Tumor necrosis factor (TNF) is a multifunctional proinflammatory cytokine secreted predominantly by monocytes/macrophages that has effects on lipid metabolism, coagulation, insulin resistance, and endothelial function. TNF was originally identified in mouse serum after injection with Mycobacterium bovis strain ... Tumor necrosis factor (TNF) is a multifunctional proinflammatory cytokine secreted predominantly by monocytes/macrophages that has effects on lipid metabolism, coagulation, insulin resistance, and endothelial function. TNF was originally identified in mouse serum after injection with Mycobacterium bovis strain bacillus Calmette-Guerin (BCG) and endotoxin. Serum from such animals was cytotoxic or cytostatic to a number of mouse and human transformed cell lines and produced hemorrhagic necrosis and in some instances complete regression of certain transplanted tumors in mice (Shirai et al., 1985; Pennica et al., 1984).
Single-nucleotide polymorphisms (SNPs) in regulatory regions of cytokine genes have been associated with susceptibility to a number of complex disorders. TNF is a proinflammatory cytokine that provides a rapid form of host defense against infection but is fatal ... Single-nucleotide polymorphisms (SNPs) in regulatory regions of cytokine genes have been associated with susceptibility to a number of complex disorders. TNF is a proinflammatory cytokine that provides a rapid form of host defense against infection but is fatal in excess. Because TNF is employed against a variety of pathogens, each involving a different pattern of risks and benefits, it might be expected that this would favor diversity in the genetic elements that control TNF production. Herrmann et al. (1998) used PCR-SSCP and sequencing to screen the entire coding region and 1,053 bp upstream of the transcription start site of the TNFA gene for polymorphisms. Five polymorphisms were identified: 4 were located in the upstream region at positions -857, -851, -308 (191160.0004), and -238 from the first transcribed nucleotide, and 1 was found in a nontranslated region at position +691. Three SNPs located at nucleotides -238, -308, and -376 (191160.0003) with respect to the TNF transcriptional start site are all substitutions of adenine for guanine. Knight et al. (1999) referred to the allelic types as -238G/-238A, -308G/-308A, and -376G/-376A. They stated that variation in the TNFA promoter region had been found to be associated with susceptibility to cerebral malaria (McGuire et al., 1994), with mucocutaneous leishmaniasis (Cabrera et al., 1995), with death from meningococcal disease (Nadel et al., 1996), with lepromatous leprosy (Roy et al., 1997), with scarring trachoma (Conway et al., 1997), and with asthma (Moffatt and Cookson, 1997). Flori et al. (2003) tested for linkage between polymorphisms within the MHC region and mild malaria; see 609148. Two-point analysis indicated linkage of mild malaria to TNFd (lod = 3.27), a highly polymorphic marker in the MHC region. Multipoint analysis also indicated evidence for linkage of mild malaria to the MHC region, with a peak close to TNF (lod = 3.86). The authors proposed that genetic variation within TNF may influence susceptibility to mild malaria, but the polymorphisms TNF-238, TNF-244, and TNF-308 (191160.0004) are unlikely to explain linkage of mild malaria to the MHC region. Statistical analyses by Funayama et al. (2004) showed a possible interaction between polymorphisms in the optineurin (OPTN; 602432) and TNF genes that would increase the risk for the development and probably progression of glaucoma in Japanese patients with POAG (137760). By sequencing the promoter regions 500 bp upstream from the transcriptional start sites of members of the TNF and TNFR superfamilies, Kim et al. (2005) identified 23 novel regulatory SNPs in Korean donors. Sequence analysis suggested that 9 of the SNPs altered putative transcription factor binding sites. Analysis of SNP databases suggested that the SNP allele frequencies were similar to those for Japanese subjects but distinct from those of Caucasian or African populations. - Insulin Resistance and Diabetes Zinman et al. (1999) studied the relationship between TNF-alpha and anthropometric and physiologic variables associated with insulin resistance and diabetes in an isolated Native Canadian population with very high rates of NIDDM (125853). Using the homeostasis assessment (HOMA) model to estimate insulin resistance, they found moderate, but statistically significant, correlations between TNF-alpha and fasting insulin, HOMA insulin resistance, waist