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Hexamethylene diisocyanate asthma is associated with genetic polymorphisms of CD14, IL-13, and IL-4 receptor alpha.
Bernstein DI; Kissling GE; Hershey GK; Yucesoy B; Johnson VJ; Cartier A; Gautrin D; Sastre J; Boulet L-P; Malo J-L; Quirce S; Tarlo SM; Langmeyer S; Luster MI; Lummus ZL
J Allergy Clin Immunol 2011 Aug; 128(2):418-420
Diisocyanates are among the most common causes of occupational asthma. However, susceptibility factors and immune biomarkers of diisocyanate asthma (DA) have not been clearly defined. For example, serum diisocyanate antigen-specific IgE and IgG have been extensively investigated, but these immunoassays lack diagnostic accuracy in identifying workers with confirmed DA. Various genetic variants have been identified as risk factors for DA in association studies. Certain HLA class II alleles and single nucleotide polymorphisms (SNPs) of antioxidant enzymes (e.g., glutathione-s-transferases, N-acetyl transferases) have been associated with confirmed DA, although these findings have not yet been replicated in multiple populations. In 2006, we first reported that DA confirmed by specific inhalation challenge (SIC) testing was significantly associated with cytokine genotype combinations of IL-4 receptor a (IL4RA), IL13, and CD14 SNPs, but exclusively in hexamethylene diisocyanate (HDI)-exposed workers. In this report, we confirm the aforementioned genotype associations in an expanded group of workers with confirmed DA compared with diisocyanate-exposed workers without DA. A total of 368 diisocyanate-exposed workers were recruited by clinical investigators at 4 occupational disease clinics (Hopital du Sacre-Coeur de Montreal, Montreal, Quebec, Canada; Hopital Laval, Sainte-Foy, Quebec, Canada; University Health Network, Toronto, Ontario, Canada; and Fundacion Jimenez Diaz, Madrid, Spain) and included 103 diagnosed with DA (DA+) on the basis of a positive SIC test, 115 symptomatic workers with negative SIC tests (DA-), and 150 HDI-exposed asymptomatic control spray paint workers (i.e., healthy subjects not exhibiting respiratory symptoms). Blood samples were obtained for DNA extraction and genotyped for IL4RA (I50V), IL4RA (Q551R), IL4RA (E375A), IL13 (R110Q), and CD14 (C159T) SNPs, as previously described. Subjects were predominantly male (91%), white (99%), and of European descent (90.8% French Canadian, 2.7% English Canadian, 1.9 % Spanish). Of 103 workers with DA, 50, 22, and 31 were exposed to HDI, methylene diphenyldiisocyanate (MDI), and toluene diisocyanate (TDI), respectively. Of the 115 DA2 symptomatic workers, 91, 18, and 6 were exposed to HDI, MDI, and TDI, respectively, whereas all asymptomatic controls were exposed to HDI. The duration of workplace exposure in months (mean 6 SD) was 137 6 13.9 for DA1, 157.9 6 14.2 for DA2, and 65.6 6 2.2 for asymptomatic HDI workers. All SNPs studied were in Hardy-Weinberg equilibrium (x2 tests, all P >.10). No significant associations were identified (by the x2 test) between DA and individual alleles or genotypes of the candidate SNPs for IL4RA, IL13, or CD14. Genotypes w(I50V), IL4RA (Q551R), IL4RA (E375A), IL13 (R110Q), and CD14 (C159T) SNPs, as previously described.5 Subjects were predominantly male (91%), white (99%), and of European descent (90.8% French Canadian, 2.7% English Canadian, 1.9 % Spanish). Of 103 workers with DA, 50, 22, and 31 were exposed to HDI, methylene diphenyldiisocyanate (MDI), and toluene diisocyanate (TDI), respectively. Of the 115 DA2 symptomatic workers, 91, 18, and 6 were exposed to HDI, MDI, and TDI, respectively, whereas all asymptomatic controls were exposed to HDI. The duration of workplace exposure in months (mean 6 SD) was 137 6 13.9 for DA1, 157.9 6 14.2 for DA2, and 65.6 6 2.2 for asymptomatic HDI workers. All SNPs studied were in Hardy-Weinberg equilibrium (x2 tests, all P >.10). No significant associations were identified (by the x2 test) between DA and individual alleles or genotypes of the candidate SNPs for IL4RA, IL13, or CD14. Genotypes were dichotomized for further statistical analyses as follows: IL4RA (I50V), II versus IV or VV; IL4RA (Q551R), QQ versus QR or RR; IL4RA (E375A), EE versus EA or AA; IL13 (R110Q), RR versus RQ or QQ; and CD14 (C159T), CT versus CC or