结核病患者中靶向调控维生素D受体的microRNA的初步筛选

doi:10.3877/cma.j.issn.1674-6902.2020.06.003

目的

筛选与结核病相关，且靶向调控维生素D受体(vitamin D receptor, VDR)的microRNA(miRNA)，为深入研究维生素D(vitamin D, VitD)辅助抗结核病机制及其临床应用提供一定的参考依据。

方法

选择5例明确诊断肺结核病患者和5例非结核病的志愿者作为研究组和对照组。分别收集临床基线资料以及采集两组外周血单个核细胞(peripheral blood mononuclear cell, PBMC)作为临床样本，提取总RNA后，采用高通量测序技术(high-throughput sequencing)，检测两组间的miRNA差异表达情况。

结果

5例肺结核病患者和5例非结核病志愿者临床基线资料经统计学分析得出两组间23项指标的同质性和异质性，其中性别、年龄、吸烟饮酒习惯等两组间无统计学差异；体重指数(BMI)、总胆固醇(TC)、血红蛋白(Hb)白蛋白(ALB)、球蛋白(GLB)及总蛋白(TP)研究组低于对照组，有统计学差异(P<0.05)。高通量测序从研究组和对照组5对样本中共筛选出1 560条miRNAs，得到miRNA在两组中差异表达谱。分层聚类和火山图进一步综合分析发现研究组中最有差异的23条miRNAs(P<0.05)，其中15条miRNAs在研究组中表达下(∣LOG2FC∣>1)，8条miRNAs表达上调(FC>1)。综合高通量测序结果和生物信息学预测，从差异表达谱中筛选出2条有统计学意义且靶向VDR的miRNAs：hsa-miR-326(P<0.05、FC＝1.37)、hsa-miR-654-5p(P<0.05、∣LOG2FC∣＝1.06)。

结论

通过临床样本高通量测序分析及生物信息学预测，发现了结核病中的既差异表达又靶向VDR的两条miRNAs，这两条miRNAs可能是肺结核病潜在的诊断标志及新的治疗靶点，为结核病的防治提供了新的策略和方向。

关键词: 肺结核病, microRNA, 维生素D, 高通量测序, 生物信息学

Objective

MicroRNA with significantly differential expression and targeted regulation of Vitamin D receptor(VDR) in Tuberculosis were screened by High-throughput sequencing and bioinformatics methods, whichprovided the further study of Vitamin D anti-tuberculosis mechanism and clinical application.

Method

According to the inclusion and exclusion criteria, 5 patients with definite diagnosis of tuberculosis and 5 non-tuberculosis volunteers were selected as the study group and control group. Peripheral blood mononuclear cells(PBMC) of the two groups were collected as clinical samples. After total RNA was extracted, high-throughput sequencing technology was used to detect the differential expression of miRNA between the two groups.

Result

The clinical baseline data of 5 tuberculosis patients and 5 non-tuberculosis volunteers were collected, and the homogeneity and heterogeneity of 23 items between the two groups were obtained by statistical analysis. It was found that there were no significatly statistical differences in gender, age, smoking and drinking habits between the two groups. Body mass index (BMI), total cholesterol (TC), hemoglobin (Hb) albumin (ALB), globulin (GLB) and total protein (TP) in the study group were lower than those in the control group with significatly statistical differences(P<0.05). A total of 1560 miRNAs were screened out by miRNA sequencing. Through stratified cluster and comprehensive volcanic map analysis, 23 miRNAs with the most significant (P<0.05) differences were found in the case group, among which 15 were down-regulated(∣LOG2FC∣>1) and 8 were up-regulated(FC>1). In short, Combined with bioinformatics predictions, two miRNAs targeted VDR that differentially expressed in tuberculosis patients were screened out: hsa-miR-326(P<0.05、FC=1.37)、hsa-miR-654-5p(P<0.05、∣LOG2FC∣=1.06).

