Genetic variants with gene regulatory effects are associated with diisocyanate-induced asthma

Abstract

We identified 5 DA-associated potential regulatory SNPs. Four variants exhibited effects on gene regulation (ATF rs11571537, CDH17 rs2446824 and rs2513789, and TACR1 rs2287231). A fifth variant (FAM71A rs147978008) showed nonrisk allele preferential binding to H1 histones. These results demonstrate that many DA-associated genetic variants likely act by modulating gene regulation.

Influence of Genetic Variance on Biomarker Levels After Occupational Exposure to 1,6-Hexamethylene Diisocyanate Monomer and 1,6-Hexamethylene Diisocyanate Isocyanurate

“…A total of 63 candidate genes were evaluated. Of those, 55 were directly from previously published papers on isocyanate-asthma: ACMSD, AHNAK, ALK, ASTN2, ATF3, C11orf74, CDH17, CRTAC1, CTNNA1, CTNNA3, DOCK2, EPHX1, FAM71A, GADL1, GSTM1, GSTP1, HERC2, HLA-A, HLA-B, HLA-C, HLA-DOA, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DRB1, HLA-E, IBTK, IL4RA, KCNIP4, LHPP, MBL2, NAT1, NAT2, NPAS3, ODZ3, PCNX, PCTK2, PDGFD, PFKFB3, PITPNC1, PRKCA, PTGS1, PTGS2, SAMD12, SLC24A2, SLC6A12, SOD2, TACR1, TGFβ1, TNFα, TRPM8, TUSC3, UGT2B4, and ZBTB16 (Bernstein, 2011;Yucesoy et al, 2012Yucesoy et al, , 2014Yucesoy et al, , 2015aYucesoy et al, ,b, 2016Hur and Park, 2015;Bernstein et al, 2018). An additional eight candidate genes were added to the list after lifting positions for asthma-associated SNPs to the newest genome build, GRCh38/hg38.…”

“…They also showed that the increase in calcium triggered the release of the pro-inflammatory cytokine interleukin-4 (IL4) (Chiung et al, 2010). Additionally, research on isocyanate-induced asthma has correlated a calciumdependent cell adhesion gene, CDH17, with isocyanate asthma risk (Yucesoy et al, 2015a;Bernstein et al, 2018). Likewise, calcium-mediated changes in cell adhesions may also be able to impact isocyanate toxicokinetics because calcium has been shown to be critical for the formation and maintenance of cell adhesions (Gao et al, 2000), which strengthen endothelial barrier function by decreasing vascular permeability (Gao et al, 2000).…”

“…Furthermore, the 20 statistically significant SNPs may all have a role in gene regulation regardless of whether they were intronic or intergenic. Recently, it was observed that non-coding SNPs associated with isocyanate-induced asthma can result in alleledependent changes in gene expression and differential nuclear protein and histone binding (Bernstein et al, 2018). Other studies have shown that intronic SNPs can impact enhancer activity and splicing, which can result in altered mRNA and protein expression and can change the characteristics of those genes (Wang et al, 2014;Wang and Sadee, 2016;Schwartz et al, 2017).…”

“…Multiple studies have reported genetic markers associated with risk of developing isocyanateinduced occupational asthma. Among these studies, susceptibility and/or protective genetic markers in the human leukocyte antigen (HLA), glutathione S-transferase (GST), alpha catenin (CTNNA), cadherin (CDH), N-acetyltransferase (NAT), and Krüppel C2H2-type zinc-finger (ZBTB) gene families have been reported in two or more studies (Mapp et al, 2000;Piirilä et al, 2001;Wikman et al, 2002;Choi et al, 2009;Kim et al, 2009;Yucesoy et al, 2012Yucesoy et al, , 2014Yucesoy et al, , 2015aBernstein et al, 2013Bernstein et al, , 2018. These genes have functions including antigen presentation, xenobiotic metabolism, ell-cell adhesion, and inflammatory response (Mapp et al, 2000;Piirilä et al, 2001;Wikman et al, 2002;Choi et al, 2009;Kim et al, 2009;Yucesoy et al, 2012Yucesoy et al, , 2014Bernstein et al, 2013).…”

Update on the Management of Occupational Asthma and Work-Exacerbated Asthma

“…Systematic reviews and consensus statements have also advised primary prevention as the preferred method of prevention. Although there are genetic host factors in workers who develop occupational asthma due to sensitization to a work agent,59606162 known genetic factors and other predisposing host factors are not sufficiently sensitive or specific to identify workers who should not have any exposure to a specific sensitizer, and primary prevention is focused on exposure prevention. Ideally, this consists of avoiding the use of agents that cause occupational asthma when possible and substituting safer substances for these agents, e.g ., substituting orthophthalaldehyde for glutaraldehyde (although ortho-phthalaldehyde has less commonly been reported to cause sensitization and asthma63).…”