INHERITED GSTM1 AND NAT2 DEFECTS AS CONCURRENT RISK MODIFIERS IN ASBESTOS-RELATED HUMAN-MALIGNANT MESOTHELIOMA

Besides asbestos exposure, the factors that determine susceptibility t o malignant mesothelioma are unknown. We evaluated the risk of GSTM1 n ull genotype and slow acetylation-associated NAT2 genotype for maligna nt mesothelioma in relation to asbestos exposure. Both the GSTM1 null genotype and the NAT2 slow acetylator genotype placed individuals at a bout 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 t he patients were divided into low/moderate and high exposure groups ac cording to their asbestos exposure histories, the effect of the at-ris k 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 a nd NAT2 genes, respectively). The individuals with combined GSTM1 and NAT2 defects had about a 4-fold risk of developing malignant mesotheli oma compared to those with the GSTM1 gene and NAT2 fast acetylator gen otype (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 t han 7-fold greater compared to those with the more beneficial genotype s of both GSTM1 and NAT2 genes (OR = 7.4; 95% CI = 1.6-34.0).