02；P=0.001）。此外，与对照组相比，携带至少一个变异等位基因的受试者发生 CCRCC 的风险增加了 4.4 倍（比值比=4.40，95%置信区间=2.41-6.72；P=0.0001）。MTHFR 多态性与血清总 Hcy 和叶酸水平之间没有显著的相互作用，无法增加 CCRCC 的风险。