亚甲基四氢叶酸还原酶基因677C／T和1298A／CSNP与肺癌的相关性研究

Relationship between methylenetetrahydrofolate reductase gene 677C / T, 1298A / C SNP and lung cancer

目的探讨我国黑龙江地区汉族人群亚甲基四氢叶酸还原酶（MTHFR）基因单核苷酸多态与肺癌的相关性。方法纳入225例肺癌患者作为实验组，以门诊体检健康人群225名为对照组，采用病例对照研究法进行MTHFR基因677C/T 、1298A/C SNP与肺癌的关联分析，以Sanger双脱氧链终止法检测基因分型。结果在对照组中，MTHFR基因C677T的野生型CC、突变杂合子CT、突变纯合子TT基因型频率分别为34.2%、55.1%、10.7%，实验组中3种基因型频率分别为26.7%、50.2%、23.1%，C677T各SNP基因型频率在实验组和对照组间分布差异有统计学意义（P＝0.002），其中突变纯合子TT携带者发生肺癌风险是野生型CC的2.78倍[OR（95%CI）：2.78（1.54～5.02） , P＝0.001]；MTHFR基因A1298C位点实验组AA、AC、CC基因型频率分别为34.2%、55.1%、10.7%，对照组分别为64.0%、32.0%、4.0%，两组间比较差异无统计学意义（P＝0.247）。单倍体分析结果显示，TA单倍型在实验组的分布频率明显高于对照组（43.1%与35.3%），两组比较差异有统计学意义[OR（95%CI）：1.39（1.06～1.81），P＝0.016]；而CC单倍型在实验组和对照组的分布频率分别为10.6%、17.1%，差异有统计学意义[OR（95%CI）：0.58（0.39～0.85），P＝0.005]。MTHFR基因677和1298两位点之间存在连锁不平衡关系（D＇＝0.48，P＝0.003）。对MTHFR基因C677T多态性进行基因-环境相互作用分析显示：TT与CC基因型相比，年龄大于60岁[OR（95%CI）：4.0（1.78～9.32）, P＝0.001]、男性[OR（95%CI）：5.55（2.10～14.67），P＝0.000]、吸烟[OR（95%CI）：8.13（2.29～28.85） , P＝0.000]、小细胞肺癌[OR（95%CI）：1.28（1.10～1.44） ，P＝0.000]均可使肺癌的发病风险增加；CT与CC基因型相比，女性[OR（95%CI）：2.09（1.05～4.16），P＝0.030]、不吸烟人群[OR（95%CI）：2.43（1.25～4.74），P＝0.008]、小细胞肺癌[OR（95%CI）：0.31（1.16～1.59），P＝0.000]的肺癌患病风险也增加。结论MTHFR基因C677T是肺癌发病的遗传易感基因，且与肺癌发病风险有关。

ObjectiveTo explore the relationship between MTHFR gene polymorphism and lung cancer in Han population of Heilongjiang Province.MethodsTwo hundred and twenty-five lung cancer patients were selected as the experimental group and the healthy subjects in the outpatient physical examination as the control group, A case-control study was used to analyze the association of MTHFR gene 677C/T, 1298A/C SNP and lung cancer, and the gene typing was detected by Sanger double deoxidization chain termination method.ResultsIn the control group, the frequencies of wild-type CC, mutant heterozygote CT, and homozygous TT genotypes of the MTHFR gene C677T were 34.2%, 55.1%, and 10.7%, respectively.The frequencies of the three genotypes in the experimental group were 26.7%, 50.2%, 23.1%, respectively.The difference in the distribution of C677T SNP genotype frequencies of the experimental group and the control group was statistically significant （P=0.002）, in which the mutation homozygous TT carriers were 2.78 times more likely to develop lung cancer than wild-type CC（OR（95%CI）： 2.78（1.54~5.02） , P=0.001）; AA, AC and CC genotype frequencies of the A1298C locus of the MTHFR gene were 34.2%, 55.1%, and 10.7%, respectively, and the control group was 64.0%.32.0%, 4.0%, there was no significant difference between the two groups （P=0.247）. The frequencies of AA, AC and CC genotypes in the A1298C locus of the MTHFR gene were 34.2%, 55.1%, and 10.7%, respectively, and 64.0%, 32.0%, and 4.0% in the control group, respectively.There was no significant difference between the two groups （P）. =0.247）. The haploid analysis showed that the distribution frequency of TA haplotype in the experimental group was significantly higher than that in the control group （43.1% vs.35.3%）. There was a statistically significant difference between the two groups （OR（95%CI）： 1.39 （1.06-1.81）, P=0.016）; while the frequencies of CC haplotypes in the experimental group and the control group were 10.6% and 17.1%, respectively.The difference was statistically significant （OR（95%CI）： 0.58 （0.39-0.85）. P=0.005）. There was a linkage disequilibrium between the two points of MTHFR gene 677 and 1298 （D＇=0.48, P=0.003）. The gene-environment interaction analysis of the MTHFR gene C677T polymorphism showed that based on the comparison between TT and CC genotype, age over 60 （OR（95%CI）： 4.0（1.78-9.32）, P=0.001）, male （OR （95%CI）： 5.55 （2.10-14.67）, P=0.000）, smoking （OR（95%CI）： 8.13 （2.29-28.85）, P=0.000） and small cell lung cancer （OR （95%CI） ： 1.28 （1.10-1.44）, P=0.000） can increase the risk of lung cancer; based on the comparison between CT and CC genotype, women （OR（95%CI）： 2.09 （1.05-4.16）, P=0.030）, non-smoking population （OR（95%CI）： 2.43 （1.25-4.74）, P=0.008） and small cell lung cancer （OR （95% CI）： 0.31 （1.16-1.59）, P=0.000） can increase the risk of lung cancer.ConclusionMTHFR gene C677T is a genetic susceptibility gene for lung cancer and is associated with the risk of lung cancer.