The relationship between the promoter polymorphism (−308G/A) of the tumor necrosis factor-alpha (TNF-α) gene and the susceptibility to asthma has been tested in several studies. However, the results have been inconsistent. Therefore, we performed an updated meta-analysis to evaluate the relationship between this promoter polymorphism of the TNF-α gene and the risk of asthma.
Methods:
Fifty case-control studies were included in this meta-analysis which provided 17,937 controls and 9961 asthma patients. The pooled p-value, odds ratio (OR), and 95% confidence interval (95% CI) were used to investigate the strength of the association of this polymorphism of the TNF-α gene with the risk of asthma. The meta-analysis was carried out by Comprehensive Meta-Analysis software.
Results:
The results of our meta-analysis revealed that the TNF-α polymorphism (−308, G/A) was strongly associated with the risk of asthma (p < 0.05 in the allelic, dominant, and recessive models, respectively). In further analyses, based on age group and ethnicity, we observed this association for all subpopulations examined (p < 0.05 in allelic, dominant, and recessive models, respectively).
Conclusion:
This large-scale meta-analysis supports a strong association between the TNF-α gene promoter polymorphism (−308G/A) and the development to asthma in both children and adults.
Get full access to this article
View all access options for this article.
References
1.
AhluwaliaSK, MatsuiEC (2011) The indoor environment and its effects on childhood asthma. Curr Opin Allergy Clin Immunol, 11:137-143.
2.
AlbuquerqueRV, HaydenCM, PalmerLJ, et al. (1998) Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma. Clin Exp Allergy, 28:578-584.
3.
AytekinC, DoguF, IkinciogullariA, et al. (2009) [TGF-Beta1-915G/C and TNF-alpha-308G/A polymorphisms in children with asthma]. Tuberk Toraks, 57:62-67.
4.
BegheB, PadoanM, MossCT, et al. (2004) Lack of association of HLA class I genes and TNF alpha-308 polymorphism in toluene diisocyanate-induced asthma. Allergy, 59:61-64.
5.
BilolikarH, NamAR, RosenthalM, et al. (2005) Tumour necrosis factor gene polymorphisms and childhood wheezing. Eur Respir J, 26:637-646.
6.
BuckovaD, HollaLI, VaskuA, et al. (2002) Lack of association between atopic asthma and the tumor necrosis factor alpha-308 gene polymorphism in a Czech population. J Investig Allergol Clin Immunol, 12:192-197.
7.
CarswellEA, OldLJ, KasselRL, et al. (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A, 72:3666-3670.
8.
Castro-GinerF, KogevinasM, ImbodenM, et al. (2009) Joint effect of obesity and TNFA variability on asthma: two international cohort studies. Eur Respir J, 33:1003-1009.
9.
ChaganiT, ParePD, ZhuS, et al. (1999) Prevalence of tumor necrosis factor-alpha and angiotensin converting enzyme polymorphisms in mild/moderate and fatal/near-fatal asthma. Am J Respir Crit Care Med, 160:278-282.
10.
ChiangCH, ChuangCH, LiuSL, ShenHD (2013) Genetic polymorphism of transforming growth factor beta1 and tumor necrosis factor alpha is associated with asthma and modulates the severity of asthma. Respir Care, 58:1343-1350.
11.
ConteD, HolcikM, LefebvreCA, et al. (2006) Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival. Mol Cell Biol, 26:699-708.
12.
CuiL, WangH (2010) The association between TNF-α gene polymorphisms and bronchial asthma among mongolia and Han nationality in inner mongolia. J Inner Mongolia Med Univ, 4:354-357.
13.
DaleyD, LemireM, AkhabirL, et al. (2009) Analyses of associations with asthma in four asthma population samples from Canada and Australia. Hum Genet, 125:445-459.
14.
de NijsSB, VenekampLN, BelEH (2013) Adult-onset asthma: is it really different?. Eur Respir Rev, 22:44-52.
15.
De SanctisGT, MerchantM, BeierDR, et al. (1995) Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice. Nat Genet, 11:150-154.
16.
DespotovicM, StoimenovTJ, StankovicI, et al. (2015) Gene polymorphisms of tumor necrosis factor alpha and antioxidant enzymes in bronchial asthma. Adv Clin Exp Med, 24:251-256.
17.
DhaouadiaT, SfaraI, AouadiaH, et al. (2011) Polymorphismes des cytokines pro-inflammatoires (TNFα et IL1) au cours de l'asthme allergique. Rev Fr Allergol, 51:659-663.
18.
El BahlawanL, ChristensenM, BinaeiS, et al. (2003) Lack of association between the tumor necrosis factor-alpha regulatory region genetic polymorphisms associated with elevated tumor necrosis factor-alpha levels and children with asthma. Chest, 123:374S-375S.
