Association of cytokine genetic polymorphisms with susceptibility to diabetic pulmonary tuberculosis

doi:10.3969/j.issn.1000-6621.2018.10.005

Abstract

Abstract: Objective

This study aims to reveal the associations among IFN-γ +874 A/T, IL-10 -592 A/C, -1082 G/A SNPs and risk of diabetic pulmonary tuberculosis, and consequently provide further evidence for research on pathogenesis of diabetic pulmonary tuberculosis (PTB-DM) and the screening for diabetic pulmonary tuberculosis patients.

Methods

A case-control study based on the screening of DM in PTB patients (142 cases) was carried out in 3 counties in Jiangsu Province from 1 April, 2013 to 31 March, 2014. Cases in this study were all diagnosed diabetic pulmonary tuberculosis patients, whereas control groups were PTB patients (147 cases) and DM patients (141 cases) matching with gender and age. Social demographic information was collected by a questionnaire and DNA was extracted from the blood sample collected.The polymorphisms of IFN-γ +874 A/T, IL-10 -592 A/C and -1082 G/A were detected by PCR-RFLF methods and followed by direct sequencing. Statistical analyses were conducted using the EpiData and SPSS software version 16.0. Pearson chi-square and logistic regression were used to estimate the associations among IFN-γ+874 A/T, IL-10 -592 A/C, -1082 G/A SNPs and risk of diabetic pulmonary tuberculosis.

Results

In the study on IL-10 -1082 G/A, statistical differences were discovered between PTB-DM patients and DM controls (A allele, 92.61% (263/284) versus 87.59% (247/282)(χ²=3.995, P=0.046); AA genotype, 85.21% (121/142) versus 75.18% (106/141). The AA genotype of IL-10 had a 1.970 fold increased risk for diabetic pulmonary tuberculosis individuals (OR=1.970, 95%CI=1.066-3.643, respectively). Linkage disequilibrium was found between IL-10 -592 and IL-10 -1082 (D'=0.959,r²=0.181,P<0.001) and statistical significance was also found in IL-10 -592C/-1082A haplotype between diabetic pulmonary tuberculosis patients and DM controls (25.90% versus 17.60%, P=0.026); IL-10 -592C/-1082A haplotype had a 1.590 fold increased risk for diabetic pulmonary tuberculosis individuals (OR=1.590, 95%CI=1.056-2.396, respectively).

Conclusion

Our results indicated an association between IL-10 -1082G/A polymorphism and susceptibility to diabetic pulmonary tuberculosis. Novel risk haplotype of IL-10 has been identified, of which -592C/-1082A haplotype was found to be strongly linked to diabetic pulmonary tuberculosis susceptibility. However, no association was found between IL-10 -592 or IFN-γ +874 and the risk of diabetic pulmonary tuberculosis.

Key words: Tuberculosis, pulmonary, Diabetes mellitus, Comorbidity, Cytokines, Amplified fragment length polymorphism analysis, Disease susceptibility, Genetic association studies

Si-jia DONG,Li YUAN,Cheng CHEN,Wei-li JIANG,Qi ZHAO. Association of cytokine genetic polymorphisms with susceptibility to diabetic pulmonary tuberculosis[J]. Chinese Journal of Antituberculosis, 2018, 40(10): 1051-1059. doi: 10.3969/j.issn.1000-6621.2018.10.005

