Possible Association of SLC22A2 Polymorphisms with Aspirin-Intolerant Asthma

Abstract

Background: Aspirin-intolerant asthma (AIA) is a clinical syndrome characterized by acute bronchoconstriction following the ingestion of aspirin. Solute carrier family 22, member 2 (SLC22A2), also known as organic cation transporter 2 (OCT2), is predominantly expressed in the luminal membrane of airway epithelial cells and has been shown to mediate the transport of prostaglandins on the cyclooxygenase pathway which is regulated by aspirin blockage. Recently, SLC22A2-mediated uptake inhibition by several nonsteroidal anti-inflammatory drugs and decreased SLC22A2 transport activity by its genetic variants have been elucidated in asthma. Methods: To investigate the associations between AIA and genetic polymorphisms of the SLC22A2 gene, 18 variants were genotyped in 163 AIA subjects and 429 aspirin-tolerant asthma (ATA) controls. Logistic analyses were used to evaluate p values for the associations of SLC22A2 polymorphisms with AIA. Results: One common polymorphism in intron 5, i.e. rs316021, was significantly associated with susceptibility to AIA (p = 0.004, P^corr = 0.05, OR = 0.60, 95% CI = 0.43–0.85 in a codominant model). The minor allele frequency of rs316021 in the AIA group was significantly lower than that in the ATA controls. In addition, a polymorphism in intron 4 (rs3912161) and a haplotype (SLC22A2-ht3) showed significantly stronger association signals with the FEV₁ fall rate induced by aspirin provocation in AIA subjects compared with ATA controls (p = 0.004, P^corr = 0.05). Conclusion: Our findings suggest that SLC22A2 could be a susceptibility gene for aspirin intolerance in asthmatics.

Expression of Arachidonate Metabolism Enzymes and Receptors in Nasal Polyps of Aspirin-Hypersensitive Asthmatics

“…It is therefore suggested that there are not only local but also generalized changes in the arachidonic acid metabolism in AERD [23]. This theory is further supported by the association of some genetic polymorphisms in enzymes and eicosanoid receptors with aspirin hypersensitivity [24,25,26,27]. …”

State of the art paper Does aspirin-induced oxidative stress cause asthma exacerbation?

“…Some of them are associated with the arachidonic acid pathway (LTC4S [ 79 ], COX2 [ 80 ], cysLTR1 [ 81 ], cysLTR2 [ 82 ]), and some are related to eosinophilic inflammation (ACE [ 83 ], CCR3 [ 84 ], NLRP3 [ 85 ], TBX21 [ 86 ]) and pathogenesis of nasal polyps (TGF-β1 [ 87 ]). There are also gene polymorphisms whose relationship with AIA is not fully ascertained (FSIP1 [ 88 ], CEP68 [ 72 ], SLC22A2 [ 89 , 90 ], ADAM33 [ 91 ], EMID2 [ 92 ], TLR3 [ 93 ], ADORA1 [ 94 ], CACNG6 [ 95 ], WDR46 [ 96 ], ZNRD1 [ 97 ], KIFC1 [ 98 ], CYP2C19 [ 99 ]).…”

Association analysis of ILVBL gene polymorphisms with aspirin-exacerbated respiratory disease in asthma

“…For the past two decades, many genetic association studies have demonstrated strong association of genetic variants on biologically plausible genes responsible for arachidonic acid metabolism, including LTC4S [ 5 ] ALOX5 [ 6 ], CYSLT1R [ 7 ], CYSLT2R [ 8 ], PTGER [ 9 – 11 ], TBXAS1 [ 12 ], and TBXA2R [ 13 ], with the development of AERD. Other studies also identified that genes in the immune response and inflammatory pathways were associated with the adverse reaction to aspirin,, including HLA-DPB1 [ 14 ], IL-4 [ 15 ], T-Box [ 16 ], FcepsilonR1 [ 17 , 18 ], TLR3 [ 19 ], NLRP3 [ 20 ], ADAM33 [ 21 ], ADORA1 [ 22 ], ACE [ 23 ], CRTH2 [ 24 ], PPARG [ 25 ], KIF3A [ 26 ], SLC6A12 [ 27 ], SLC22A2 [ 28 ] and CACNG6 [ 29 ]. These findings suggest that additional genetic variation in the extra-arachidonate pathways could be related to the development of AERD.…”