19.
GaoJ, LinY, QiuC, et al. (2003) The association between tumor necrosis factor alpha gene polymorphism and asthma. Chin Med Sci J, 18:248-253.
20.
GoldDR, WrightR (2005) Population disparities in asthma. Annu Rev Public Health, 26:89-113.
21.
GuoY, ZhouS (2004) Investigation of association between tumour necrosis factor-alpha promotor polymorphism and asthma. J Jiangxi Med Coll, 44:28-30.
22.
GuptaV, SarinBC, ChangotraH, SehajpalPK (2005) Association of G-308A TNF-alpha polymorphism with bronchial asthma in a North Indian population. J Asthma, 42:839-841.
23.
HakonarsonH, BjornsdottirUS, OstermannE, et al. (2001) Allelic frequencies and patterns of single-nucleotide polymorphisms in candidate genes for asthma and atopy in Iceland. Am J Respir Crit Care Med, 164:2036-2044.
24.
HaoK, NiuT, XuX, et al. (2005) Single-nucleotide polymorphisms of the KCNS3 gene are significantly associated with airway hyperresponsiveness. Hum Genet, 116:378-383.
HongSJ, KimHB, KangMJ, et al. (2007) TNF-alpha (-308 G/A) and CD14 (-159T/C) polymorphisms in the bronchial responsiveness of Korean children with asthma. J Allergy Clin Immunol, 119:398-404.
27.
HsuHY, NicholsonAC, HajjarDP (1996) Inhibition of macrophage scavenger receptor activity by tumor necrosis factor-alpha is transcriptionally and post-transcriptionally regulated. J Biol Chem, 271:7767-7773.
28.
HuangH, NieW, QianJ, et al. (2014) Effects of TNF-alpha polymorphisms on asthma risk: a systematic review and meta-analysis. J Investig Allergol Clin Immunol, 24:406-417.
29.
JiaN, GuanL, LiH, et al. (2012) Association of TNFGene-308 G/A Polymorphism with Bronchial Asthma of Children. Acta Acad Med Weifang, 34:455-457.
30.
JiffriEH, ElhawaryNA (2011) The impact of common tumor necrosis factor haplotypes on the development of asthma in children: an Egyptian model. Genet Test Mol Biomarkers, 15:293-299.
31.
Jimenez-MoralesS, Velazquez-CruzR, Ramirez-BelloJ, et al. (2009) Tumor necrosis factor-alpha is a common genetic risk factor for asthma, juvenile rheumatoid arthritis, and systemic lupus erythematosus in a Mexican pediatric population. Hum Immunol, 70:251-256.
32.
Kamali-SarvestaniE, GhayomiMA, NekoeeA (2007) Association of TNF-alpha -308 G/A and IL-4 -589 C/T gene promoter polymorphisms with asthma susceptibility in the south of Iran. J Investig Allergol Clin Immunol, 17:361-366.
33.
KangSW, KimSK, ChungJH, et al. (2016) Genetic polymorphism of angiotensin-converting enzyme and chronic obstructive pulmonary disease risk: an updated meta-analysis. Biomed Res Int, 2016:7636123.
34.
KangSW, KimSK, ParkHJ, et al. (2017) Human 8-oxoguanine DNA glycosylase gene polymorphism (Ser326Cys) and cancer risk: updated meta-analysis. Oncotarget, 8:44761-44775.
35.
KimHB, KangMJ, LeeSY, et al. (2008) Combined effect of tumour necrosis factor-alpha and interleukin-13 polymorphisms on bronchial hyperresponsiveness in Korean children with asthma. Clin Exp Allergy, 38:774-780.
36.
KimJ, KimJ, LeeJ (2017a) Effect of compression garments on delayed-onset muscle soreness and blood inflammatory markers after eccentric exercise: a randomized controlled trial. J Exerc Rehabil, 13:541-545.
37.
KimSH, YeYM, LeeSK, et al. (2006) Association of TNF-alpha genetic polymorphism with HLA DPB1*0301. Clin Exp Allergy, 36:1247-1253.
38.
KimSK, SeokH, ParkHJ, et al. (2017b) Association Between Secretoglobin Family 3A Member 2 (SCGB3A2) Gene Polymorphisms and Asthma in a Korean Population. Med Sci Monit, 23:1880-1885.
39.
KumarA, GuptaV, ChangotraH, et al. (2008) Tumor necrosis factor—alpha and transforming growth factor—beta1 polymorphisms in bronchial asthma. Indian J Med Sci, 62:323-330.
40.
KurotaniR, TomitaT, YangQ, et al. (2008) Role of secretoglobin 3A2 in lung development. Am J Respir Crit Care Med, 178:389-398.