Conclusion

These two differentially expressed miRNAs mentioned abovemay be potential diagnostic markers and new therapeutic targets for tuberculosis.This found provides a new strategy and feasible direction for the prevention and treatment of Tuberculosis.

Key words: Tuberculosis, microRNA, Vitamin D, High-throughput sequencing, Bioinformatics

表1 研究组和对照组临床资料比较

临床资料	研究组(n＝5)	对照组(n＝5)	P值
年龄(岁)	44.2±9.24	51.60±20.29	0.491
性别[男(%)]	100.00	100.00	1.000
身高(cm)	165.6±5.86	162.8±11.54	0.642
体重(kg)	55.5±5.77	63.1±14.09	0.242
体重指数(BMI)	20.19±0.79	23.53±3.2	0.036
吸烟史	0.8±0.45	0.2±0.45	0.067
饮酒史	0.2±0.45	0.4±0.55	0.545
WBC(10⁹/L)	6.442±1.52	6.93±1.71	0.641
Hb(g/L)	114±15.24	148.60±27.64	0.042
PLT(10⁹)	297.6±86.11	246.40±74.84	0.345
TC(mmol/L)	2.72±0.63	5.12±0.78	0.001
TG(mmol/L)	0.99±0.24	2.10±1.74	0.197
HDL(mmol/L)	1.13±0.20	1.32±0.18	0.147
LDL(mmol/L)	1.91±0.25	2.69±0.82	0.077
ALT(IU/L)	17.4±14.10	27.90±9.99	0.211
AST(IU/L)	26.40±10.78	23.24±3.86	0.554
ALB(g/L)	35.9±5.78	51.98±3.38	0.001
GLB(g/L)	24.26±1.91	27.88±1.51	0.010
TP(g/L)	60.16±4.78	79.86±4.10	0.000
Cr(μmol/L)	63.54±12.96	77.42±18.29	0.204
BUN(mmol/L)	4.92±0.69	5.18±2.00	0.790
TBILI(μmol/L)	13.62±4.23	15.74±4.94	0.487
GLU(mmol/L)	7.14±4.16	4.96±0.82	0.283

表1 研究组和对照组临床资料比较

临床资料	研究组(n＝5)	对照组(n＝5)	P值
年龄(岁)	44.2±9.24	51.60±20.29	0.491
性别[男(%)]	100.00	100.00	1.000
身高(cm)	165.6±5.86	162.8±11.54	0.642
体重(kg)	55.5±5.77	63.1±14.09	0.242
体重指数(BMI)	20.19±0.79	23.53±3.2	0.036
吸烟史	0.8±0.45	0.2±0.45	0.067
饮酒史	0.2±0.45	0.4±0.55	0.545
WBC(10⁹/L)	6.442±1.52	6.93±1.71	0.641
Hb(g/L)	114±15.24	148.60±27.64	0.042
PLT(10⁹)	297.6±86.11	246.40±74.84	0.345
TC(mmol/L)	2.72±0.63	5.12±0.78	0.001
TG(mmol/L)	0.99±0.24	2.10±1.74	0.197
HDL(mmol/L)	1.13±0.20	1.32±0.18	0.147
LDL(mmol/L)	1.91±0.25	2.69±0.82	0.077
ALT(IU/L)	17.4±14.10	27.90±9.99	0.211
AST(IU/L)	26.40±10.78	23.24±3.86	0.554
ALB(g/L)	35.9±5.78	51.98±3.38	0.001
GLB(g/L)	24.26±1.91	27.88±1.51	0.010
TP(g/L)	60.16±4.78	79.86±4.10	0.000
Cr(μmol/L)	63.54±12.96	77.42±18.29	0.204
BUN(mmol/L)	4.92±0.69	5.18±2.00	0.790
TBILI(μmol/L)	13.62±4.23	15.74±4.94	0.487
GLU(mmol/L)	7.14±4.16	4.96±0.82	0.283

