Download PDF
Am J Perinatol 2015; 32(04): 363-370
DOI: 10.1055/s-0034-1387929
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Toll-Like Receptor 4 Polymorphisms in Gram-Negative Bacterial Infections of Han Chinese Neonates

Jian-Guo Zhou
1   Division of Neonatology, Children's Hospital of Fudan University, Shanghai, China
*   These authors contributed equally to this work.
,
Jin-Ping Zhang
1   Division of Neonatology, Children's Hospital of Fudan University, Shanghai, China
*   These authors contributed equally to this work.
,
Ben H. Lee
2   MidAtlantic Neonatology Associates, Morristown, New Jersey
,
Shu-Lian Zhang
1   Division of Neonatology, Children's Hospital of Fudan University, Shanghai, China
,
Li Zhu
1   Division of Neonatology, Children's Hospital of Fudan University, Shanghai, China
,
Chao Chen
1   Division of Neonatology, Children's Hospital of Fudan University, Shanghai, China
› Author Affiliations
Further Information

Publication History

06 March 2014

24 June 2014

Publication Date:
13 September 2014 (online)

    Permissions and Reprints

Abstract

Background Human toll-like receptor 4 (TLR4) is an important receptor in innate immunity, particularly against gram-negative bacterial infection (GNBI). In our study, we evaluated associations of TLR4 single nucleotide polymorphisms (SNPs) with GNBI in Han Chinese neonates.

Patients and Methods Polymorphisms in TLR4 were genotyped in 201 neonates with GNBI and 279 gestational age and birth weight–matched controls without GNBI. Polymorphism analyses were applied to allele frequencies of the detected TLR4 SNPs and their associations with various clinical entities, including premature birth and GNBI were assessed.

Results A total of six SNPs with more than 5% frequency were found in several promoter sequences, including rs10759931, rs2737190, rs10116253, rs10983755, rs1927914, and rs10759932. Mutation allele frequencies ranged from 23 to 41%. There were no SNPs with a frequency greater than 5% in exon analyses. Allele G rs2737190 mutations and GGCGGC haplotypes were more frequent among preterm GNBI neonates (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.02–1.71 and OR, 1.89; 95% CI, 1.19–3.00, respectively). No specific alleles or haplotypes were associated with GNBI status among term neonates.

Conclusion In this study population of Han Chinese, there was a significant association between an ethnical unique SNP in the TLR4 promoter region and preterm neonatal GNBIs.

Keywords

TLR4 polymorphism - neonate - gram-negative bacterial infection - toll-like receptor - SNP - preterm birth
 

