不同级别子宫颈病变与lncRNA HOTTIP和H19单核苷酸多态性的关系研究

doi:10.19401/j.cnki.1007-3639.2022.04.005

中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (4): 324-334.doi: 10.19401/j.cnki.1007-3639.2022.04.005

不同级别子宫颈病变与lncRNA HOTTIP和H19单核苷酸多态性的关系研究

王春桃¹()(), 葛安兴¹, 吴红雁¹, 张学艳¹, 杨圣², 袁红香³, 程艳萍², 冯延璐², 陆欣苑², 梁戈玉²()()

1.江苏医药职业学院,江苏盐城 224001
2.环境医学工程教育部重点实验室,东南大学公共卫生学院,江苏南京 210009
3.盐城市第一人民医院放疗科,江苏盐城 224001

收稿日期:2021-08-18 修回日期:2022-03-02 出版日期:2022-04-30 发布日期:2022-05-07
通信作者: 梁戈玉 E-mail:yammy_taotao@163.com;gyliang@seu.edu.cn
作者简介:王春桃（ORCID: 0000-0002-6391-3304）,硕士,副教授,江苏医药职业学院科技处副处长 E-mail: yammy_taotao@163.com
基金资助:
国家自然科学基金(81673132);国家自然科学基金(81972998);江苏省卫健委项目(Z2018043);江苏省青蓝工程(2019);江苏省高职院校教师专业带头人高端研修项目资助(2021GRFX030);校级自然科学基金(20204103)

The association between cervical lesions of different grades and lncRNA HOTTIP and H19 single nucleotide polymorphisms

WANG Chuntao¹()(), GE Anxing¹, WU Hongyan¹, ZHANG Xueyan¹, YANG Sheng², YUAN Hongxiang³, CHENG Yanping², FENG Yanlu², LU Xinyuan², LIANG Geyu²()()

1. Jiangsu Vocational College of Medicine, Yancheng 224001, Jiangsu Province, China
2. Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, Jiangsu Province, China
3. Department of Radiotherapy, Yancheng No.1 People's Hospital, Yancheng 224001, Jiangsu Province, China

Received:2021-08-18 Revised:2022-03-02 Published:2022-04-30 Online:2022-05-07
Contact: LIANG Geyu E-mail:yammy_taotao@163.com;gyliang@seu.edu.cn

摘要/Abstract

摘要：

背景与目的：HOTTIP和H19都是lncRNA（long non-coding RNA,lncRNA）中的一员,在肿瘤的发生、发展和迁移过程中发挥重要作用。本研究探讨HOTTIP rs2067087、H19 rs2839698和H19 rs2107425单核苷酸多态性（single nucleotide polymorphism,SNP）与不同级别子宫颈病变发病风险的关系。方法：收集2018年11月—2020年12月盐城市第一人民医院收治的345例子宫颈病变患者的外周静脉血及相关临床资料,其中子宫颈上皮内瘤变（cervical intraepithelial neoplasia,CIN）220例,子宫颈癌（cervical cancer,CC）125例, 选取同期住院的360例无子宫颈病变患者为对照。采用TaqMan实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction,RTFQ-PCR）方法对2组人群中的HOTTIP基因的SNP位点rs2067087和H19基因的SNP位点rs2839698、rs2107425进行基因分型,采用χ²检验和非条件logistic回归分析3个SNP位点与不同级别子宫颈病变的相关性。结果：与对照组相比,HOTTIP rs2067087和 H19 rs2839698在子宫颈病变患者中的基因型分布存在显著差异。在隐性模型中,携带HOTTIP rs2067087 GG基因型患者发生子宫颈病变的频率增加了52.2%（95% CI：1.021 ~ 2.269,P <0.05）,分层分析发现,该位点GG基因型主要增加了CIN的发病风险（OR=1.730,95% CI：1.117 ~ 2.680,P<0.05）;与CC+CT基因型相比,携带H19 rs2839698 TT基因型患者发生子宫颈癌的风险减少了70.8%（95% CI：0.087 ~ 0.976,P <0.05）。未发现H19 rs2107425位点与不同级别子宫颈病变相关（P>0.05）。结论： HOTTIP基因SNP位点rs2067087与不同级别子宫颈病变相关,其GG基因型可能是宫颈上皮内瘤变发生的危险因素;H19基因SNP位点rs2839698与子宫颈癌发病风险相关,其TT基因型可能是子宫颈癌发生的保护因素。

关键词: 子宫颈病变, 子宫颈癌, HOTTIP, H19, 单核苷酸多态性, 相关性

Abstract:

