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NM_000594.3(TNF):c.-488G>A AND Migraine without aura, susceptibility to

Germline classification:
risk factor (1 submission)
Last evaluated:
Mar 1, 2006
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:

Allele description [Variation Report for NM_000594.3(TNF):c.-488G>A]


TNF:tumor necrosis factor [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000006.12:g.31575254G>A
  • NG_007462.1:g.4682G>A
  • NG_012010.1:g.8156G>A
  • NC_000006.11:g.31543031G>A
Nucleotide change:
PharmGKB: 655384799; PharmGKB: 655384799PA10004; PharmGKB: 655384799PA164713366; PharmGKB: 655384799PA449515; PharmGKB: 655384799PA452639; PharmGKB Clinical Annotation: 655384799; OMIM: 191160.0004; dbSNP: rs1800629
NCBI 1000 Genomes Browser:


Migraine without aura, susceptibility to

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
no assertion criteria provided
risk factor
(Mar 1, 2006)
germlineliterature only

PubMed (13)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only



Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study.

Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riché F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut JF.

JAMA. 1999 Aug 11;282(6):561-8.

PubMed [citation]

Tumor necrosis factor-alpha promoter polymorphism TNF2 is associated with a stronger delayed-type hypersensitivity reaction in the skin of borderline tuberculoid leprosy patients.

Moraes MO, Duppre NC, Suffys PN, Santos AR, Almeida AS, Nery JA, Sampaio EP, Sarno EN.

Immunogenetics. 2001 Feb;53(1):45-7. No abstract available.

PubMed [citation]
See all PubMed Citations (13)

Details of each submission

From OMIM, SCV000033439.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (13)


Mira et al. (1999) referred to the TNFA promoter polymorphisms at position -308 as TNF1 for guanine and TNF2 for adenine. In a multicenter study involving 7 institutions, they found a significant association between the TNF2 allele and susceptibility to septic shock and death from septic shock. The septic shock group was defined by the following 6 criteria within a 12-hour period: (1) clinical evidence of infection; (2) hyperthermia or hypothermia; (3) tachycardia; (4) tachypnea; (5) necessity for vasopressor to maintain systolic blood pressure; and (6) evidence of inadequate organ function or perfusion.

Moraes et al. (2001) found that the TNF2 polymorphism is significantly associated with a stronger response (Mitsuda reaction) to lepromin in borderline tuberculoid leprosy patients. Epigenetic factors such as a history of BCG vaccination or a reversal reaction, but not both, were also associated with boosted Mitsuda reactions. Moraes et al. (2001) concluded that augmented TNF production may be associated with the TNF2 allele and an increased granulomatous response.

Ma et al. (1998) found a higher frequency of the rare T2 TNFA polymorphism (-308G-A) in 43 Japanese Guillain-Barre syndrome (139393) patients who had had antecedent infection with C. jejuni than in 85 community controls.

Witte et al. (2002) evaluated the relation between the -308G-A promoter polymorphism and risk of asthma (600807) in 236 cases and 275 nonasthmatic controls. Logistic regression analyses indicated that having 1 or 2 copies of the -308A allele increased the risk of asthma (odds ratio = 1.58), the magnitude of which was increased when restricting the cases to those with acute asthma (odds ratio = 1.86, P = 0.04) or further restricting the subjects to those with a family history of asthma and those of European American ancestry (odds ratio = 3.16, P = 0.04).

Shin et al. (2004) genotyped 550 Korean asthmatics and 171 Korean controls at 5 SNPs in TNFA and 2 SNPs in TNFB. Six common haplotypes could be constructed in the TNF gene cluster. The -308G-A polymorphism showed a significant association with the risk of asthma (p = 0.0004). The frequency of the -308A allele-containing genotype in asthmatics (9.8%) was much lower than that in normal controls (22.9%). The protective effects of this polymorphism on asthma were also evident in separated subgroups by atopic status (p = 0.05 in nonatopic subjects and p = 0.003 in atopic subjects). The most common haplotype of the TNF gene cluster (TNF-ht1-GGTCCGG) was associated with total serum IgE levels (147050) in asthma patients, especially in nonatopic patients (p = 0.004). Shin et al. (2004) concluded that genetic variants of TNF may be involved in the development of asthma and total serum IgE level in bronchial asthma patients.

Aoki et al. (2006) did not find a significant association between the TNF -308G-A polymorphism and childhood atopic asthma in 2 independent Japanese populations; however, metaanalysis of a total of 2,477 asthma patients and 3,217 control individuals showed that the -308G-A polymorphism was significantly associated with asthma. The combined odds ratio was 1.46 for fixed or random effects (p = 0.0000001 and p = 0.00014, respectively).

Quasney et al. (2001) stated that immunologic mechanisms resulting in macrophage infiltration and glial cell activation in the brain are thought to be involved in the pathophysiology of HIV dementia. Moreover, elevated levels of TNF-alpha have been found in the brains of patients with HIV dementia. In a study of 16 patients with HIV dementia, 45 HIV-infected patients without dementia, and 231 controls, they found an increased frequency of the -308A allele in patients with HIV dementia (0.28 vs 0.11 in controls and 0.07 in HIV patients without dementia). There were no individuals with the A/A genotype in either of the HIV-infected groups. Quasney et al. (2001) noted that the -308A allele is associated with higher TNF-alpha secretion in response to an inflammatory stimulus and that evidence has shown a role for TNF-alpha in neuronal damage, thus suggesting a genetic predisposition to the development of HIV dementia.

Cox et al. (1994) reported that the -308A allele has an increased frequency in type I diabetes mellitus (222100). Krikovszky et al. (2002) studied ambulatory blood pressure in 126 Hungarian adolescents with type I diabetes mellitus. They found that the prevalence of the -308A allele was higher in diabetic adolescents than in the Hungarian reference population. TNFA genotype was associated with both systolic and diastolic blood pressure values. The -308A allele carrier state appeared to be associated with lower systolic and diastolic blood pressure values.

Szalai et al. (2002) found an increased frequency of the C4B*Q0 allele (see 120820) in patients with severe coronary artery disease (CAD) who underwent bypass surgery compared to healthy controls (14.2% vs 9.9%). Investigation of specific allelic combinations revealed that C4B*Q0 in combination with the TNF-alpha -308A allele was significantly higher in CAD patients, particularly those with preoperative myocardial infarction.

In a study of 147 patients with psoriatic arthritis (607507) and 389 controls, Balding et al. (2003) found that the -308A allele was significantly associated with both the presence and progression of joint erosions in psoriatic arthritis, and that the AA genotype was associated with the lowest mean age at onset of psoriasis (p = 0.0081).

In a group of 261 patients with migraine without aura (see, e.g., 157300), Rainero et al. (2004) found that the G/G genotype was associated with an increased risk of migraine (odds ratio of 3.30). Rainero et al. (2004) suggested that TNF-alpha may be involved in the pathogenesis of migraine, perhaps due to its effect on cerebral blood flow; alternatively, a closely linked locus may be involved.

In a metaanalysis of 19 studies, Lee et al. (2006) found an association between the -308A/A genotype and the -308A allele and systemic lupus erythematosus (SLE; 152700) in European-derived population (odds ratio of 4.0 for A/A and 2.1 for the A allele), but not in Asian-derived populations.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2024