亚甲基四氢叶酸还原酶C677T基因多态性及相关代谢物与内耳疾病的关系

Association of methylenetetrahydrofolate reductase C677T gene polymorphism and related metabolites with inner ear disease

摘要:

目的 研究亚甲基四氢叶酸还原酶（methylenetetrahydrofolate reductase，MTHFR）C677T基因多态性及相关代谢物与内耳疾病的关系。方法 选取2019年4月—2019年11月山西医科大学第二医院进行内科治疗的内耳疾病患者和同期的健康体检者各175例作为疾病组和对照组，对比两组患者的MTHFR C677T基因多态性、血清同型半胱氨酸（Hcy）及血清叶酸结果，分析内耳疾病发病风险；同时根据病因及临床诊断将疾病组分为突发性聋（SSHL）组、梅尼埃病（MD）组、感音神经性聋（SHL）组和前庭功能障碍（VD）组，对其MTHFR C677T基因多态性结果进行分析。结果 MTHFR C677T基因检测产生3种基因型，分别为CC、CT和TT。疾病组MTHFR C677T基因型CC频率低于对照组，CT+TT高于对照组，差异具有统计学意义（P<0.05），CT、TT频率均略高于对照组（P>0.05）。CT+TT发生内耳疾病的风险是CC的1.397倍（P<0.05），其中CT、TT分别是1.408倍（P<0.05）、1.375倍（P>0.05）。等位基因C、T频率差异具有统计学意义（P<0.05），T发生内耳疾病风险是C的1.264倍（P<0.05）。疾病组血清Hcy异常率高于对照组，差异具有统计学意义（P<0.05），各基因型中血清Hcy平均浓度均高于对照组，仅在TT型中差异具有统计学意义（P<0.05）。疾病组各基因型间血清Hcy平均浓度和异常率差异均有统计学意义（P均=0.000），CC型发生Hcy异常的风险分别是CT、TT型的0.762倍（P>0.05）、0.207倍（P<0.05），CT型是TT型的0.272倍（P=0.000）。各基因型间血清叶酸水平和异常率差异无统计学意义（P均>0.05）。内耳病分类分析中，MD组CC频率低于对照组，CT+TT频率高于对照组，差异具有统计学意义（P<0.05），CT+TT发生MD的风险是CC的3.615倍（P<0.05），其中TT、CT分别是CC的4.476倍（P<0.05）、3.138倍（P>0.05）。除SHL组，其余各组等位基因C、T分布与对照组相比差异具有统计学意义（P均<0.05）。结论 MTHFR C677T基因多态性与内耳疾病具有一定相关性，可增加内耳疾病发生风险，尤以CT型明显，T等位基因可成为内耳疾病发病的危险因素。血清Hcy与内耳疾病相关，MTHFR基因多态性可增加血清Hcy升高风险，进而影响内耳，尤以TT型明显。在内耳疾病中，MTHFR C677T基因多态性与MD相关，可明显增加MD发生风险，尤以TT型突出。

Abstract:

Objective To investigate the association of methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism and related metabolites with inner ear disease. Methods A total of 175 patients with inner ear diseases hospitalized in our department from April to Nov 2019 and 175 healthy subjects in the same period were selected as the disease group and the control group respectively. The results of MTHFR C677T gene polymorphism, serum homocysteine (Hcy), and folic acid from the two groups were collected for comparative analysis and risk analysis of inner ear diseases. Meanwhile, according to the etiology and clinical diagnosis of the inner ear diseases, the disease group was subdivided into sudden sensorineural hearing loss (SSHL) group, Ménière's disease (MD) group, sensorineural hearing loss (SHL) group and vestibular dysfunction (VD) group, and their results of MTHFR C677T gene polymorphism were analyzed. Results Genetic testing of MTHFR C677T revealed three genotypes including CC, CT and TT. The frequency of MTHFR C677T genotype CC was lower and the frequency of CT+TT higher in the disease group than in the control group, and the differences were both statistically significant (both P<0.05). The frequencies of CT type and TT type in the disease group were slightly higher than in the control group, but the differences were both statistically insignificant (both P>0.05). The risk of inner ear disease of CT+TT type was 1.397 times higher than that of CC type (P<0.05), while CT or TT were 1.408 times (P<0.05) or 1.375 times higher than CC type respectively (P>0.05). The frequency difference between alleles C and T was statistically significant (P<0.05), and the risk of inner ear disease in T was 1.264 times higher than in C (P<0.05). The abnormal rate of serum Hcy was higher in the disease group than in the control group, and the difference was statistically significant (P<0.05). The mean serum Hcy concentration of each genotype was higher in the disease group than in the control group, but with only statistically significant difference in TT type (P<0.05). There were statistically significant differences in the mean serum Hcy concentration and abnormal rate among genotypes in the disease group (all P=0.000). The risk of Hcy abnormality in CC type was 0.762 times higher than in CT type (P>0.05) and 0.207 times in TT type (P<0.05). The risk of Hcy abnormality in CT type was 0.272 times higher than in TT type (P=0.000). The differences in serum folic acid level and abnormal rate among genotypes were all statistically insignificant (all P>0.05). In the analysis of the classification of inner ear diseases, CC frequency was lower and CT+TT frequency higher in the MD group than in the control group, and the differences were both statistically significant (both P<0.05). The risk of MD in CT+TT was 3.615 times higher than in CC (P<0.05), in which TT was 4.476 times (P<0.05) and CT 3.138 times (P>0.05) higher than CC. Except for SHL group, there were statistically significant differences in the distribution of allele C or T among the other groups (all P<0.05). Conclusion MTHFR C677T gene polymorphism is associated with inner ear disease, and T allele can be a risk factor for inner ear disease. MTHFR C677T mutation, especially the heterozygous mutation CT type, can increase the risk of inner ear disease. Serum Hcy level is associated with inner ear disease. MTHFR gene polymorphism, especially homozygous mutation TT type, can increase the risk of elevated serum Hcy level, thus affect the inner ear. In inner ear diseases, MTHFR C677T gene polymorphism especially TT type is associated with MD and can significantly increase the risk of MD.