Genetic variants in the major histocompatibility complex class I and class II genes are associated with diisocyanate-induced Asthma.

Diisocyanates, low-molecular-weight reactive chemicals used in the production of paints and polyurethanes, are one of the most common causes of occupational asthma. Toluene diisocyanate (TDI), 4,4′-diphenylmethane diisocyanate (MDI), and hexamethylene diisocyanate (HDI) are the most commonly used isocyanates. Between 5% and 15% of workers with continuous long-term exposure to diisocyanates develop asthma.1–3 Toluene diisocyanate alone was reported to account for between 2.9% and 13% of all occupational asthma cases in Korea.4 Genetic association studies have underscored the importance of human leucocyte antigen (HLA) genes within major histocompatibility complex (MHC) as susceptibility loci for a number of complex diseases with an immune/inflammatory nature including occupational asthma.5–7 Since both HLA class I and II molecules are involved in the presentation of antigens to T-cell receptors, genetic research has focused on identifying interindividual differences in their ability to bind peptides and influence T-cell recognition. Evidence has shown that certain HLA class II alleles contribute to the risk of asthma caused by diisocyanates and other low-molecular-weight sensitizers (eg, trimellic anhydride and platinum salts).8–10 Earlier studies reported associations between the HLA-DQB1 alleles and altered risk of diisocyanate-induced asthma (DA).8,11 Recently, haplotypes including HLA-DRB1, -DQB1, and -DPB1 alleles were found to be associated with an increased risk of TDI asthma in Koreans.12,13 Hur et al 14 also reported an association between a haplotype carrying the HLA-DRB1, -DQB1, and -DPB1 alleles and elevated serum-specific immunoglobulin G (IgG) levels in MDI-exposed workers. Although the HLA complex is one of the most extensively studied regions in the human genome, other genes in the MHC region have not yet been sufficiently investigated with regard to disease association. The MHC, located on the short arm of chromosome 6 (6p21.3, 28 970 148- 33 883 424 bp), is one of the most polymorphic and gene-dense regions of the genome. This region spans nearly 4 Mb and encodes more than 180 highly polymorphic genes, many of which influence immune function, susceptibility to complex diseases, and the outcome of tissue transplantation.15 In addition to genes in the HLA complex, several functionally important genes are located in this region including the genes for complement proteins C4, C2, and Factor B, the cytokines tumor necrosis factor α and β, and TAP (antigen peptide transporter) genes that function in antigen processing. The dense genetic organization and extensive linkage disequilibrium (LD) patterns of the region complicate the search for susceptibility alleles. Although various MHC variants have been shown to be involved in susceptibility to autoimmune, infectious, and inflammatory diseases, thus far, only a limited number of HLA genes have been examined with respect to DA. This is the first study investigating the association of single nucleotide polymorphisms (SNPs) located across the entire MHC region with DA in a well-characterized worker population using microarray technology.