图1 10例样本高通量测序；注：A：为样本中miRNAs表达分为上调、下调和没有显著差异；B：为所有miRNAs差异表达谱FC>2的68条miRNAs在各个样本中的表达情况，以热图表示

表2 肺结核病患者差异表达显著的miRNAs

编　号	miRNA名称	miRNA序列	上调/下调	倍数(FC)	倍数(log2FC)	P值(T检验)
1	hsa-miR-1291_L+1R+1	GTGGCCCTGACTGAAGACCAGCAGTT	up	3.91	1.97	0.004
2	hsa-miR-27a-3p_R-1	TTCACAGTGGCTAAGTTCCG	up	1.37	0.45	0.006
3	hsa-miR-339-3p_R-2	TGAGCGCCTCGACGACAGAGC	up	1.52	0.61	0.016
4	hsa-miR-326_R+1	CCTCTGGGCCCTTCCTCCAGT	up	1.37	0.45	0.021
5	hsa-mir-6516-p3	TGTATGATACTGCAAACAGGA	up	3.13	1.65	0.034
6	hsa-miR-301a-3p	CAGTGCAATAGTATTGTCAAAGC	up	6.26	2.65	0.037
7	hsa-miR-30b-5p	TGTAAACATCCTACACTCAGCT	up	1.46	0.55	0.046
8	hsa-miR-30d-3p	CTTTCAGTCAGATGTTTGCTGC	up	2.9	1.54	0.047
9	hsa-miR-432-5p	TCTTGGAGTAGGTCATTGGGTGG	down	0.4	-1.34	0.000
10	hsa-miR-134-5p	TGTGACTGGTTGACCAGAGGGG	down	0.46	-1.11	0.001
11	hsa-miR-485-5p_R+1	AGAGGCTGGCCGTGATGAATTCG	down	0.5	-1.01	0.008
12	hsa-miR-4667-3p_R+1	TCCCTCCTTCTGTCCCCACAGT	down	0.27	-1.91	0.011
13	hsa-miR-127-3p	TCGGATCCGTCTGAGCTTGGCT	down	0.43	-1.21	0.012
14	hsa-miR-433-3p	ATCATGATGGGCTCCTCGGTGT	down	0.44	-1.18	0.012
15	hsa-miR-493-5p	TTGTACATGGTAGGCTTTCATT	down	0.47	-1.08	0.012
16	hsa-miR-382-5p	GAAGTTGTTCGTGGTGGATTCG	down	0.47	-1.1	0.014
17	hsa-miR-323a-3p_L+1	GCACATTACACGGTCGACCTCT	down	0.48	-1.07	0.018
18	hsa-miR-431-5p_R-1	TGTCTTGCAGGCCGTCATGC	down	0.4	-1.33	0.018
19	hsa-miR-654-5p	TATGTCTGCTGACCATCACC	down	0.48	-1.06	0.020
20	hsa-miR-941	CACCCGGCTGTGTGCACATGTGC	down	0.29	-1.81	0.021
21	hsa-miR-409-3p	GAATGTTGCTCGGTGAACCCCT	down	0.49	-1.03	0.022
22	hsa-miR-758-3p_R-1	TTTGTGACCTGGTCCACTAAC	down	0.5	-1.01	0.032
23	hsa-miR-550a-3-5p_R+1	AGTGCCTGAGGGAGTAAGAGA	down	0.23	-2.11	0.048

