Influence of TNFα gene polymorphisms on TNFα production and disease

doi:10.1016/S0198-8859(01)00322-6

Human Immunology

Volume 62, Issue 11, November 2001, Pages 1191-1199

https://doi.org/10.1016/S0198-8859(01)00322-6 Get rights and content

Abstract

Tumor necrosis factor α (TNFα) is a potent inflammatory cytokine. In human, the TNFα gene is located within the highly polymorphic major histocompatibility complex (MHC) region on chromosome 6p21.3. TNF gene cluster contains many polymorphisms including microsatellites and single nucleotide polymorphisms (SNPs). Many of these polymorphisms were found to be in linkage disequilibrium with HLA class I and II alleles. Some of the TNFα gene polymorphisms were found to influence TNFα production in vitro, for example the −308 SNP. Many studies have shown that this SNP and others within the TNFα gene associate with different inflammatory conditions. Whether this phenomenon is due to the direct influence of the SNP in question and/or due to linkage disequilibrium with other polymorphisms within the TNFα gene or the HLA system is still controversial.

Introduction

TNFα is a pleotropic cytokine produced mainly by macrophages and T cells [1]. TNF is synthesized as a membrane protein, which is cleaved to produce its soluble 17 Kd form. Soluble TNF exerts a range of inflammatory and immunomodulatory activities that are important in host defense. Over-expression of TNF has been implicated in the pathogenesis of several conditions including rheumatoid arthritis (RA) and sepsis.

Circulating TNF levels are regulated at different stages: gene transcription, post-transcription control of mRNA stability, cleavage of the membrane form to liberate the soluble form, and the expression of receptors.

TNF mediates its functions by binding to TNF receptors (TNFRs). There are several members of the TNFR family of which the first two discovered, TNFR1 and TNFR2, have been the most investigated. TNFR2 has a higher affinity for TNF and seems to bind TNF better at lower concentrations. Signals through TNFRs influence T cell proliferation and proinflammatory responses [2].

Both TNFR1 and TNFR2 receptors are shed from the cell surface in a soluble form [3], thus adding another level to regulation of TNF function. Soluble TNFRs neutralize TNF activity by competing with cell-bound receptors, but, at the same time, they stabilize the TNFα molecule and prevent its degradation [4].

Mutations in the extracellular domain of the TNFR1 gene were found to be linked to dominantly inherited autoinflammatory syndromes. These mutations lead to decreased shedding and increased cell surface expression of the TNFR1 [5]. Presumably, this shifts the balance towards higher circulating levels of functionally active TNFα and greater cell-surface expression of the receptors for TNFα.

Section snippets

TNF polymorphisms

The TNF gene cluster is located within the class III region of the highly polymorphic major histocompatibility complex (MHC) on human chromosome 6p21. The TNFα gene lies between lymphotoxin α (TNFβ) and LTB genes (Figure 1).

There are many polymorphisms within the TNF gene cluster. So far, six polymorphic microsatellites have been described (Table 1). Originally Udalova et al. [6] described five microsatellites; TNF a-e (Figure 1). More recently, Tsukamoto et al. [7] described a sixth

TNF single nucleotide polymorphisms (SNPs)

There are many SNPs within the TNF gene. In the promoter, these are at positions (relative to the transcription start site) −1031 (T→C), −863 (C→A), −857 (C→A), −851 (C→T), −419 (G→C), −376 (G→A), −308 (G→A), −238 (G→A), −162 (G→A), and −49 (G→A), although those at positions −419, −163, −49 are rare in Caucasians [9]. Hence, the 5′ region of the TNFα gene is highly polymorphic. In addition, there is an insertion of a cytosine at position +70 in the first exon [10], a G → A substitution at

Genetic regulation of TNFα production

Several studies have shown an association between HLA DRB1 alleles and the in vitro production of TNFα. There are some concerns regarding differences in the methodology in such experiments that will be discussed later. In overview, HLA DR3, DR1, DR4, and DR7 have all been associated with higher TNFα production 15, 16, 17. while DR2 and DR5 have been associated with lower TNFα responses 15, 16, 17, 18. Linkage disequilibrium between TNFα polymorphisms and HLA-DR types probably explains this

TNF microsatellites and TNFα production

There are conflicting results on the associations between TNF microsatellites and TNFα production in vitro. Pocoit et al. [17] reported that both TNFa2 and c2 were associated with high TNFα production while TNF a6 and c1 were associated with low TNFα production. However, Derkx et al. [19] showed that TNFa2, a6, a10 were associated with lower TNFα production while a4 and a11 were associated with higher TNFα production.