TT. Combinations of genotypes were also dichotomized to compare the indicated combination with all other possible combinations. For example, the combination of IL4RA and IL13 RR compared IL4RA (I50V) 5 II and IL13 (R110Q) 5 RR to all other combinations of IL4RA (I50V) and IL13 (R110Q). Logistic regression analysis revealed significant interactions of diisocyanate exposure (HDI vs MDI, TDI) with specific genotype combinations (i.e., IL4RA II 1 IL13 RR; IL4RA II 1 CD14 CT; and IL4RA II 1 IL13 RR 1 CD14 CT) for distinguishing confirmed DA status (DA1) compared with SIC-negative workers (DA2), after adjusting for significantly associated demographic variables (Table I). In logistic regression analyses comparing HDI-exposed DA1 workers (n 5 50) with HDI-exposed DA2 workers (n 5 91), DA remained significantly associated with IL4RA II 1 CD14 CT and IL4RA II 1 IL13 RR 1 CD14 CT genotype combinations after adjustment for smoking status and sex. When comparing HDI-exposed DA1 workers (n 5 50) with asymptomatic HDI-exposed workers (n 5 150), the association between DA and the IL4RA II 1 CD14 CT and IL4RA II 1 IL13 RR 1 CD14 CT genotype combinations approached statistical significance (P < .10) after adjustment for age at diagnosis and smoking status. These results in an expanded group of workers confirm our original findings of significant associations of DA with IL4RA (I50V), IL13 (R110Q), and CD14 (C159T) genotype combinations modified by exposure to HDI.5 Unique to this report is the finding that 2 genotype combinations remain significantly associated with DA compared with DA2 workers, and a similar, but not statistically significant, association was observed when compared with an asymptomatic cohort of HDI-exposed workers. Significant associations between genotype and occupational asthma were found only after adjustment for work-relevant diisocyanate exposure (ie, HDI vs TDI, MDI). The reason for restriction of this finding to the HDI-exposed population is unknown and may be an artifact of the greater numbers of HDI-exposed subjects available for statistical analysis. This study used a case-control design with a candidate gene approach. The rarity of diisocyanate asthma and the relatively small numbers of subjects able to be recruited compared with genetic studies of nonoccupational asthma are limitations of this study and hindrances to future replication studies. However, the issue of small group sizes could be counterbalanced by the ability to define the DA phenotype precisely by using objective SIC-tests with work-relevant diisocyanate chemicals. The role of these genotype combinations in the pathogenesis of DA is unknown and awaits functional characterization. Nevertheless, susceptibility genes associated with TH2- cell differentiation (e.g., IL4RA, IL13) and innate immunity (CD14) have been extensively investigated in nonoccupational asthma.6 The IL13 (R110Q) SNP has been associated with asthma and airway hyperresponsiveness, and IL4RAvariant V and R alleles (I50Vand Q551R, respectively) have been associated with asthma and atopy. No such associations were detected in the current study of workers not enriched with atopic subjects. In summary, we have confirmed a previous observation in expanded groups of workers: a reported association between genotype combinations associated with TH2 and innate immunity and diisocyanate-induced asthma caused by HDI. Replication of these results in other background populations will be necessary to define the possible value of these genetic markers for risk assessment.
Allergens; Allergic-reactions; Allergies; Antigens; Bioassays; Diagnostic-techniques; Genetic-factors; Inhalation-studies; Mathematical-models; Occupational-respiratory-disease; Painters; Risk-analysis; Risk-factors; Sensitivity-testing; Statistical-analysis; Work-areas; Work-operations; Work-organization; Workplace-studies; Respiratory-system-disorders; Pulmonary-system-disorders; Bronchial-asthma
David I. Bernstein MD, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0563
Issue of Publication
Healthcare and Social Assistance; Services
Journal of Allergy and Clinical Immunology
WV; OH; NC
University of Cincinnati
Page last reviewed: May 5, 2020
Content source: National Institute for Occupational Safety and Health Education and Information Division