Background and purpose: Both HOTTIP and H19 are members of long non-coding RNA(lncRNA). They have been found to play an important role in the occurrence, development and migration of tumors. This study aimed to investigate the association between single nucleotide polymorphisms (SNP) of HOTTIP rs2067087, H19 rs2839698 and H19 rs2107425 and the risk of cervical lesions of different grades. Methods: The peripheral venous blood and related clinical data of 345 cases of cervical lesions were collected from Nov. 2018 to Dec. 2020 in Yancheng No.1 People's Hospital, including 220 cases of cervical intraepithelial neoplasia (CIN) and 125 cases of cervical cancer (CC). Three hundred and sixty patients without cervical lesions hospitalized during the same period were selected as the control. TaqMan real-time fluorescence quantitative polymerase chain reaction (RTFQPCR) was used to genotype the HOTTIP SNP rs2067087, H19 SNP rs2839698 and rs2107425 in the two groups, and χ² test and unconditional logistic regression were used to analyze the association of the three SNP loci with cervical lesions of different grades. Results: Compared with the control group, there were significant differences in genotype distribution of HOTTIP rs2067087 and H19 rs2839698 in patients with cervical lesions. In the recessive model, the frequency of cervical lesions in patients with HOTTIP rs2067087 GG genotype increased by 52.2% (95% CI: 1.021-2.269, P<0.05). Stratified analysis showed that GG genotype at this locus mainly increased the risk of CIN (OR =1.730, 95% CI: 1.117-2.680, P<0.05); Stratified analysis showed that the GG genotype at this locus mainly increased the risk of CIN (OR=1.730, 95% CI:1.117-2.680, P<0.05). Compared with CC+CT genotype, the risk of cervical cancer in patients with H19 rs2839698 TT genotype was reduced by 70.8% (95% CI: 0.087-0.976, P<0.05). No correlation was found between H19 rs2107425 and cervical lesions of different grades (P>0.05). Conclusion: HOTTIP rs2067087 SNP is associated with different levels of cervical lesions, and the GG genotype may be a risk factor for CIN; H19 rs2839698 SNP is associated with the risk of cervical cancer, and the TT genotype may be a protective factor for cervical cancer.

Key words: Cervical lesions, Cervical cancer, HOTTIP, H19, Single nucleotide polymorphism, Association

中图分类号:

R737.33

王春桃, 葛安兴, 吴红雁, 张学艳, 杨圣, 袁红香, 程艳萍, 冯延璐, 陆欣苑, 梁戈玉. 不同级别子宫颈病变与lncRNA HOTTIP和H19单核苷酸多态性的关系研究[J]. 中国癌症杂志, 2022, 32(4): 324-334.

WANG Chuntao, GE Anxing, WU Hongyan, ZHANG Xueyan, YANG Sheng, YUAN Hongxiang, CHENG Yanping, FENG Yanlu, LU Xinyuan, LIANG Geyu. The association between cervical lesions of different grades and lncRNA HOTTIP and H19 single nucleotide polymorphisms[J]. China Oncology, 2022, 32(4): 324-334.

图/表 7

图1

表1

表2

表3

表4

HOTTIP rs2067087和H19 rs2839698、rs2107425基因型及等位基因在CIN组、宫颈癌组及健康对照组中的分布"