41.
LiM, HanT, ZhangW, et al. (2018) Simulated altitude exercise training damages small intestinal mucosa barrier in the rats. J Exerc Rehabil, 14:341-348.
42.
LiuD, LiuR, CuiT, WuJ (2004) Correlation between polymorphisms in the IL-4 promoter region and tumour necrosis factor-alpha gene and susceptibility of allergic asthma in chinese children of Han nationality in Hubei province. J Huazhong Univ Sci Technol Med Sci, 33:196-198.
43.
LouisR, LeyderE, MalaiseM, et al. (2000) Lack of association between adult asthma and the tumour necrosis factor alpha-308 polymorphism gene. Eur Respir J, 16:604-608.
44.
MahdavianiSA, RezaeiN, MoradiB, et al. (2009) Proinflammatory cytokine gene polymorphisms among Iranian patients with asthma. J Clin Immunol, 29:57-62.
MakJC, KoFW, ChuCM, et al. (2007) Polymorphisms in the IL-4, IL-4 receptor alpha chain, TNF-alpha, and lymphotoxin-alpha genes and risk of asthma in Hong Kong Chinese adults. Int Arch Allergy Immunol, 144:114-122.
47.
MartinezFD (2007) Genes, environments, development and asthma: a reappraisal. Eur Respir J, 29:179-184.
48.
MichelS, LiangL, DepnerM, et al. (2010) Unifying candidate gene and GWAS Approaches in Asthma. PLoS One, 5:e13894.
49.
MichlewskaS, DransfieldI, MegsonIL, RossiAG (2009) Macrophage phagocytosis of apoptotic neutrophils is critically regulated by the opposing actions of pro-inflammatory and anti-inflammatory agents: key role for TNF-alpha. FASEB J, 23:844-854.
MurkW, RisnesKR, BrackenMB (2011a) Prenatal or early-life exposure to antibiotics and risk of childhood asthma: a systematic review. Pediatrics, 127:1125-1138.
52.
MurkW, WalshK, HsuLI, et al. (2011b) Attempted replication of 50 reported asthma risk genes identifies a SNP in RAD50 as associated with childhood atopic asthma. Hum Hered, 71:97-105.
53.
ParkKH, KimSK (2015) Promoter polymorphisms of NDUFA4 gene were associated with prostate enlargement of benign prostatic hyperplasia. Mol Cell Toxicol, 11:401-406.
54.
PreussCV, WoodTC, SzumlanskiCL, et al. (1998) Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity. Mol Pharmacol, 53:708-717.
55.
RosenwasserLJ, KlemmDJ, DresbackJK, et al. (1995) Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy. Clin Exp Allergy 25 Suppl 2,74-78; discussion. 95-96.
56.
SandfordAJ, ChanHW, WongGW, et al. (2004) Candidate genetic polymorphisms for asthma in Chinese schoolchildren from Hong Kong. Int J Tuberc Lung Dis, 8:519-527.
57.
SantosAC, de MouraEL, FerreiraJM, et al. (2017) Meta-Analysis of the Relationship between TNF-alpha (-308G/A) and IL-10 (-819C/T) Gene Polymorphisms and Susceptibility to Dengue. Immunol Invest, 46:201-220.
58.
SchubertK, von BonnsdorfH, BurkeM, et al. (2006) A comprehensive candidate gene study on bronchial asthma and juvenile idiopathic arthritis. Dis Markers, 22:127-132.
59.
SeokH, KimSK, YooKH, et al. (2014) Association of BID SNPs (rs8190315 and rs2072392) and clinical features of benign prostate hyperplasia in Korean population. J Exerc Rehabil, 10:383-388.
60.
ShakerOG, SadikNA, El-HamidNA (2013) Impact of single nucleotide polymorphism in tumor necrosis factor-alpha gene 308G/A in Egyptian asthmatic children and wheezing infants. Hum Immunol, 74:796-802.
61.
SharmaS, SharmaA, KumarS, et al. (2006) Association of TNF haplotypes with asthma, serum IgE levels, and correlation with serum TNF-alpha levels. Am J Respir Cell Mol Biol, 35:488-495.
62.
ShinHD, ParkBL, KimLH, et al. (2004) Association of tumor necrosis factor polymorphisms with asthma and serum total IgE. Hum Mol Genet, 13:397-403.
63.
SongD, ChengD (2017) Associations of TNFalpha-308G/A and TNFalpha-238G/A Polymorphisms with Ischemic Stroke in East Asians and Non-East Asians: A Meta-Analysis. Genet Test Mol Biomarkers, 21:10-16.
64.
