Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis.
Silicosis, an interstitial lung disease prevalent among miners, sand blasters, and quarry workers, is manifested as a chronic inflammatory response leading to severe pulmonary fibrotic changes. Proinflammatory cytokines, such as TNFalpha and IL-1, produced in the lung by type II epithelial cells and alveolar macrophages, have been strongly implicated in the formation of these lesions. Recently, a number of single nucleotide polymorphisms (SNPs), which quantitatively affect mRNA synthesis, have been identified in the TNFalpha promoter and IL-1 gene cluster and their frequency is associated with certain chronic inflammatory diseases. To assess the role of these SNPs in silicosis, we examined their frequency in 325 ex-miners with moderate and severe silicosis and 164 miners with no lung disease. The odds ratio of disease for carriers of the minor variant, TNFalpha (-238), was markedly higher for severe silicosis (4.0) and significantly lower for moderate silicosis (0.52). Regardless of disease severity, the odds ratios of disease for carriers of the IL-1RA (+2018) or TNFalpha (-308) variants were elevated. There were no significant consistent differences in the distribution of the IL-1alpha (+4845) or IL-1beta (+3953) variants with respect to disease status. In addition, several significant gene-gene and gene-gene-environment interactions were observed. Different associations between moderate cases and controls versus severe cases and controls were also observed in a number of these multigene comparisons. These studies suggest that gene-environment interactions involving cytokine polymorphisms play a significant role in silicosis by modifying the extent of and susceptibility to disease.
Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, West Virginia 26505, USA.
B
B
Yucesoy
V
V
Vallyathan
D P
DP
Landsittel
D S
DS
Sharp
A
A
Weston
G R
GR
Burleson
P
P
Simeonova
M
M
McKinstry
M I
MI
Luster
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003032:Coal Mining; D004247:DNA / Q000032:analysis; D017931:DNA Primers / Q000737:chemistry; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics*; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012829:Silicosis / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D012907:Smoking; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014481:United States / Q000453:epidemiology
D017931:DNA Primers; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D004247:DNA