circumference, fasting triglycerides, and systolic blood pressure; in all cases, coefficients for females were stronger than those for males. The authors concluded that in this homogeneous Native Canadian population, circulating TNF-alpha concentrations were positively correlated with insulin resistance across a spectrum of glucose tolerance. The data suggested a possible role for TNF-alpha in the pathophysiology of insulin resistance. Rasmussen et al. (2000) investigated whether the -308 and -238 G-to-A genetic variants of TNF were associated with features of the insulin resistance syndrome or alterations in birth weight in 2 Danish study populations comprising 380 unrelated young healthy subjects and 249 glucose-tolerant relatives of type 2 diabetic patients, respectively. Neither of the variants was related to altered insulin sensitivity index or other features of the insulin resistance syndrome. Birth weight and the ponderal index were also not associated with the polymorphisms. Their study did not support a major role of the -308 or -238 substitutions in TNF in the pathogenesis of insulin resistance or altered birth weight among Danish Caucasian subjects. Obayashi et al. (2000) investigated the influence of TNF-alpha on the predisposition to insulin dependency in adult-onset diabetic patients with type I diabetes (IDDM; 222100)-protective HLA haplotypes. Also see HLA-DQB1 (604305). The TNF-alpha of 3 groups of DRB1*1502-DQB1*0601-positive diabetic patients who had initially been nonketotic and noninsulin dependent for more than 1 year was analyzed. Group A included 11 antibodies to glutamic acid decarboxylase (GADab)-positive patients who developed insulin dependency within 4 years of diabetes onset. Group B included 11 GADab-positive patients who remained noninsulin dependent for more than 12 years. Group C included 12 GADab-negative type 2 diabetes, and a control group included 18 nondiabetic subjects. In the group C and control subjects, DRB1*1502-DQB1*0601 was strongly associated with the TNFA-13 allele. DRB1*1502-DQB1*0601 was strongly associated with the TNFA-12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFA-12 and non-TNFA-13 in group B reacted with GAD65 protein by Western blot. The authors concluded that TNF-alpha is associated with a predisposition to progression to insulin dependency in GADab/DRB1*1502-DQB1*0601-positive diabetic patients initially diagnosed with type II diabetes and that determination of these patients' TNF-alpha genotype may allow for better prediction of their clinical course. To study whether the TNFA gene could be a modifying gene for diabetes, Li et al. (2003) studied TNFA promoter polymorphisms (G-to-A substitution at positions -308 and -238) in relation to HLA-DQB1 genotypes in type 2 diabetes patients from families with both type 1 and type 2 diabetes (type 1/2 families) or common type 2 diabetes families as well as in patients with adult-onset type 1 diabetes and control subjects. The TNFA(308) AA/AG genotype frequency was increased in adult-onset type 1 patients (55%, 69 of 126), but it was similar in type 2 patients from type 1/2 families (35%, 33/93) or common type 2 families (31%, 122 of 395), compared with controls (33%, 95/284; P less than 0.0001 vs type 1). The TNFA(308) A and DQB1*02 alleles were in linkage disequilibrium in type 1 patients (Ds = 0.81; P less than 0.001 vs Ds = 0.25 in controls) and type 2 patients from type 1/2 families (Ds = 0.59, P less than 0.05 vs controls) but not in common type 2 patients (Ds = 0.39). The polymorphism was associated with an insulin-deficient phenotype in type 2 patients from type 1/2 families only together with DQB*02, whereas the common type 2 patients with AA/AG had lower waist-to-hip ratio [0.92 (0.12) vs 0.94 (0.11), P = 0.008] and lower fasting C-peptide concentration [0.48 (0.47) vs 0.62 (0.46) nmol/liter, P = 0.020] than those with GG, independently of the presence of DQB1*02. The authors concluded that TNFA is unlikely to be the second gene on the short arm of chromosome 6 responsible for modifying the phenotype of type 2 diabetic patients from families with both type 1 and type 2 diabetes. Shbaklo et al. (2003) evaluated TNFA promoter polymorphisms at positions -863 (191160.0006) and -1031 and their association with type 1 diabetes in a group of 210 diabetic patients in Lebanon. Their results showed that in that population, the C allele is predominant at position -863, whereas the A allele is rare (2%). At position -1031, however, the C and T allele distribution was similar in both the patient (17.8% vs 82.2%, respectively) and