Figures/Tables 6

References 27

[1]	World Health Organization . Global tuberculosis report 2017.Geneva, World Health Organization, 2017.
[2]	吴哲渊, 梅建, 李锐 , 等. 结核病合并糖尿病流行现状与控制措施的研究进展. 环境与职业医学, 2013,30(3):229-232.
[3]	Carreira S, Costeira J, Gomes C , et al. Impact of diabetes on the presenting features of tuberculosis in hospitalized patients. Rev Port Pneumol, 2012,18(5):239-243. doi: 10.1016/j.rppnen.2012.04.011 URL pmid: 22609057
[4]	南京市鼓楼区人民政府办公室. 2014年南京市鼓楼区国民经济和社会发展统计公报 [EB/OL].( 2015- 07- 24)[2018-5-1]. .
[5]	朱红 . 2型糖尿病并发肺结核病遗传和环境危险因素探讨. 天津:天津医科大学, 2006. doi: 10.7666/d.y881241 URL
[6]	de Albuquerque AC, Rocha LQ, de Morais Batista AH , et al. Association of polymorphism +874 A/T of interferon-gamma and susceptibility to the development of tuberculosis: meta-analysis. Eur J Clin Microbiol Infect Dis, 2012,31(11):2887-2895.
[7]	Liang B, Guo Y, Li Y , et al. Association between IL-10 gene polymorphisms and susceptibility of tuberculosis: evidence based on a meta-analysis. PLoS One, 2014,9(2):e88448.
[8]	Bai H, Jing D, Guo A , et al. Association between interleukin 10 gene polymorphisms and risk of type 2 diabetes mellitus in a Chinese population. J Int Med Res, 2014,42(3):702-710.
[9]	Rodrigues KF, Pietrani NT, Sandrim VC , et al. Association of a Large Panel of Cytokine Gene Polymorphisms with Complications and Comorbidities in Type 2 Diabetes Patients. J Diabetes Res, 2015: 605965.
[10]	车南颖, 姜世闻, 高铁杰 , 等. 中国汉族人群Toll样受体2基因多态性与肺结核易感性之间关系. 中国防痨杂志, 2011,33(4):204-208.
[11]	Wang XH, Ma AG, Han XX , et al. Relationship between Toll-like receptor 4 and type-2 diabetes mellitus complicated by tuberculosis. Int J Tuberc Lung Dis, 2017,21(8):910-915.
[12]	中华人民共和国卫生部. WS 288—2008 肺结核诊断标准. 北京:中华人民共和国卫生部, 2008.
[13]	Zhao Q, Xiao X, Lu W , et al. Screening diabetes in tuberculosis patients in eastern rural China: a community-based cross-sectional study. Int J Tuberc Lung Dis, 2016,20(10):1370-1376.
[14]	乐永长 . 上海地区人群Toll样受体基因多态性与结核病易感性的关联研究. 上海:复旦大学, 2013. doi: 10.7666/d.Y2705608 URL
[15]	周春燕, 冯作化 . 医学分子生物学. 北京: 人民卫生出版社, 2014.
[16]	Liu Y, Yu MC, Zhang AQ , et al. Interleukin-10 gene promoter polymorphism and risk of liver cirrhosis. Genet Mol Res, 2015,14(1):1229-1234. doi: 10.4238/2015.February.13.1 URL pmid: 25730061
[17]	Cil E, Kumral A , Kanmaz-Özer M, et al. Interleukin-10-1082 gene polymorphism is associated with papillary thyroid cancer. Mol Biol Rep, 2014,41(5):3091-3097. doi: 10.1007/s11033-014-3169-7
[18]	Ovsepyan VA, Gabdulkhakova AKh, Shubenkiva AA , et al. Role of Interleukin-10 Gene Promoter Region Polymorphism in the Development of Chronic Lymphoid Leukemia. Bull Exp Biol Med, 2015,160(2):275-277.
[19]	Garcia-Elorriaga G, Vera-Ramirez L,Del Rey-Pineda G, et al. -592 and -1082 interleukin-10 polymorphisms in pulmonary tuberculosis with type 2 diabetes. Asian Pac J Trop Med, 2013,6(7):505-509. doi: 10.1016/S1995-7645(13)60086-3 URL
[20]	谢琨 . 中国Ⅰ型糖尿病患者生命质量评价及影响因素分析. 天津:天津大学, 2014.
[21]	Lopez-Maderuelo D, Arnalich F, Serantes R , et al. Interferon-gamma and interleukin-10 gene polymorphisms in pulmonary tuberculosis. Am J Respir Crit Care Med, 2003,167(7):970-975.
[22]	Rossouw M, Nel HJ, Cooke GS , et al. Association between tuberculosis and a polymorphic NF kappa B binding site in the interferon gamma gene. Lancet, 2003,361(9372):1871-1872.
[23]	Hu Y, Wu L, Li D , et al. Association between cytokine gene polymorphisms and tuberculosis in a Chinese population in Shanghai: a case-control study. BMC Immunol, 2015,16:8.
[24]	Siekiera U, Jarosz-Chobot P, Janusz J , et al. Polymorphism of TNF-alpha (308 A/G), IL-10 (1082 A/G, 819 C/T 592 A/C), IL-6 (174 G/C), and IFN-gamma (874 A/T); genetically conditioned cytokine synthesis level in children with diabetes type 1. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw, 2002,8(1):29-34.
[25]	Tsiavou A, Hatziagelaki E, Chaidaroglou A , et al. Correlation between intracellular interferon-gamma (IFN-gamma) production by CD4 + and CD8 + lymphocytes and IFN-gamma gene polymorphism in patients with type 2 diabetes mellitus and latent autoimmune diabetes of adults (LADA) . Cytokine, 2005,31(2):135-141. doi: 10.1016/j.cyto.2005.02.011
[26]	陈水连 . IL-18基因多态性与系统性红斑狼疮的关联性研究. 上海:复旦大学, 2013. doi: 10.7666/d.Y2701654 URL
[27]	王牡丹, 许菲菲, 陈必成 , 等. 浙南地区汉族IL-10基因启动子区G-1082A、C-592A多态性分布调查. 浙江预防医学, 2008,20(9):8-9,12. doi: 10.3969/j.issn.1007-0931.2008.09.004 URL

