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.
Yucesoy
B
B
Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, West Virginia 26505, USA.
Vallyathan
V
V
Landsittel
D P
DP
Sharp
D S
DS
Weston
A
A
Burleson
G R
GR
Simeonova
P
P
McKinstry
M
M
Luster
M I
MI
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