Genotype	Controls n (%)	CIN n (%)	P value	OR (95% CI)	CC, n %	P value	OR (95% CI)
HOTTIP rs2067087
Codominant
CC	133 (36.9)	75 (34.1)		1.000	35 (28.0)		1.000
CG	177 (49.2)	97 (44.1)	0.882	0.972 (0.667-1.415)	70 (56.0)	0.085	1.503 (0.945-2.390)
GG	50 (13.9)	48 (21.8)	0.032	1.702 (1.046-2.770)	20 (16.0)	0.199	1.520 (0.803-2.878)
Dominant
CC	133 (36.9)	75 (34.1)		1.000	35 (28.0)		1.000
CG+GG	227 (63.1)	145 (65.9)	0.487	1.133 (0.797-1.610)	90 (72.0)	0.071	1.507 (0.965-2.352)
Recessive
CC+CG	310 (86.1)	172 (78.2)		1.000	105 (84.0)		1.000
GG	50 (13.9)	48 (21.8)	0.014	1.730 (1.117-2.680)	20 (16.0)	0.563	1.181 (0.672-2.075)
Allele
C	443 (61.5)	247 (56.1)		1.000	140 (56.5)		1.000
G	277 (38.5)	193 (43.9)	0.070	1.250 (0.982-1.590)	108 (43.5)	0.159	1.234 (0.921-1.653)
H19 rs2839698
Codominant
CC	195 (54.2)	117 (53.2)		1.000	62 (49.6)		1.000
CT	137 (38.1)	84 (38.2)	0.905	1.022 (0.686-1.396)	60 (48.0)	0.131	1.377 (0.908-2.090)
TT	28 (7.8)	19 (8.6)	0.700	1.131 (0.605-2.115)	3 (2.4)	0.082	0.337 (0.099-1.147)
Dominant
CC	195 (54.2)	117 (53.2)		1.000	62 (49.6)		1.000
CT+TT	165 (45.8)	103 (46.8)	0.817	1.040 (0.743-1.456)	63 (50.4)	0.378	1.201 (0.799-1.805)
Recessive
CC+CT	332 (92.2)	201 (91.4)		1.000	122 (97.6)		1.000
TT	28 (7.8)	19 (8.6)	0.713	1.121 (0.610-2.059)	3 (2.4)	0.046	0.292 (0.087-0.976)
Allele
C	527 (73.2)	318 (72.3)		1.000	184 (73.6)		1.000
T	193 (26.8)	122 (27.7)	0.732	1.048 (0.803-1.367)	66 (26.4)	0.901	0.979 (0.707-1.357)
H19 rs2107425
Codominant
CC	120 (33.3)	66 (30.0)		1.000	48 (38.4)		1.000
CT	168 (46.7)	117 (53.2)	0.226	1.266 (0.864-1.855)	56 (44.8)	0.428	0.833 (0.531-1.308)
TT	72 (20.0)	37 (16.8)	0.789	0.934 (0.568-1.536)	21 (16.8)	0.293	0.729 (0.404-1.316)
Dominant
CC	120 (33.3)	66 (30.0)		1.000	48 (38.4)		1.000
CT+TT	240 (66.7)	154 (70.0)	0.404	1.167 (0.812-1.676)	77 (61.6)	0.305	0.802 (0.526-1.223)
Recessive
CC+CT	288 (80.0)	183 (83.2)		1.000	104 (83.2)		1.000
TT	72 (20.0)	37 (16.8)	0.342	0.809 (0.522-1.253)	21 (16.8)	0.434	0.808 (0.473-1.380)
Allele
C	408 (56.7)	249 (56.6)		1.000	152 (60.8)		1.000
T	312 (43.3)	191 (43.4)	0.980	1.003 (0.790-1.274)	98 (39.2)	0.255	0.843 (0.629-1.131)

表4

表5

表6

参考文献 28

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Age/year	Genotype	Controls n (%)	Cases n (%)	P value	OR	95 % CI
HOTTIP rs2067087
≤50	Dominant
	CG+GG	108 (64.7)	123 (66.5)		1.000
	CC	59 (35.3)	62 (33.5)	0.720	0.923	0.594-1.433
	Recessive
	CC+CG	139 (83.2)	145 (78.4)		1.000
	GG	28 (16.8)	40 (21.6)	0.250	1.369	0.801-2.341
>50	Dominant
	CG+GG	119 (61.7)	112 (70.0)		1.000
	CC	74 (38.3)	48 (30.0)	0.102	0.689	0.441-1.076
	Recessive
	CC+CG	171 (88.6)	132 (82.5)		1.000
	GG	22 (11.4)	28 (17.5)	0.104	1.649	0.902-3.013
H19 rs2839698
≤50	Dominant
	CC	94 (56.3)	96 (51.9)		1.000
	CT+TT	73 (43.7)	89 (48.1)	0.409	1.194	0.784-1.817
	Recessive
	CC+CT	157 (94.0)	171 (92.4)		1.000
	TT	10 (6.0)	14 (7.6)	0.558	1.285	0.555-2.977
>50	Dominant
	CC	101 (52.3)	83 (51.9)		1.000
	CT+TT	92 (47.7)	77 (48.1)	0.932	1.018	0.670-1.549
	Recessive
	CC+CT	175 (90.7)	152 (95.0)		1.000
	TT	18 (9.3)	8 (5.0)	0.127	0.512	0.216-1.210
H19 rs2107425
≤50	Dominant
	CC	49 (29.3)	64 (34.6)		1.000
	CT+TT	118 (70.7)	121 (65.4)	0.292	0.785	0.500-1.232
	Recessive
	CC+CT	127 (76.0)	153 (82.7)		1.000
	TT	40 (24.0)	32 (17.3)	0.124	0.664	0.394-1.118
>50	Dominant
	CC	71 (36.8)	50 (31.3)		1.000
	CT+TT	122 (63.2)	110 (68.8)	0.276	1.280	0.821-1.996
	Recessive
	CC+CT	161 (83.4)	134 (83.8)		1.000
	TT	32 (16.6)	26 (16.3)	0.934	0.976	0.554-1.719

