Correlation of MAPK1 and NRAS Gene Polymorphisms with Cervical Intraepithelial Neoplasia in Yunnan Han Population
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摘要:
目的 探讨在云南汉族人群中NRAS基因与MAPK1基因rs14804和rs9340多态性位点与宫颈上皮内瘤变（cervical intraepithelial neoplasia，CIN）易感性的相关性。 方法 随机选取2017年5月至2019年10月昆明医科大学第三附属医院416例CIN患者和983例健康对照个体，通过TaqMan探针法对NRAS基因与MAPK1基因的SNPs位点（rs14804和rs9340）进行基因分型，分析2个SNPs位点与云南汉族人群CIN发生风险的相关性。 结果 MAPK1基因的SNP位点rs9340等位基因（P = 0.008）和基因型（P = 0.002）在CIN组与对照组的分布频率差异具有统计学意义，等位基因A可能与更高的CIN发生风险相关（OR = 1.28，95%CI 1.07 ～ 1.54），尤其是低年龄组（≤ 50岁）人群的CIN风险相关（OR = 1.35，95%CI 1.09 ～ 1.67）。 结论 MAPK1基因的SNP位点rs9340可能与云南汉族人群CIN发生风险具有相关性。 Abstract:Objective NRAS and MAPK1 genes are important regulators of the Ras/Raf/MEK/ERK signaling pathway, and their functions and expression levels have been associated with a variety of human tumors. This study aims to investigate the correlation between the rs14804 and rs9340 polymorphic loci of NRAS and MAPK1 genes and the susceptibility to cervical intraepithelial neoplasia （CIN） in Yunnan Han population. Methods 1399 persons of the population were enrolled in the current study, with 416 as the CIN patient group and 983 as the healthy control group. The SNPs loci （rs14804 and rs9340） in the NRAS gene and the MAPK1 gene were genotyped using the TaqMan assays, and the correlation between the two SNPs loci and the risk of CIN was analyzed. Results The difference in the frequency of distribution of SNP locus rs9340 allele （P = 0.008） and genotype （P = 0.002） of MAPK1 gene in the CIN group versus the control group was statistically significant, and allele A may be associated with a higher risk of developing CIN （OR = 1.28, 95%CI 1.07 ～ 1.54）, especially for people in the lower age group （≤ 50 years） of CIN risk （OR = 1.35, 95%CI 1.09 ～ 1.67）. Conclusion rs9340 in the MAPK1 gene might be correlated with the risk of CIN in the Chinese Han population in Yunnan. -
图 1 rs9340位点导致所在区域互补结合的miRNA发生改变
Figure 1. The rs9340 causes the different miRNA binding pattern
表 1 选取病例的临床特征[（$ \bar{x} \pm s $），岁]
Table 1. The clinical characteristics of the subjects enrolled in this study [（$ \bar{x} \pm s $），years old]
分组 临床分期/年龄分层 n 年龄分布 t P 对照组 高龄组 314 56.21 ± 3.85 低龄组 718 41.91 ± 6.86 总计 961 45.77 ± 8.87 CIN组 CIN2 51 45.59 ± 10.13 −1.535 0.903 CIN3 365 44.92 ± 9.48 −2.923 0.137 高龄组 102 58.09 ± 6.09 −3.523 0.00048* 低龄组 265 40.75 ± 5.92 −2.771 0.006* 总计 416 45.00 ± 9.55 −1.446 0.148 *P < 0.05。 
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表 2 2个SNPs位点在CIN和对照组间等位基因和基因型分布比较[n（%）]
Table 2. The comparison of allelic and genotypic distribution of the two SNPs between CIN and control groups[n（%）]
SNPs 等位基因/基因型 对照组 CIN组 χ2 P OR（95%CI） rs14804 A 49（2.50） 22（2.64） 0.055 0.815 1.06（0.64 ～ 1.77） G 1917（97.50） 810（97.36） A/A 0（0.00） 1（0.24） 2.382 0.304 A/G 49（4.98） 20（4.81） G/G 934（95.02） 395（94.95） HWE，P 0.423 0.177 rs9340 A 456（23.19） 232（27.88） 6.936 0.008* 1.28（1.07 ～ 1.54） G 1510（76.81） 600（72.12） A/A 55（5.60） 22（5.29） 12.568 0.002* A/G 346（35.20） 188（45.19） G/G 582（59.20） 206（49.52） HWE，P 0.705 0.012 *P < 0.025（统计学结果经Bonferroni校正，n = 2）。
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表 3 高龄组和低龄组中rs9340位点与CIN的相关性分析[n（%）]
Table 3. The association of rs9340 with CIN in different age groups [n（%）]
年龄分层 等位基因/基因型 对照组 CIN组 χ2 P OR（95%CI） 高年龄组 A 131（24.72） 55（26.96） 0.108 0.743 1.07（0.73 ～ 1.55） G 399（75.28） 149（73.04） A/A 17（6.42） 4（3.92） 0.814 0.367 0.42（0.13 ～ 1.38） A/G 97（36.60） 47（46.08） 2.046 0.212 0.58（0.18 ～ 1.88） G/G 151（56.98） 51（50.00） 3.102 0.153 低年龄组 A 325（22.63） 177（28.18） 7.4 0.007* 1.35（1.09 ～ 1.67） G 1111（77.37） 451（71.82） A/A 38（5.29） 18（5.73） 10.37 0.001* 1.59（1.19 ～ 2.08） A/G 249（34.69） 141（44.90） 0.898 0.343 1.33（0.74 ～ 2.38） G/G 431（60.02） 155（49.37） 10.453 0.005 *P < 0.05。
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表 4 rs9340位点与CIN分期进展的相关性[n（%）]
Table 4. Correlation of rs9340 locus polymorphism with different CIN stages [n（%）]
等位基因此/基因型 CIN2组 CIN3组 χ2 P OR（95%CI） A 22（21.57） 210（28.77） 2.323 0.127 0.68（0.41 ～ 1.12） G 80（78.43） 520（71.23） A/A 1（1.96） 21（5.75） 1.515 0.218 0.28（0.04 ～ 2.14） A/G 20（39.22） 168（46.03） 1.381 0.24 0.70（0.38～ 1.27） G/G 30（58.82） 176（48.22） 0b b该项为参照项，因此设置为0。
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表 5 rs9340位点对MAPK1基因3'UTR区域miRNA互补结合的影响
Table 5. The effect of rs9340 on miRNA binding to the 3'UTR of MAPK1
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