SpriggsDR, DeutschS, KufeDW (1992) Genomic structure, induction, and production of TNF-alpha. Immunol Ser, 56:3-34.
65.
TakadaY, SungB, SethiG, et al. (2007) Evidence that genetic deletion of the TNF receptor p60 or p80 inhibits Fas mediated apoptosis in macrophages. Biochem Pharmacol, 74:1057-1064.
66.
TanEC, LeeBW, TayAW, et al. (1999) Asthma and TNF variants in Chinese and Malays. Allergy, 54:402-403.
67.
TolgyesiG, KeszeiM, UngvariI, et al. (2006) Involvement of TNFalpha -308A promoter polymorphism in the development of asthma in children infected with Chlamydophila pneumoniae. Pediatr Res, 60:543-548.
68.
TrajkovD, Mirkovska-StojkovikjJ, ArsovT, et al. (2008) Association of cytokine gene polymorphisms with bronchial asthma in Macedonians. Iran J Allergy Asthma Immunol, 7:143-156.
69.
Van EerdeweghP, LittleRD, DupuisJ, et al. (2002) Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature, 418:426-430.
70.
WangJY, LiouYH, WuYJ, et al. (2009) An association study of 13 SNPs from seven candidate genes with pediatric asthma and a preliminary study for genetic testing by multiple variants in Taiwanese population. J Clin Immunol, 29:205-209.
71.
WangP, WangJ, YuM, LiZ (2016a) Tumor necrosis factor-alpha T-857C (rs1799724) polymorphism and risk of cancers: a meta-analysis. Dis Markers, 2016:4580323.
72.
WangTN, ChenWY, WangTH, et al. (2004) Gene-gene synergistic effect on atopic asthma: tumour necrosis factor-alpha-308 and lymphotoxin-alpha-NcoI in Taiwan's children. Clin Exp Allergy, 34:184-188.
73.
WangY, GhoshalAG, Bin Abdul MuttalifAR, et al. (2016b) Quality of Life and Economic Burden of Respiratory Disease in Asia-Pacific-Asia-Pacific Burden of Respiratory Diseases Study. Value Health Reg Issues, 9:72-77.
74.
WinchesterEC, MillwoodIY, RandL, et al. (2000) Association of the TNF-alpha-308 (G—>A) polymorphism with self-reported history of childhood asthma. Hum Genet, 107:591-596.
75.
WitsellAL, SchookLB (1992) Tumor necrosis factor alpha is an autocrine growth regulator during macrophage differentiation. Proc Natl Acad Sci U S A, 89:4754-4758.
76.
WitteJS, PalmerLJ, O'ConnorRD, et al. (2002) Relation between tumour necrosis factor polymorphism TNFalpha-308 and risk of asthma. Eur J Hum Genet, 10:82-85.
77.
YangG, ChenJ, XuF, et al. (2014) Association between tumor necrosis factor-alpha rs1800629 polymorphism and risk of asthma: a meta-analysis. PLoS One, 9:e99962.
78.
YangYH, LiuYQ, ZhangL, et al. (2015) Genetic polymorphisms of the TNF-alpha-308G/A are associated with metabolic syndrome in asthmatic patients from Hebei province, China. Int J Clin Exp Pathol, 8:13739-13746.
79.
YangZC, XuF, TangM, XiongX (2017) Association Between TNF-alpha Promoter -308 A/G Polymorphism and Systemic Lupus Erythematosus Susceptibility: A Case-Control Study and Meta-Analysis. Scand J Immunol, 85:197-210.
80.
YingL, XiaJ, WangH, JiaS (2013) Single nucleotide polymorphism and expression of TNF-α, plasma levels of TNF-α, ET-I in bronchial asthma. Int J Respir, 33:165-169.
81.
ZhaiF, LiY (2004) Association between polymorphism of tumor necrosis factor-α promoter gene and asthma. Shan Dong Yi Yao, 44:4-6.
82.
ZhangJ, MinQH, XuYM, et al. (2017) Association between TNF-alpha -308G/A polymorphism and risk of immune thrombocytopenia: a meta-analysis. Genet Test Mol Biomarkers, 21:80-85.
83.
ZhaoH, DingY, LiuY, et al. (2005) Association between polymorphism of tumor necrosis factor promoter gene and asthma. J Jilin Univ Med Ed, 31:449-451.
84.
ZhengBQ, WangGL, YangS, et al. (2012) Study of genetic susceptibility in 198 children with asthma. Zhongguo Dang Dai Er Ke Za Zhi, 14:811-814.
85.
ZhifangL, JingrouL, XiaofangS, BaopingL (2003) Lack of association between childhood asthma and the tumor necrosis factor-alpha gene -308 polymorphism. New Chin Med, 34:217-218.