the control (21.4% vs 79.6%) groups. No association of TNFA genotype at position 1031 with type 1 diabetes was found as demonstrated by the family-based association test and the transmission disequilibrium test. However, when patient genotypes were compared, the recessive CC genotype was found in type 1 diabetic males but not in type 1 diabetic females. - Coronary Heart Disease From studies of 641 patients with myocardial infarction and 710 control subjects, Herrmann et al. (1998) concluded that polymorphisms of the TNFA gene are unlikely to contribute to coronary heart disease risk in an important way, but that the -308 mutation should be investigated further in relation to obesity. - Obesity Because TNF-alpha expression had been reported to be increased in adipose tissue of both rodent models of obesity and obese humans, TNFA was considered a candidate gene for obesity (see 601665). Norman et al. (1995) scored Pima Indians for genotypes at 3 polymorphic dinucleotide repeat loci near the TNFA gene. In a sib-pair linkage analysis, the percentage of body fat, as measured by hydrostatic weighing, was linked (304 sib pairs, P = 0.002) to the marker closest (10 kb) to TNFA. The same marker was associated (P = 0.01) by analysis of variants with body mass index (BMI). To search for DNA variants in TNFA possibly contributing to obesity, they performed SSCP analysis on the gene from 20 obese and 20 lean subjects. No association could be demonstrated between alleles at the single polymorphism located in the promoter region and percent of body fat. Rosmond et al. (2001) examined the potential impact of the G-to-A substitution at position -308 of the TNFA gene promoter on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones including salivary cortisol in 284 unrelated Swedish men born in 1944. Genotyping revealed allele frequencies of 0.77 for allele G and 0.23 for allele A. Tests for differences in salivary cortisol levels between the TNFA genotypes revealed that, in homozygotes for the rare allele in comparison with the other genotypes, there were significantly higher cortisol levels in the morning, before as well as 30 and 60 minutes after stimulation by a standardized lunch. In addition, homozygotes for the rare allele had a tendency toward higher mean values of body mass index, waist-to-hip ratio, and abdominal sagittal diameter compared with the other genotype groups. The results also indicated a weak trend toward elevated insulin and glucose levels among men with the A/A genotype. Rosmond et al. (2001) suggested that the increase in cortisol secretion associated with this polymorphism might be the endocrine mechanism underlying the previously observed association between the NcoI TNFA polymorphism and obesity, as well as insulin resistance. - Hyperandrogenism To evaluate the role of TNF-alpha in the pathogenesis of hyperandrogenism, Escobar-Morreale et al. (2001) evaluated the serum TNF-alpha levels, as well as several polymorphisms in the promoter region of the TNF-alpha gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index. Hyperandrogenic patients presented with mildly increased serum TNF-alpha levels as compared with controls. When subjects were classified by body weight, serum TNF-alpha was increased only in lean patients as compared with lean controls; this difference was not statistically significant when comparing obese patients with obese controls. The TNF-alpha gene polymorphisms studied were equally distributed in hyperandrogenic patients and controls. However, carriers of the -308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. The authors concluded that the TNF-alpha system might contribute to the pathogenesis of hyperandrogenism. - Septic Shock De Groof et al. (2002) evaluated the GH (see 139250)/IGF1 (147440) axis and the levels of IGF-binding proteins (IGFBPs), IGFBP3 protease (146732), glucose, insulin (176730), and cytokines in 27 children with severe septic shock due to meningococcal sepsis during the first 3 days after admission. The median age was 22 months. Nonsurvivors had extremely high GH levels that were significantly different compared with mean GH levels in survivors during a 6-hour GH profile. Significant differences were found between nonsurvivors and survivors for the levels of total IGF1, free IGF1, IGFBP1, IGFBP3 protease activity, IL6 (147620), and TNFA. The pediatric risk of mortality score correlated significantly with levels of IGFBP1, IGFBP3 protease activity, IL6, and TNFA and with levels of total IGF1 and free IGF1. Levels of GH and IGFBP1 were extremely elevated in