Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia
Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia
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DOI：
10.1182/blood.v99.10.3786
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发表时间：
2002-05-15
期刊：
影响因子：
20.3
通讯作者：
Morgan, GJ
中科院分区：
文献类型：
--
作者：
Skibola, CF;Smith, MT;Morgan, GJ
我们先前报道了5，10-亚甲基四氢叶酸还原酶(MTHFR)基因C677T和A1298C两个多态性与成人急性淋巴细胞白血病(ALL)的低风险相关。在目前的研究中，我们研究了其他叶酸代谢基因的多态是否在所有易感性中起作用。甲硫氨酸合成酶(MS A2756G)、胞浆丝氨酸羟甲基转移酶(SHMT1C1420T)和胸腺嘧啶酸合成酶(TS)启动子区域的双(2R2R)或三(3R3R)28个碱基串联重复序列的多态性被发现调节了所有的风险。在单变量分析中，SHMT1 1420CT个体的所有风险降低了2.1倍(优势比[OR]=0.48；95%可信区间[CI]，0.25-0.91)，而1420TT基因型的风险降低了3.3倍(OR=0.31；95%CI，0.10-0.90)。同样，TS 2R3R个体的所有风险降低了2.8倍(OR=0.36；95%CI：0.16-0.83)，而TS 3R3R基因型提供了更高的保护水平(OR=0.25；95%CI，0.08-0.78)。然而，与MS 2756AG多态无明显关联(OR=0.79；95%CI，0.38-1.7)。此外，还观察到了SHMT1与TS或MS基因之间的潜在相互作用。携带SHMT11420CT/TT基因的TS3R3R个体所有风险降低13.9倍(OR=0.072；95%CI，0.0067~0.77)。此外，携带SHMT1 1420CT/TT的MS 2756AG个体的所有风险降低了5.6倍(OR=0.18；95%CI，0.05-0.63)。这项研究表明，尿嘧啶的错误结合和由此导致的染色体损伤在ALL的发病机制中起着重要作用，涉及叶酸代谢基因低外显性多态的遗传交互作用可能会增加ALL的风险。(C)2002年，由美国血液病学会公布。
We previously reported that 2 polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene at positions C677T and A1298C were associated with lower risk of adult acute lymphocytic leukemia (ALL). In the present study, we have examined whether polymorphisms in other folate-metabolizing genes play a role in ALL susceptibility. Polymorphisms in methionine synthase (MS A2756G), cytosolic serine hydroxymethyltransferase (SHMT1 C1 420T), and a double (2R2R) or triple (3R3R) 28-bp tandem repeat in the promoter region of thymidylate synthase (TS) were studied and found to modulate ALL risk. In a univariate analysis, SHMT1 1420CT individuals exhibited a 2.1-fold decrease in ALL risk (odds ratio [OR] = 0.48; 95% confidence Interval [CI], 0.25-0.91), whereas the 1420TT genotype conferred a 3.3-fold reduction in risk (OR = 0.31; 95% Cl, 0.10-0.90). Similarly, TS 2R3R individuals exhibited a 2.8-fold reduction in ALL risk (OR = 0.36; 95% Cl: 0.16-0.83), while the TS 3R3R genotype conferred an even greater level of protection (OR = 0.25; 95% Cl, 0.08-0.78). However, no significant associations were evident for the MS 2756AG polymorphism (OR = 0.79; 95% Cl, 0.38-1.7). In addition, potential interactions between the SHMT1 and TS or MS genes were observed. TS 3R3R Individuals who were SHMT1 1420CT/TT had a 13.9-fold decreased ALL risk (OR = 0.072; 95% Cl, 0.0067-0.77). Further, MS 2756AG Individuals who were SHMT1 1420CT/TT had a 5.6-fold reduction in ALL risk (OR = 0.18; 95% Cl, 0.05-0.63). This study suggests an important role for uracil misincorporation and resultant chromosomal damage In the pathogenesis of ALL, and that genetic interactions Involving low penetrance polymorphisms in folate-metabolizing genes may increase ALL risk. (C) 2002 by The American Society of Hematology.