各位点基因型指标	PTB-DM组(142例)			&#x003c7;²值	P值	PTB组(147例)			&#x003c7;²值	P值	DM组(141例)			&#x003c7;²值	P值
IFN-&#x003b3;+874A/T	AA	AT	TT	0.110	0.740	AA	AT	TT	6.700	0.009	AA	AT	TT	0.018	0.894
观察频数 (频率,%)	107 (75.35)	32 (22.54)	3 (2.11)			118 (80.82)	23 (15.75)	5 (3.43)			108 (76.60)	31 (21.99)	2 (1.41)
预期频数 (频率,%)	106 (74.65)	33 (23.24)	3 (2.11)			115 (78.77)	29 (19.86)	2 (1.37)			108 (76.60)	31 (21.99)	2 (1.41)
IL-10 -592A/C	AA	AC	CC	0.218	0.640	AA	AC	CC	0.548	0.459	AA	AC	CC	0.100	0.572
观察频数 (频率,%)	63 (44.37)	65 (45.77)	14 (9.86)			60 (40.82)	71 (38.30)	16 (10.88)			73 (53.28)	53 (38.69)	11 (8.03)
预期频数 (频率,%)	64 (45.07)	63 (44.37)	15 (10.56)			62 (42.18)	67 (45.58)	18 (12.24)			72 (52.94)	54 (39.71)	10 (7.35)
IL-10 -1082G/A	GG	GA	AA	0.905	0.341	GG	GA	AA	2.193	0.139	GG	GA	AA	2.831	0.092
观察频数 (频率,%)	0 (0.00)	21 (14.79)	121 (85.21)			0 (0.00)	32 (21.77)	115 (78.23)			0 (0.00)	35 (24.82)	106 (75.18)
预期频数 (频率,%)	1 (0.70)	19 (13.38)	122 (85.92)			1 (0.68)	29 (19.73)	117 (79.59)			2 (1.41)	31 (21.99)	108 (76.60)

等位基因	PTB-DM组(142例)		PTB组(147例)		DM组(142例)		&#x003c7;²值^a	P值^a	&#x003c7;²值^b	P值^b	&#x003c7;²值^c	P值^c
等位基因	频数	频率(%)	频数	频率(%)	频数	频率(%)	&#x003c7;²值^a	P值^a	&#x003c7;²值^b	P值^b	&#x003c7;²值^c	P值^c
IFN-&#x003b3; +874A/T							0.576	0.750	0.576	0.448	0.118	0.731
A	246	86.62	259	88.70	247	87.59
T	38	13.38	33	11.30	35	12.41
IL-10 -592A/C							4.011	0.135	0.337	0.561	1.914	0.167
A	191	67.25	191	64.97	199	72.63
C	93	32.75	103	35.03	75	27.37
IL-10 -1082G/A							4.084	0.130	2.113	0.146	3.995	0.046
G	21	7.39	32	10.88	35	12.41
A	263	92.61	262	89.12	247	87.59

基因型	PTB-DM组(142例)		PTB组(147例)		DM组(141例)		&#x003c7;²值	P值
基因型	频数	频率(%)	频数	频率(%)	频数	频率(%)	&#x003c7;²值	P值
IFN-&#x003b3; +874A/T							3.633	0.458
AA	107	75.35	118	80.82	108	76.59
AT	32	22.54	23	15.75	31	21.99
TT	3	2.11	5	3.42	2	1.42
IL-10 -592A/C							4.706	0.319
AA	63	44.37	60	40.82	73	53.28
AC	65	45.77	71	48.30	53	38.69
CC	14	9.86	16	10.88	11	8.03
IL-10 -1082G/A							4.609	0.100
GG	0	0.00	0	0.00	0	0.00
GA	21	14.79	32	21.77	35	24.82
AA	121	85.21	115	78.23	106	75.18

单倍型	PTB-DM组(142例)		PTB组(147例)		OR(95%CI)值	P值
单倍型	频数	频率(%)	频数	频率(%)	OR(95%CI)值	P值
A-A	189.51	66.70	191.00	65.00	1.990(0.778~1.552)	0.592
C-A	73.49	25.90	71.00	24.20	1.104(0.758~1.610)	0.606
C-G	19.51	6.90	32.00	10.90	0.607(0.337~1.094)	0.094
A-G	-	-	-	-	-	-

单倍型	PTB-DM组(142例)		DM组(147例)		aOR(95%CI)值	P值
单倍型	频数	频率(%)	频数	频率(%)	aOR(95%CI)值	P值
A-A	189.51	66.70	191.17	70.00	0.797(0.554~1.148)	0.233
C-A	73.49	25.90	48.29	17.60	1.590(1.056~2.396)	0.026
C-G	19.51	6.90	26.71	9.70	0.666(0.362~1.226)	0.189
A-G	-	-	-	-	-	-