low molecular weight ( lmw ) allergens such as diisocyanates , acid anhydrides , and metallic salts are reactive chemicals with molecular weight less than 1000  kd . they act as haptens and can cause sensitization that may or may not be associated with specific immunoglobulin e ( ige ) . while some lmw agents such as acid anhydrides , platinum salts , and persulfates stimulate ige antibodies , many others including isocyanates and glutaraldehyde rarely cause ige - mediated sensitization . on the other hand , high molecular weight ( hmw ) protein - derived agents ( e.g. , proteases , flour , and laboratory animal allergens ) cause allergic sensitization through mechanisms mediated by ige . early detection of sensitization is very important since sensitized individuals can have life - threatening reactions to future exposures even years after the cessation of exposure . although the risk of sensitization for individuals with underlying atopy is higher for some exposures ( particularly ige - mediated responses ) , high prevalence ( around 20% ) of atopy in the general population indicates that atopy alone is not the determining factor . although the main factors that affect the onset of the symptoms are the types , duration , and intensity of allergen exposure ,   host genetic factors can modulate how individuals interact with these agents and induce a shift in the dose - response relationship . recent genetic epidemiology research focused on common gene variants and identified a number of genetic associations and gene - environment interactions for allergic respiratory diseases . understanding gene - environment interactions is especially important to improve occupational and public health since environmental / occupational factors that influence genetic risk are modifiable . in this respect , the results of molecular epidemiology studies have the potential to be used in risk evaluation and to help determine more accurate safe occupational exposure levels , thereby contributing to improved protection of workers at high risk . this paper will summarize the contribution of genetic variability to two important occupational respiratory diseases , diisocyanate - induced asthma ( da ) and chronic beryllium disease ( cbd ) . among lmw substances , the diisocyanates are the most frequently reported cause of respiratory sensitization in the workplace . these agents are widely used in polymerization reactions for manufacturing surface coatings , varnishes , paints , urethane foams , insulation , and adhesives . workers in these industries and workers that use these end products may be influenced by potential adverse health effects of such chemicals . national occupational exposure survey   database , national institute for occupational safety and health ( niosh ) , showed that at least 280,000 workers were potentially exposed to some form of isocyanates in the united states alone . isocyanates are the leading cause of occupational asthma ( oa ) , estimated to cause asthma in 510% of chronically exposed workers [ 68 ] . despite improved industrial hygiene efforts , new cases of oa continue to occur [ 9 , 10 ] . the most common isomers used in industry are : the aliphatic agent 1,6-hexamethylene diisocyanate ( hdi ) , used principally as a hardener in spray paints , 4,4-diphenylmethane diisocyanate ( mdi ) , and toluene diisocyanate ( tdi ) . early diagnosis of oa leads to favorable clinical outcomes ( i.e. , less risk of chronic and severe asthma ) if affected workers are promptly recognized and removed from harmful exposure [ 9 , 11 ] . in addition to early case detection , it is also important to more closely monitor the most susceptible workers at a preclinical stage . genetic epidemiologic studies have identified a number of susceptibility markers for a variety of asthma phenotypes including oa . most of these genetic studies were hindered by difficulty in defining asthma , a complex phenotype representing allergic and nonallergic types . this has led to selection of intermediate or quantifiable phenotypes ( e.g. , airway hyperresponsiveness , lung function , and serum ige levels ) in some association studies . on the other hand , oa is a unique model in that the phenotype can be defined accurately by specific inhalation challenge ( sic ) testing often considered the gold standard for diagnosing oa . for this reason , oa is an excellent model for studying gene - environment interactions since the causal agent can be identified with sic and the lag period between initial exposure and onset of sensitization and clinical symptoms can be followed . given its immune - inflammatory nature , oa phenotypes are likely associated with specific variants of immune-/inflammatory - related genes . linkage studies have suggested a variety of candidate genes for asthma and related phenotypes in chromosomal regions 2q14-q32 , 5q31-q33 , 6p24-p21 , 7p15-p14 , 11q13-q21 , 12q21-q24 , 13q12-q14 , and 20p13     [ 1421 ] . in particular , variants of interleukin ( il)-4 , il-4ra , il-13 , -adrenergic receptor ( -ar ) , tumor necrosis factor ( tnf)- , human leukocyte antigen ( hla)-drb1 , dqb1 , the -subunit of the high - affinity ige receptor ( fceri ) , cd14 , a disintegrin and a metalloproteinase 33 ( adam33 ) genes have been consistently associated with asthma - related phenotypes in independent studies [ 22 , 23 ] . as in other forms of asthma , inflammatory changes and allergen - specific t - lymphocytes are found in the airways of many patients with oa , along with eosinophils , cytokines , and serum ige antibodies [ 2426 ] . thus , similar genetic associations as in immune - mediated asthma might be expected to occur in oa . although a number of genetic association studies have been conducted on individuals with allergic asthma from environmental causes , there are only limited studies on oa . the human leukocyte antigen ( hla ) class ii molecules play a role in the presentation of intracellularly processed peptides to cd4 + t - helper cells . hla class ii molecules are highly polymorphic and the variations in their protein structure may determine the specific epitopes presented to t cells . therefore , hla class ii molecules are also plausible candidates for controlling specific immunological responses to allergens . demonstrated that hla dqb1 * 0503 and the allelic combination dqb1 * 0201/0301 were associated with susceptibility to da   whereas the dqb1 * 0501 allele and the dqa1 * 0101-dqb1 * 0501-dr1 haplotype were considered protective . subsequently , mapp et al . confirmed the association with hla - dqb1 * 0503 and reported that the dqa1 * 0104 allele was increased in da compared with asymptomatic exposed workers . they also showed that  protective  alleles , hla - dqb1 * 0501 and dqa1 * 0101 , were increased in asymptomatic exposed workers versus those with da . in another study , a significantly higher proportion of subjects with da were found to express the hla - dqb1 * 0503-associated aspartic acid at residue 57 . hla associations with da were also investigated in a population of asian workers exposed to diisocyanates but the associations found in european workers were not entirely replicated . the hla haplotypes drb1 * 15-dpb1 * 05 and   hla drb1 * 1501-dqb1 * 0602-dpb1 * 0501 were reported as a susceptibility marker for the development of tdi - induced asthma in koreans [ 29 , 30 ] . bernstein et al . , investigated association between known snps in immune response genes ( il-4r , il-13 , and cd14 ) and da in a group of exposed workers undergoing sic testing . the results demonstrated increased frequencies of il-4ra i50v allele and combinatorial genotypes of il4ra ( i50v ) , il-13 ( r110q ) , and cd14 ( c159 t ) in hdi - exposed workers suggesting an exposure - specific interaction . these finding supported the notion that immune mechanisms play an important role in the pathogenesis of da . since isocyanates are known to cause oxidative injury to respiratory epithelial cells , variations within antioxidant defense genes have been examined in workers with da . glutathione , a major antioxidant protein found in the bronchial lining fluid and in respiratory epithelial cells , is likely to serve a protective function by binding with free isocyanate molecules and , thereby , preventing damage to respiratory epithelial cells or intracellular binding to respiratory epithelial proteins or proteins in the bronchial lumen . examined polymorphisms of the glutathione s - transferase ( gst ) genes ( gstm1 , gstm3 , gstp1 , and gstt1 ) in workers with da . subjects with gstm1 null and gstm3 aa genotypes developed late reaction in the specific bronchial provocation test with diisocyanates , individually or in combination . later , mapp et al . assessed the gstp1 gene in tdi - exposed asymptomatic and asthmatic workers . the frequency of the gstp1 ile105val val / val genotype was lower in subjects with da , and was significantly lower among subjects with airway hyperresponsiveness . in another study , the n - acetyltransferase ( nat1 ) slow acetylator genotype was associated with a 2.5-fold risk of oa among diisocyanate - exposed workers . interestingly , a far greater 7.77-fold risk of oa was reported among workers exposed to tdi , suggesting an exposure - specific association . in addition , a gene - gene interactive effect was identified in diisocyanate - exposed workers with the combined nat1 or nat2 slow acetylator genotypes and gstm1 null genotype . broberg et al . investigated the influence of variants in tdi - metabolizing genes on the associations between tdi in air ( 2,4-tdi and 2,6-tdi ) and its metabolites toluene diamine ( 2,4-tda and 2,6-tda ) in plasma and urine . their results showed that the gstp1 ile105val variant