One must realize that it is not easy to investigate alleles of TNF

TNF SNPs and TNFα production

As described above, there are many SNPs within the TNFα gene promoter. The effect of those SNPs on transcription factors binding has not been fully explored. Many studies have concentrated on one SNP in isolation of others. The −308 G/A SNP has been the most studied polymorphism.

In vitro stimulation of TNFα production by cells from −308∗G/G homozygous individuals and G/A heterozygote individuals has produced conflicting results. Two studies have reported higher TNFα production by cells from G/A

Associations between TNFα polymorphisms and disease

What can we learn about TNFα gene function in the mouse model? Over-expression of the TNFα gene in mice leads to arthritis [40]. Conversely, when mice homozygous for the TNFα gene knockout were infected with Corynebacterium parvum, there was little or no initial response, but the mice went on to develop a severe and fatal inflammatory reaction [41]. By contrast, normal mice developed an early inflammatory response that resolved. This suggests that TNFα has a dual function, being proinflammatory

Association between TNF polymorphisms and infection

In multiply injured patients with severe sepsis the TNFβ Nco I polymorphism (TNFB2 allele) acts as a predictor of severe post traumatic sepsis and increased levels of circulating TNFα 31, 42. On the other hand, the −308 TNFα polymorphism was not associated with survival in severe sepsis [31]. How can this result be interpreted? The authors measured circulating levels of soluble TNFα, but did not attempt to measure TNFβ. Whether the assay was specific to TNFα or can detect TNFβ is not clear. The

TNF polymorphisms and autoimmune diseases

In autoimmune diseases, TNFα is one of the most studied genes. As most autoimmune diseases are associated with HLA, results of TNF polymorphism studies could be interpreted by linkage disequilibrium with HLA or, indeed, vice versa.

SLE is associated with the HLA DRB1∗ 0301, B8, A1 haplotype. In UK Caucasians we found that the TNFa2, b1, and d3 alleles are associated with SLE. This may be explained by the strong linkage disequilibrium between these alleles and the HLA DR3, B8, A1 haplotype [52].

TNF polymorphisms and transplantation

Biopsies from rejecting kidney or heart transplants show the presence of an inflammatory infiltrate of cells capable of producing TNFα. Studies in heart transplant recipients [19], kidney 69, 70, and liver [71] transplant recipients revealed an association between TNFα −308 polymorphisms and acute rejection. Death of heart transplant recipients as a consequence of irreversible acute rejection of their graft is exclusively confined to those of the TNFα −308∗A genotype 72, 73.

Poli et al. [74]

Conclusions

It is difficult to make general statements about the associations of TNF polymorphisms and TNFα production or pathology. The TNF polymorphisms are found in a region of great polymorphic variation and they are in linkage disequilibrium with the HLA genes and with each other. Because of differences in the distribution of HLA alleles one might expect variation in associations between TNF polymorphisms and various conditions in different geographical areas. Dissecting out a primary association with

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Influence of TNFα gene polymorphisms on TNFα production and disease

Abstract

Introduction

Section snippets

TNF polymorphisms

TNF single nucleotide polymorphisms (SNPs)

Genetic regulation of TNFα production

TNF microsatellites and TNFα production

TNF SNPs and TNFα production

Associations between TNFα polymorphisms and disease

Association between TNF polymorphisms and infection

TNF polymorphisms and autoimmune diseases

TNF polymorphisms and transplantation

Conclusions

Cell

Genomics

J Neuroimmunol

J Neuroimmunol

Neurosci Lett

Immunity

Hum Immunol

J Neuroimmunol

J Neurol Sci

Kidney Int

Transplantation

Human Immunol

Cytokine

Blood

Transplantation

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Tumour necrosis factor (TNF) gene polymorphism influences TNF-alpha production in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans

Clin Exp Immunol

Increased frequency of the uncommon allele of a tumour necrosis factor alpha gene polymorphism in rheumatoid arthritis and systemic lupus erythematosus

Dis Markers

Identification of an AP-2 element in the −323 to −285 region of the TNF-alpha gene

Biochem Mol Biol Int