Atopic asthma and TNF-308 alleles: linkage disequilibrium and association analyses

doi:10.1016/S0198-8859(02)00819-4

Human Immunology

Volume 64, Issue 3, March 2003, Pages 359-365

https://doi.org/10.1016/S0198-8859(02)00819-4 Get rights and content

Abstract

The association of a tumor necrosis factor −308 allele (TNF2) to asthma has been reported in some studies but not in others. The aim of this study was to test this association in a population recruited on the basis of allergy to Parietaria. In the study population, asthma was positively associated to HLA-DRB1*03 (p = 0.01) and to the haplotype TNF2/DRB1*03 (p = 0.02). In the parent subgroup, the proportion of asthmatics was increased in patients with TNF2 (p = 0.01), but the primary association of asthma was to the haplotype TNF2/DRB1*1104 (p = 0.005). The study population was subdivided according to prick skin test (ST) positivity to Lolium, Parietaria, and D. pteronyssinus. Asthma was associated to HLA-DRB1*03 and to the haplotype TNF2/DRB1*03 (p = 0.0015 and 0.0001, respectively) in patients ST positive to Lolium, and to the haplotype TNF2/DRB1*1104 (p = 0.025) in patients ST positive to Parietaria. The transmission disequilibrium test detected excess transmission of HLA-DRB1*03 and of the haplotype TNF2/DRB1*03 (p = 0.03 and 0.04, respectively) to siblings with asthma and ST positivity to Lolium and of HLA-DRB1*1104 and of the haplotype TNF2/DRB1*1104 (p = 0.04 and 0.015, respectively) to siblings with asthma and ST positivity to Parietaria. Taken together, these observations indicate that the haplotypes TNF2/DRB1*03 and TNF2/*B1*1104 contain alleles controlling atopic asthma in patients with sensitization to Lolium and Parietaria, respectively. This suggests that the association of asthma to TNF2 reflects linkage disequilibrium with genes influencing specific immune response.

Section snippets

Abbreviations

TNF

tumor necrosis factor

HLA

human leukocyte antigen

prick skin test

BBS

borate buffered saline

TDT

transmission disequilibrium test

DARIA

double antibody radioimmunoassay

Study population

The study population (239 patients) has been previously described [5]. Participants were analyzed by ST for reactivity towards 18 glycerinated extracts of common inhalant allergens (Hollister-Stier Laboratories, Spokane, WA, USA). ST positivity was defined by a wheal diameter > 3 mm more than the negative control. Atopy was defined as ST positivity to at least one of the allergenic extract tested. As the results of tests performed with P. judaica and P. officinalis pollen extracts were in each

Association of TNF-308 alleles an TNF/HLA-DRB1* haplotypes to ST reactivity to D. Pteronyssinus, Lolium Perenne, and Parietaria

Atopics were subdivided according to ST reactivity to D. pteronyssinus, Lolium perenne, and Parietaria and the association between these phenotypes, TNF alleles, and selected TNF/HLA-DRB1* haplotypes was investigated (Table 2).

No association of TNF-308 alleles with responsiveness to specific allergens was observed. The association of HLA-DRB1*03 to responsiveness to Lolium allergens has been reported by other groups [7] . The positive and negative association of ST positivity to Parietaria to

Discussion

The results of this study indicate that TNF2 is transmitted to asthmatics with the DRB1* alleles associated with atopy, and suggests that haplotypes TNF2/DRB1*03 and TNF2/DRB1*1104 contain functional alleles controlling asthma and atopy to Lolium and Parietaria, respectively. The modest association of asthma to TNF2 observed in the parents subgroup appears to be secondary to association to TNF2/DRB1*1104 (Table 3). These observations do not support the hypothesis that HLA region genes control

Acknowledgements

This study is supported by Telethon, Italy (grant E487).

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The conflicting evidence regarding the association of TNF-α-308A with asthma may be attributed to the complex genetic origin of asthma. It has been suggested that the association of TNF-α-308A with asthma reflected linkage disequilibrium with genes influencing a specific immune response [21,30,31]. The TNF-α gene is located within the class III region of the MHC.
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There is a great deal of evidence that points to the association of the tumor necrosis factor-alpha (TNF-α) gene as a common genetic factor in the pathogenesis of diseases that are caused by inflammatory and/or autoimmune etiologies. Two single nucleotide polymorphisms (SNPs) identified in the TNF-α promoter region have been associated with disease susceptibility and severity. We investigated whether −308G/A and −238G/A TNF-α polymorphisms were associated with asthma, systemic lupus erythematosus (SLE), and juvenile rheumatoid arthritis (JRA) in a pediatric Mexican population. In a case-control study of 725 patients (asthma: 226, JRA: 171, and SLE: 328) and 400 control subjects, the participants were analyzed using the allelic discrimination technique. The genotype distribution of both TNF-α polymorphisms was in Hardy-Weinberg equilibrium in each group. However, there were significant differences in the allele frequency of TNF-α-308A between the patients and the healthy controls. This allele was detected in 2.9% of the controls, 6.0% of asthmatic and JRA patients (p = 0.002 and p = 0.0086), and 6.7% of SLE patients (p = 0.00049); statistical significance was maintained after ancestry stratification (asthma: p = 0.0143, JRA: p = 0.0083, and SLE: p = 0.0026). Stratification by gender showed that the risk for the −308A allele in asthma and JRA was greater in females (OR = 4.16, p = 0.0008 and OR = 4.4, p = 0.0002, respectively). The TNF-α -238A allele showed an association only with JRA in males (OR = 2.89, p = 0.004). These results support the concept that the TNF-α gene is a genetic risk factor for asthma, SLE, and JRA in the pediatric Mexican population.
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Atopic asthma and TNF-308 alleles: linkage disequilibrium and association analyses

Abstract

Section snippets

Abbreviations

Study population

Association of TNF-308 alleles an TNF/HLA-DRB1* haplotypes to ST reactivity to D. Pteronyssinus, Lolium Perenne, and Parietaria

Discussion

Acknowledgements

Chest

Hum Immunol

Hum Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Am J Hum Genet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Hepatol

Hum Immunol

Am J Hum Genet

Allergic aetiology and immunology of asthma

Ann Allergy

Molecular concepts of IgE-initiated inflammation in atopic and nonatopic asthma

Allergy

Linkages and associations to intermediate phenotypes underlying asthma and allergic disease

Curr Opin Allergy Clin Immunol

Genetics of allergy

Ann Allergy

Association of HLA-DR3 with human immune response to Lol p I and Lol p II allergens in allergic subjects

Tissue Antigens

Genetic linkage of HLA class II locus to mite-specific IgE responsiveness

Clin Exp Allergy

Tumour necrosis factor-alphathe role of this multifunctional cytokine in asthma

Immunol Cell Biol

Tumor necrosis factor increases airway responsiveness and sputum neutrophilia in normal human subjects

Am J Respir Crit Care Med

Cytokine and eosinophil responses in the lung, peripheral blood, and bone-marrow compartments in a murine model of allergen-induced airway inflammation

Am J Respir Cell Mol Biol

Tumor necrosis factor (TNF) causes bronchial hyperresponsiveness in rats

Am Rev Respir Dis

IL-4 induces germ-line IgE heavy chain gene transcription in human fetal pre-B cells. Evidence for differential expression of functionalIL-4 and IL-13 receptors during B cell ontogeny

J Immunol