modifies the association between 2,4-tda   in plasma and in urine , supporting the importance of gst system for the metabolism of tdi . based on the role of neurogenic inflammation in tdi - induced airway hyperresponsiveness , the association between neurokinin-2 receptor ( nk2r ) gene polymorphisms and tdi - induced asthma was investigated in a korean population . an association was found between the nk2r 7853gg genotype and increased serum vegf levels , suggesting that nk2r variants may modulate the airway inflammation conferred by vegf . another korean study investigated the possible role of 2-adrenergic receptor gene ( adrb2 ) polymorphisms in tdi - induced asthma . a > g , leu134leu g > a , and arg175arg c > a snps and haplotype   [ ttacgc ] were found to be associated with specific ige sensitization in tdi - exposed workers . in another study , genome - wide association was performed to identify susceptibility alleles associated with asthma induced by tdi . the results showed significant association between genetic polymorphisms ( rs10762058 , rs7088181 , rs4378283 , and rs1786929 ) of catenin 3 ( ctnna3 ) and susceptibility to tdi - induced asthma . the ctnna3 variants have been suggested to influence tdi - induced asthma risk by increasing epithelial damage and airway inflammation . chronic beryllium disease ( cbd ) is a serious granulomatous lung disease caused by beryllium ( be ) exposure in the workplace . cbd continues to occur in industries where be is manufactured and processed such as aerospace , nuclear , automotive , and electronics . niosh estimated that up to 134,000 workers in the united states were exposed to beryllium . be exposure leads to a cell - mediated   hypersensitivity ( delayed , type iv ) reaction in which be haptenates native proteins leading to the production of the specific allergen . it is known that accumulation of be - specific cd4(+ ) t cells and persistent lung inflammation play a key role in the immunopathogenesis of cbd . prior to the development of cbd , many exposed workers become sensitized and many of those eventually develop cbd . be - specific t - cell proliferative responses are detected in the blood of exposed workers using the be lymphocyte proliferation test ( belpt ) [ 43 , 44 ] . the belpt has been shown to   identify approximately 70 to 94% of cases of bes and cbd and widely used in screening and surveillance of be - exposed workers [ 4547 ] . epidemiological studies showed the prevalence rates of bes and cbd to be between 521% and 321% among beryllium workers , respectively [ 48 , 49 ] . the pathologic progression from bes to cbd is not well understood warranting further research into the pathophysiological mechanisms and susceptibility markers of bes and cbd . such efforts will be important for early detection and disease prevention in be - exposed workers . a number of molecular epidemiology studies showed that the presence of glutamic acid in position 69 of the b1 chain of the hla - dpb1 molecule confers an increased risk for both bes and cbd   [ 41 , 5054 ] . the hla - dpb1glu69 frequency was reported to be between 3990% in sensitized workers and 5397% in workers with cbd as compared to 1948% in nonsensitized workers     [ 41 , 5052 , 5561 ] . importantly ,   studies have demonstrated a dose - dependent effect of hla - dpb1glu69 alleles suggesting that glu69 is a potential marker of disease severity in addition to overall disease risk . although hla - dpb1glu69 is more frequent in individuals with bes and cbd ( 7395% ) , 3040% of exposed workers carrying hla - dpb1glu69 do not develop cbd or bes [ 41 , 50 , 62 ] . this suggests that other host and environmental factors likely play key roles in the pathogenesis of cbd . studies investigating the interaction between the hla - dpb1 glu69 and be exposure showed independent and additive effects of   glu69 carriage and be exposure in the development of bes and cbd [ 58 , 63 ] . rossman et al . reported that hla - dqb1gly86 and hla - drb1ser11 alleles occurred more often in individuals with cbd . maier et al . found that hla - drb1 * 01 and dqb1 * 05 alleles were less frequent in workers with cbd . they also reported that drb1 * 13 and dqb1 * 06 were associated with cbd in the absence of glu69 . a recent study showed that the dre71 allele is a risk factor for both cbd and bes in the absence of glu69 and highlighted the importance of interactions between peptides and t cells in the development of cbd . glu69 alleloforms with the greatest negative surface charge   were found to confer the highest risk for cbd and irrespective of allele , equal risk for bes . current hla research includes investigating whether the risk is associated with any or only certain glu69 alleles or allelic combinations . sato et al . investigated eight snps within ccr5 gene that is implicated in the chemotaxis and activation of leukocyte