Analysis of TNF-alpha promoter polymorphisms in the susceptibility to beryllium hypersensitivity.
OBJECTIVE
In susceptible individuals beryllium (Be)-exposure may cause Be-hypersensitivity (BH), leading to a spectrum of immune abnormalities ranging from the systemic responsiveness to Be to the CD4+ T-cell dominated chronic granulomatous pneumonitis known as berylliosis. Two gene markers have been previously associated with berylliosis: HLA-DP allelic variants carrying glutamate in position 69 of the beta-chain and the high TNF-alpha production-associated TNF-alpha promoter allele TNFA2. Since a number of TNF-alpha promoter sequence variants have been associated with higher or lower gene-expression, the entire TNF-alpha promoter region was screened for BH-associated variants.


METHODS
Denaturating High Performance Liquid Chromatography (DHPLC) analysis followed by DNA sequence analysis of the heteroduplex observed was performed on a DNA bank obtained from a Be-exposed population composed of 73 subjects with BH and 43 Be-exposed controls.


RESULTS
The data show that the TNF-alpha TNFA2 variant (genotypic frequency: BH 26.7%, Be-exposed controls 5.8%; p < 0.0001), the -857T variant (BH 19.7%, Be-exposed controls 10.5%; p = 0.045) are significantly associated with BH and there is no linkage disequilibrium between them. Further, 64.4% of BH subjects carried at least one of higher TNF-alpha production-associated polymorphisms (Be-exposed controls 34.8%; p = 0.0036).


CONCLUSIONS
The finding that TNF-alpha production-associated polymorphisms are carried at higher frequency by BH-affected compared to Be-exposed controls suggests that the TNF-alpha may play a central role in the determination of susceptibility to BH.
Dotti
Chiara
C
Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.
D'Apice
Maria Rosaria
MR
Rogliani
Paola
P
Novelli
Giuseppe
G
Saltini
Cesare
C
Amicosante
Massimo
M
D000328:Adult; D001608:Beryllium / Q000009:adverse effects* / Q000276:immunology*; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D004781:Environmental Exposure; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha; D001608:Beryllium