nonsurvivors, whereas total and free IGF1 levels were markedly decreased and were accompanied by high levels of the cytokines IL6 and TNFA. Mira et al. (1999) reported the results of a multicenter case-control study of the frequency of the -308G-A polymorphism, which they called the TNF2 allele, in patients with septic shock. Eighty-nine patients with septic shock and 87 healthy unrelated blood donors were studied. Mortality among patients with septic shock was 54%. The polymorphism frequencies of the controls and patients differed only at the TNF2 allele (39% vs 18% in the septic shock and control groups, respectively, P = 0.002). Among the septic shock patients, TNF2 polymorphism frequency was significantly greater among those who had died (52% vs 24% in the survival group, P = 0.008). Concentrations of TNF-alpha were higher with TNF2 (68%) than with TNF1 (52%), but their median values were not statistically different. Mira et al. (1999) estimated that patients with the TNF2 allele had a 3.7-fold risk of death. - Cerebral Malaria Because fatal cerebral malaria is associated with high circulating levels of tumor necrosis factor-alpha, McGuire et al. (1994) undertook a large case-control study in Gambian children. The study showed that homozygotes for the TNF2 allele, a variant of the TNFA gene promoter region (Wilson et al., 1992), had a relative risk of 7 for death or severe neurologic sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighboring HLA alleles, McGuire et al. (1994) showed that this disease association was independent of HLA class I and class II variation. The data suggested that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biologic advantage. Hill (1999) reviewed the genetic basis of susceptibility and resistance to malaria, and tabulated 10 genes that are known to affect susceptibility or resistance to Plasmodium falciparum and/or Plasmodium vivax. He noted that the association of an upregulatory variant of the TNF gene promoter (Wilson et al., 1997) with cerebral malaria (McGuire et al., 1994) had encouraged the assessment of agents that might reduce the activity of this cytokine (van Hensbroek et al., 1996). Through systematic DNA fingerprinting of the TNF promoter region, Knight et al. (1999) identified a SNP that causes the helix-turn-helix transcription factor OCT1 (POU2F1; 164175) to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT1-binding genotype, found in approximately 5% of Africans, was associated with 4-fold increased susceptibility to cerebral malaria in large studies comparing cases and controls in West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles. See 191160.0003. - Alopecia Areata Galbraith and Pandey (1995) studied 2 polymorphic systems of tumor necrosis factor-alpha in 50 patients with alopecia areata (104000). The first biallelic TNFA polymorphism was detected in humans by Wilson et al. (1992); this involved a single base change from G to A at position -308 in the promoter region of the gene (191160.0004). The less common allele, A at -308 (called T2), shows an increased frequency in patients with IDDM, but this depends on the concurrent increase in HLA-DR3 with which T2 is associated. A second TNFA polymorphism, described by D'Alfonso and Richiardi (1994), also involves a G-to-A transition at position -238 of the gene. In alopecia areata, Galbraith and Pandey (1995) found that the distribution of T1/T2 phenotypes differed between patients with the patchy form of the disease and patients with totalis/universalis disease. There was no significant difference in the distribution of the phenotypes for the second system. The results suggested genetic heterogeneity between the 2 forms of alopecia areata and suggested that the TNFA gene is a closely linked locus within the major histocompatibility complex on chromosome 6 where this gene maps and may play a role in the pathogenesis of the patchy form of the disease. - Rheumatoid Arthritis Mulcahy et al. (1996) determined the inheritance of 5 microsatellite markers from the TNF region in 50 multiplex rheumatoid arthritis (RA; 180300) families. Overall, 47 different haplotypes were observed. One of these was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P less than 0.005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3% of the haplotypes not transmitted to affected offspring (P = 0.0003). Further study suggested that the tumor necrosis factor--lymphotoxin (TNF-LT) region influences susceptibility to RA, distinct from HLA-DR. The study illustrated the use of the transmission disequilibrium test (TDT) as described by Spielman