subsets . the results showed that ccr5 - 5663 and -3458 variants were associated with worsening pulmonary function over time in cbd . the -509c and codon 10 t variants of the transforming growth factor-1 ( tgf ) gene , a cytokine with a major role in the fibrotic / th1 response , were found to be associated with more severe granulomatous disease in cbd . since glutathione has been reported to be increased in cbd , genetic variants of the glutamate cysteine ligase ( gcl ) , a rate - limiting enzyme in gsh synthesis , were investigated . gcl consists of a catalytic subunit ( gclc ) and modifier subunit ( gclm ) . gclc trinucleotide repeat polymorphism ( 7/7 genotype ) and the gclm-588 snp were   found to be associated with altered susceptibility to cbd . while saltini et al . reported   an association between   the tnf-308 * 02 variant   and   bes   and cbd , this result was not confirmed in a large population - based study [ 57 , 68 ] . a recent study showed that il-1-1142 , -3769 , and -4697 variants were significantly associated with cbd compared to individuals with bes or nonsensitized workers after adjusting for glu69 status . these results suggested that the formation of granulomas in cbd may require an independent inflammatory response controlled by genes unrelated to beryllium recognition . genetic association studies can provide more accurate information on the interindividual variability , thereby contributing to establishment of more accurate exposure limits in the workplace . these efforts , in a larger perspective , provide opportunities to effectively target engineering controls , personal protective equipment , and intervention strategies to protect the health of high - risk workers . with the advances in high - throughput technologies and computational methodologies , this information could be used in designing better predictive models to incorporate genetic variability into risk evaluation and improving the regulation and redefinition of acceptable exposure levels in the workplace . success of such approaches depends on how molecular epidemiology studies overcome some of the current challenges . despite the rapid growth of published associations , some of the genetic associations lack consistency across different studies . the inconsistency in results might be explained by the differences in study populations , phenotype characterization , exposure assessment , characterization of other environmental exposure ( e.g. , air pollution , smoking ) , intermediate phenotypes ( e.g. , airway hyperresponsiveness ) , statistical inconsistencies and other potentially modifiable risk factors such as lifestyle . for example , allele / carrier frequencies of the hla - dpb1glu69 ranged between   0.21/0.38 to 0.33/0.59 across different ethnic populations . this emphasizes the importance of replication studies in independent populations with a different genetic background . although the genetics of allergic respiratory diseases including da and cbd have yet to be fully characterized , summarized discoveries hold promise for the identification of susceptibility profiles and characterization of gene - environment interactions . it is to be hoped that future genetic association studies with large , well - characterized populations through national and international collaborations will increase the understanding of the pathogenesis of these diseases and help identify novel therapeutic targets and preventative / educational strategies for better identification and management of occupational diseases .
respiratory sensitization can be caused by a variety of substances at workplaces , and the health and economic burden linked to allergic respiratory diseases continues to increase . although the main factors that affect the onset of the symptoms are the types and intensity of allergen exposure , there is a wide range of interindividual variation in susceptibility to occupational / environmental sensitizers . 
 a number of gene variants have been reported to be associated with various occupational allergic respiratory diseases . 
 examples of genes include , but are not limited to , genes involved in immune / inflammatory regulation , antioxidant defenses , and fibrotic processes . 
 most of these variants act in combination with other genes and environmental factors to modify disease progression , severity , or resolution after exposure to allergens . 
 therefore , understanding the role of genetic variability and the interaction between genetic and environmental / occupational factors provides new insights into disease etiology and may lead to the development of novel preventive and therapeutic strategies . 
 this paper will focus on the current state of knowledge regarding genetic influences on allergic respiratory diseases , with specific emphasis on diisocyanate - induced asthma and chronic beryllium disease .