Inherited GSTM1 and NAT2 defects as concurrent risk modifiers in asbestos-related human malignant mesothelioma.
Besides asbestos exposure, the factors that determine susceptibility to malignant mesothelioma are unknown. We evaluated the risk of GSTM1 null genotype and slow acetylation-associated NAT2 genotype for malignant mesothelioma in relation to asbestos exposure. Both the GSTM1 null genotype and the NAT2 slow acetylator genotype placed individuals at about 2-fold increased risk of developing malignant mesothelioma [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.0-3.5 and OR = 2.1, 95% CI = 1.1-4.1, for the GSTM1 and NAT2 genes, respectively]. When the patients were divided into low/moderate and high exposure groups according to their asbestos exposure histories, the effect of the at-risk genotypes was mostly attributable to the high exposure groups (OR = 2.3, 95% CI = 1.0-5.6 and OR = 3.7, 95% CI = 1.3-10.2, for the GSTM1 and NAT2 genes, respectively). The individuals with combined GSTM1 and NAT2 defects had about a 4-fold risk of developing malignant mesothelioma compared to those with the GSTM1 gene and NAT2 fast acetylator genotype (OR = 3.6; 95% CI = 1.3-9.6). Moreover, the risk among subjects highly exposed to asbestos with the double at-risk genotype was more than 7-fold greater compared to those with the more beneficial genotypes of both GSTM1 and NAT2 genes (OR = 7.4; 95% CI = 1.6-34.0).
Hirvonen
A
A
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki.
Pelin
K
K
Tammilehto
L
L
Karjalainen
A
A
Mattson
K
K
Linnainmaa
K
K
D000328:Adult; D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001194:Asbestos / Q000009:adverse effects*; D003043:Cocarcinogenesis; D005069:Evaluation Studies as Topic; D005260:Female; D005809:Genes, Regulator; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008654:Mesothelioma / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors
D007527:Isoenzymes; D001194:Asbestos; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D005982:Glutathione Transferase