  • References

  • 1 Bryce J, Boschi-Pinto C, Shibuya K, Black RE ; WHO Child Health Epidemiology Reference Group. WHO estimates of the causes of death in children. Lancet 2005; 365 (9465) 1147-1152
    CrossrefPubMedGoogle Scholar
  • 2 Müller-Alouf H, Alouf JE, Gerlach D, Ozegowski JH, Fitting C, Cavaillon JM. Comparative study of cytokine release by human peripheral blood mononuclear cells stimulated with Streptococcus pyogenes superantigenic erythrogenic toxins, heat-killed streptococci, and lipopolysaccharide. Infect Immun 1994; 62 (11) 4915-4921
    PubMedGoogle Scholar
  • 3 Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004; 4 (7) 499-511
    CrossrefPubMedGoogle Scholar
  • 4 Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2001; 2 (8) 675-680
    CrossrefPubMedGoogle Scholar
  • 5 Montes AH, Asensi V, Alvarez V , et al. The Toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and haematogenous osteomyelitis. Clin Exp Immunol 2006; 143 (3) 404-413
    CrossrefPubMedGoogle Scholar
  • 6 Hsieh YY, Wan L, Chang CC, Tsai CH, Tsai FJ. STAT2*C related genotypes and allele but not TLR4 and CD40 gene polymorphisms are associated with higher susceptibility for asthma. Int J Biol Sci 2009; 5 (1) 74-81
    PubMedGoogle Scholar
  • 7 Lorenz E, Hallman M, Marttila R, Haataja R, Schwartz DA. Association between the Asp299Gly polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res 2002; 52 (3) 373-376
    CrossrefPubMedGoogle Scholar
  • 8 Maldonado-Bernal C, Trejo-de la O A, Sánchez-Contreras ME, Wacher-Rodarte N, Torres J, Cruz M. Low frequency of Toll-like receptors 2 and 4 gene polymorphisms in Mexican patients and their association with type 2 diabetes. Int J Immunogenet 2011; 38 (6) 519-523
    CrossrefPubMedGoogle Scholar
  • 9 Paulus SC, Hirschfeld AF, Victor RE, Brunstein J, Thomas E, Turvey SE. Common human Toll-like receptor 4 polymorphisms—role in susceptibility to respiratory syncytial virus infection and functional immunological relevance. Clin Immunol 2007; 123 (3) 252-257
    CrossrefPubMedGoogle Scholar
  • 10 Türe-Ozdemir F, Gazouli M, Tzivras M , et al. Association of polymorphisms of NOD2, TLR4 and CD14 genes with susceptibility to gastric mucosa-associated lymphoid tissue lymphoma. Anticancer Res 2008; 28 (6A) 3697-3700
    PubMedGoogle Scholar
  • 11 Vainas T, Stassen FR, Bruggeman CA , et al. Synergistic effect of Toll-like receptor 4 and CD14 polymorphisms on the total atherosclerosis burden in patients with peripheral arterial disease. J Vasc Surg 2006; 44 (2) 326-332
    CrossrefPubMedGoogle Scholar
  • 12 Brand S, Staudinger T, Schnitzler F , et al. The role of Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and CARD15/NOD2 mutations in the susceptibility and phenotype of Crohn's disease. Inflamm Bowel Dis 2005; 11 (7) 645-652
    CrossrefPubMedGoogle Scholar
  • 13 Hommels MJ, Kroon AA, Netea MG , et al. The Asp299Gly Toll-like receptor 4 polymorphism in advanced aortic atherosclerosis. Neth J Med 2007; 65 (6) 203-207
    PubMedGoogle Scholar
  • 14 Hang J, Zhou W, Zhang H , et al. TLR4 Asp299Gly and Thr399Ile polymorphisms are very rare in the Chinese population. J Endotoxin Res 2004; 10 (4) 238-240
    PubMedGoogle Scholar
  • 15 Kim YS, Hwang YJ, Kim SY, Yang SM, Lee KY, Park IeB. Rarity of TLR4 Asp299Gly and Thr399Ile polymorphisms in the Korean population. Yonsei Med J 2008; 49 (1) 58-62
    CrossrefPubMedGoogle Scholar
  • 16 Okayama N, Fujimura K, Suehiro Y , et al. Simple genotype analysis of the Asp299Gly polymorphism of the Toll-like receptor-4 gene that is associated with lipopolysaccharide hyporesponsiveness. J Clin Lab Anal 2002; 16 (1) 56-58
    CrossrefPubMedGoogle Scholar
  • 17 Levy E, Xanthou G, Petrakou E , et al. Distinct roles of TLR4 and CD14 in LPS-induced inflammatory responses of neonates. Pediatr Res 2009; 66 (2) 179-184
    CrossrefPubMedGoogle Scholar
  • 18 Wang H, Tang J, Xiong Y, Li X, Gonzalez F, Mu D. Neonatal community-acquired pneumonia: pathogens and treatment. J Paediatr Child Health 2010; 46 (11) 668-672
    CrossrefPubMedGoogle Scholar
  • 19 Guo SW, Thompson EA. Performing the exact test of Hardy-Weinberg proportion for multiple alleles. Biometrics 1992; 48 (2) 361-372
    CrossrefPubMedGoogle Scholar
  • 20 Hill WG. Estimation of linkage disequilibrium in randomly mating populations. Heredity (Edinb) 1974; 33 (2) 229-239
    CrossrefPubMedGoogle Scholar
  • 21 Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 2005; 15 (2) 97-98
    CrossrefPubMedGoogle Scholar
  • 22 Rehli M, Poltorak A, Schwarzfischer L, Krause SW, Andreesen R, Beutler B. PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene. J Biol Chem 2000; 275 (13) 9773-9781
    CrossrefPubMedGoogle Scholar
  • 23 Förster-Waldl E, Sadeghi K, Tamandl D , et al. Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging. Pediatr Res 2005; 58 (1) 121-124
    CrossrefPubMedGoogle Scholar