et al. (1993). - Osteoporosis and Osteopenia Ota et al. (2000) tested 192 sib pairs of adult Japanese women from 136 families for genetic linkage between osteoporosis and osteopenia phenotypes and allelic variants at the TNFA locus, using a dinucleotide repeat polymorphism located near the gene. The TNFA locus showed evidence for linkage to osteoporosis, with mean allele sharing of 0.478 (P = 0.30) in discordant pairs and 0.637 (P = 0.001) in concordant affected pairs. Linkage with osteopenia was also significant in concordant affected pairs (P = 0.017). Analyses limited to the postmenopausal women in their cohort showed similar or even stronger linkage for both phenotypes. - Asthma Winchester et al. (2000) studied the association of the -308G-A variant of the TNFA gene and the insertion/deletion variant of angiotensin-converting enzyme (ACE; 106180) with a self-reported history of childhood asthma in 2 population groups. The -308A allele was significantly associated with self-reported childhood asthma in the UK/Irish population but not in the South Asian population. The ACE DD genotype was not associated with childhood asthma in either population. Thus, either the -308A allele or a linked major histocompatibility complex variant may be a genetic risk factor for childhood asthma in the UK/Irish sample. - Inflammatory Bowel Diseases Koss et al. (2000) found that women but not men with extensive compared to distal colitis (see IBD3, 604519) were significantly more likely to bear the -308G-A promoter polymorphism of the TNF gene (191160.0004). The association was even stronger in women who also had an A rather than a C at position 720 in the LTA gene (153440). These polymorphisms were also associated with significantly higher TNF production in patients with Crohn disease, whereas an A instead of a G at position -238 in the TNF gene was associated with lower production of TNF in patients with ulcerative colitis. For additional discussion of an association between variation in the TNF gene and inflammatory bowel disease, see IBD3 (604519). - Hepatitis B To investigate whether TNF-alpha promoter polymorphisms are associated with clearance of hepatitis B virus (HBV) infection, Kim et al. (2003) genotyped 1,400 Korean subjects, 1,109 of whom were chronic HBV carriers and 291 who spontaneously recovered. The TNF promoter alleles that were previously reported to be associated with higher plasma levels (presence of -308A or the absence of -863A alleles), were strongly associated with the resolution of HBV infection. Haplotype analysis revealed that TNF-alpha haplotype 1 (-1031T; -863C; -857C; -308G; -238G; -163G) and haplotype 2 (-1031C; -863A; -857C; -308G; -238G; -163G) were significantly associated with HBV clearance, showing protective antibody production and persistent HBV infection, respectively (P = 0.003-0.02). - Cystic Fibrosis Buranawuti et al. (2007) determined the TNF-alpha-238 and -308 genotypes in 3 groups of patients with cystic fibrosis (CF; 219700): 101 children under 17 years of age, 115 adults, and 38 nonsurviving adults (21 deceased and 17 lung transplant after 17 years of age). Genotype frequencies among adults and children with CF differed for TNF-alpha-238 (G/G vs G/A, p = 0.022), suggesting that TNF-alpha-238 G/A is associated with an increased chance of surviving beyond 17 years of age. When adults with CF were compared to nonsurviving adults with CF, genotype frequencies again differed (TNF-alpha 238 G/G vs G/A, p = 0.0015), and the hazard ratio for TNF-alpha-238 G/G versus G/A was 0.25. Buranawuti et al. (2007) concluded that the TNF-alpha-238 G/A genotype appears to be a genetic modifier of survival in patients with CF. - Role in HLA-B27-Associated Uveitis In a study of 114 Caucasian patients with HLA-B27-associated uveitis compared with 63 healthy unrelated HLA-B27-positive blood donors and 88 healthy unrelated HLA-B27-negative individuals, El-Shabrawi et al. (2006) found that the frequencies of the TNF-alpha -308GA and -238GA genotypes were significantly lower in patients with HLA-B27-associated uveitis (6.1% and 0%, respectively) when compared with the HLA-B27-negative group, 23% at -308 (p = 0.003), and 7.9% at -238 (p = 0.0003). The frequency of the -238GA genotype was also significantly lower in patients than among the healthy HLA-B27-positive group. The authors concluded that HLA-B27-positive individuals show a higher susceptibility towards development of intraocular inflammation in the presence of an A allele at nucleotide -238, and to a lesser degree, at nucleotide -308 of the TNF-alpha gene promoter.