表2 肺结核病患者差异表达显著的miRNAs

编　号	miRNA名称	miRNA序列	上调/下调	倍数(FC)	倍数(log2FC)	P值(T检验)
1	hsa-miR-1291_L+1R+1	GTGGCCCTGACTGAAGACCAGCAGTT	up	3.91	1.97	0.004
2	hsa-miR-27a-3p_R-1	TTCACAGTGGCTAAGTTCCG	up	1.37	0.45	0.006
3	hsa-miR-339-3p_R-2	TGAGCGCCTCGACGACAGAGC	up	1.52	0.61	0.016
4	hsa-miR-326_R+1	CCTCTGGGCCCTTCCTCCAGT	up	1.37	0.45	0.021
5	hsa-mir-6516-p3	TGTATGATACTGCAAACAGGA	up	3.13	1.65	0.034
6	hsa-miR-301a-3p	CAGTGCAATAGTATTGTCAAAGC	up	6.26	2.65	0.037
7	hsa-miR-30b-5p	TGTAAACATCCTACACTCAGCT	up	1.46	0.55	0.046
8	hsa-miR-30d-3p	CTTTCAGTCAGATGTTTGCTGC	up	2.9	1.54	0.047
9	hsa-miR-432-5p	TCTTGGAGTAGGTCATTGGGTGG	down	0.4	-1.34	0.000
10	hsa-miR-134-5p	TGTGACTGGTTGACCAGAGGGG	down	0.46	-1.11	0.001
11	hsa-miR-485-5p_R+1	AGAGGCTGGCCGTGATGAATTCG	down	0.5	-1.01	0.008
12	hsa-miR-4667-3p_R+1	TCCCTCCTTCTGTCCCCACAGT	down	0.27	-1.91	0.011
13	hsa-miR-127-3p	TCGGATCCGTCTGAGCTTGGCT	down	0.43	-1.21	0.012
14	hsa-miR-433-3p	ATCATGATGGGCTCCTCGGTGT	down	0.44	-1.18	0.012
15	hsa-miR-493-5p	TTGTACATGGTAGGCTTTCATT	down	0.47	-1.08	0.012
16	hsa-miR-382-5p	GAAGTTGTTCGTGGTGGATTCG	down	0.47	-1.1	0.014
17	hsa-miR-323a-3p_L+1	GCACATTACACGGTCGACCTCT	down	0.48	-1.07	0.018
18	hsa-miR-431-5p_R-1	TGTCTTGCAGGCCGTCATGC	down	0.4	-1.33	0.018
19	hsa-miR-654-5p	TATGTCTGCTGACCATCACC	down	0.48	-1.06	0.020
20	hsa-miR-941	CACCCGGCTGTGTGCACATGTGC	down	0.29	-1.81	0.021
21	hsa-miR-409-3p	GAATGTTGCTCGGTGAACCCCT	down	0.49	-1.03	0.022
22	hsa-miR-758-3p_R-1	TTTGTGACCTGGTCCACTAAC	down	0.5	-1.01	0.032
23	hsa-miR-550a-3-5p_R+1	AGTGCCTGAGGGAGTAAGAGA	down	0.23	-2.11	0.048

图2 miRNAs功能及相似性分析；注：A:经过对比，33条miRNAs中，有显著相关性的miRNA有22条；B：22条miRNAs与细胞重编程、细胞分化等功能有密切联系；C：21条miRNAs参与的相对应生物学过程