Genotype	Cervical adenocarcinoma n (%)	The squamous cell carcinoma of cervix n (%)	χ²	P value	OR	95 % CI
HOTTIP rs2067087			0.007	0.933		0.341-2.685
CC	6 (27.3)	29 (28.2)			1.000
CG+GG	16 (72.2)	74 (71.8)			0.957
H19 rs2839698			0.261	0.610		0.505-3.204
CC	12 (54.5)	50 (48.5)			1.000
CT+TT	10 (45.5)	53 (51.5)			1.272
H19 rs2107425			0.047	0.829		0.346-2.338
CC	8 (36.4)	40 (38.8)			1.000
CT+TT	14 (63.6)	63 (61.2)			0.900

不同级别子宫颈病变与lncRNA HOTTIP和H19单核苷酸多态性的关系研究

The association between cervical lesions of different grades and lncRNA HOTTIP and H19 single nucleotide polymorphisms

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Group	Genotype	Actual frequencies n (%)	Estimated frequencies n (%)	χ²	P value
HOTTIP rs2067087	CC	133 (36.9)	136 (37.8)	0.535	0.465
	CG	177 (49.2)	170 (47.4)	0.535	0.465
	GG	50 (13.9)	53 (14.8)
H19 rs2839698	CC	195 (54.2)	193 (53.6)	0.328	0.567
	CT	137 (38.1)	141 (39.2)
	TT	28 (7.8)	26 (7.2)
H19 rs2107425	CC	120 (33.3)	116 (32.1)	0.892	0.345
	CT	168 (46.7)	177 (49.0)
	TT	72 (20.0)	68 (18.9)

Genotype	Phase I n (%)		Phase Ⅱ n (%)		χ²	P value	OR	95 % CI
HOTTIP
rs2067087
CC	9	22.0	26	31.0			1.000
CG+GG	32	78.0	58	69.0	1.079	0.295	0.627	0.262-1.501
H19 rs2839698
CC	19	46.3	43	51.2			1.000
CT+TT	22	53.7	41	48.8	0.259	0.611	0.823	0.390-1.740
H19 rs2107425
CC	18	43.9	30	35.7			1.000
CT+TT	23	56.1	54	64.3	0.778	0.378	1.409	0.658-3.016

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[2]	中华医学会肿瘤学分会肿瘤支持康复治疗学组. 中国癌症相关性疲乏临床实践诊疗指南（2021年版）[J]. 中国癌症杂志, 2021, 31(9): 852-872.
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[4]	龙行涛, 周琦, 王冬, 陈月梅, 金福军 . 子宫颈癌2018年FIGO新分期ⅢC期患者预后分析[J]. 中国癌症杂志, 2021, 31(8): 725-733.
[5]	杨　佳, 刘舒媛, 王莹莹, 李盈甫, 马千里, 李　玙, 王永蓉, 李传印, 谭　芳 . 云南省汉族人群TNF-α基因多态性与非小细胞肺癌发生、发展的相关性[J]. 中国癌症杂志, 2021, 31(7): 616-628.
[6]	蒋朝阳, 王　娟, 张　伶, 高　辉, 张　涛, 李智慧 . 709例鼻咽癌颈部各区淋巴结转移的相关性分析[J]. 中国癌症杂志, 2021, 31(7): 629-634.
[7]	中国抗癌协会肿瘤内分泌专业委员会, 重庆市中西医结合学会肿瘤内分泌分会. 肿瘤相关性高血糖管理指南（2021年版）[J]. 中国癌症杂志, 2021, 31(7): 651-688.
[8]	中国抗癌协会妇科肿瘤专业委员会. 子宫颈癌诊断与治疗指南（2021年版）[J]. 中国癌症杂志, 2021, 31(6): 474-489.
[9]	董诗洁, 胡晓欣, 王　葳, 杨　孟, 岳　磊, 童　彤, 顾雅佳. 基于多序列MRI与多体系影像组学模型预测子宫颈癌淋巴结转移的研究[J]. 中国癌症杂志, 2021, 31(6): 460-467.
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[11]	张翠翠, 秦婷婷, 孟昭婷 , 李　凯 . 肺癌相关异常脂代谢的研究进展[J]. 中国癌症杂志, 2021, 31(1): 76-80.
[12]	徐珊珊 , 宋琴琴 , 仵红娇 , 付　宁 , 车玲玉 , 金　敏 , 刘　冲 , 韩素桂 , 张雪梅 , 张　志 . 膜辅助蛋白CD46 rs1970530遗传变异对肝癌发病风险的影响[J]. 中国癌症杂志, 2020, 30(9): 656-660.
[13]	王　平, 杨文秀, 周　杰, 冯江龙, 林超群. 弥漫大B细胞淋巴瘤中NF-κB/p65、PD-1、PD-L1表达相关性研究及其蛋白表达的临床意义[J]. 中国癌症杂志, 2020, 30(5): 375-382.
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