表3 可能靶向VDR的miRNAs初步筛选结果

编　号	miRNA名称	3′非翻译区位置	种子匹配数	上下文得分
1	hsa-miR-654-5p	491-498	8mer	99
2	hsa-miR-541-3p	491-498	8mer	99
3	hsa-miR-302a-3p	3157-3164	8mer	98
4	hsa-miR-302b-3p	3157-3164	8mer	98
5	hsa-miR-302d-3p	3157-3164	8mer	98
6	hsa-miR-372-3p	3157-3164	8mer	98
7	hsa-miR-373-3p	3157-3164	8mer	98
8	hsa-miR-520e	3157-3164	8mer	98
9	hsa-miR-520a-3p	3157-3164	8mer	98
10	hsa-miR-520b	3157-3164	8mer	98
11	hsa-miR-520c-3p	3157-3164	8mer	98
12	hsa-miR-520d-3p	3157-3164	8mer	98
13	hsa-miR-532-3p	1859-1866	8mer	98
14	hsa-miR-302e	3157-3164	8mer	98
15	hsa-miR-556-3p	3130-3137	8mer	97
16	hsa-miR-10a-5p	1694-1701	8mer	95
17	hsa-miR-10b-5p	1694-1701	8mer	95
18	hsa-miR-3619-5p	3052-3059	8mer	95
19	hsa-miR-1913	251-258	8mer	87
20	hsa-miR-3194-5p	2937-2943	7mer-m8	84
21	hsa-miR-520d-5p	2605-2612	8mer	80
22	hsa-miR-4640-5p	2638-2644	7mer-m8	80
23	hsa-miR-2467-3p	115-121	7mer-m8	79
24	hsa-miR-524-5p	2605-2612	8mer	78
25	hsa-miR-326	285-292	8mer	76
26	hsa-miR-4726-5p	2638-2644	7mer-m8	70
27	hsa-miR-3918	2534-2540	7mer-m8	68
28	hsa-miR-324-3p	1081-1087	7mer-m8	62
29	hsa-miR-761	316-322	7mer-1A	45
30	hsa-miR-214-3p	2542-2548	7mer-m8	43
31	hsa-miR-330-5p	1058-1064	7mer-m8	39
32	hsa-miR-515-5p	902-908	7mer-1A	21
33	hsa-miR-519e-5p	902-908	7mer-1A	21

表3 可能靶向VDR的miRNAs初步筛选结果

编　号	miRNA名称	3′非翻译区位置	种子匹配数	上下文得分
1	hsa-miR-654-5p	491-498	8mer	99
2	hsa-miR-541-3p	491-498	8mer	99
3	hsa-miR-302a-3p	3157-3164	8mer	98
4	hsa-miR-302b-3p	3157-3164	8mer	98
5	hsa-miR-302d-3p	3157-3164	8mer	98
6	hsa-miR-372-3p	3157-3164	8mer	98
7	hsa-miR-373-3p	3157-3164	8mer	98
8	hsa-miR-520e	3157-3164	8mer	98
9	hsa-miR-520a-3p	3157-3164	8mer	98
10	hsa-miR-520b	3157-3164	8mer	98
11	hsa-miR-520c-3p	3157-3164	8mer	98
12	hsa-miR-520d-3p	3157-3164	8mer	98
13	hsa-miR-532-3p	1859-1866	8mer	98
14	hsa-miR-302e	3157-3164	8mer	98
15	hsa-miR-556-3p	3130-3137	8mer	97
16	hsa-miR-10a-5p	1694-1701	8mer	95
17	hsa-miR-10b-5p	1694-1701	8mer	95
18	hsa-miR-3619-5p	3052-3059	8mer	95
19	hsa-miR-1913	251-258	8mer	87
20	hsa-miR-3194-5p	2937-2943	7mer-m8	84
21	hsa-miR-520d-5p	2605-2612	8mer	80
22	hsa-miR-4640-5p	2638-2644	7mer-m8	80
23	hsa-miR-2467-3p	115-121	7mer-m8	79
24	hsa-miR-524-5p	2605-2612	8mer	78
25	hsa-miR-326	285-292	8mer	76
26	hsa-miR-4726-5p	2638-2644	7mer-m8	70
27	hsa-miR-3918	2534-2540	7mer-m8	68
28	hsa-miR-324-3p	1081-1087	7mer-m8	62
29	hsa-miR-761	316-322	7mer-1A	45
30	hsa-miR-214-3p	2542-2548	7mer-m8	43
31	hsa-miR-330-5p	1058-1064	7mer-m8	39
32	hsa-miR-515-5p	902-908	7mer-1A	21
33	hsa-miR-519e-5p	902-908	7mer-1A	21

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A study of microRNA Prescreening that targeted and regulated Vitamin D rceptor in tuberculosis patients

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A study of microRNA Prescreening that targeted and regulated Vitamin D rceptor in tuberculosis patients