Table 2.
Genetic polymorphisms involved in NSAID hypersensitivity
| Pathway/gene name | SNPs | Associated clinical phenotype | Population |
|---|---|---|---|
| Arachidonic acid | |||
| LTC4S | -444A>C | C allele was associated with NERD and increased urine LTE4 level after aspirin challenge. | Polish [50, 51] |
| CYSLTR1 | -634C>T, -475 A>C, -336 A>G | Those SNPs were associated with NERD and could affect gene transcriptional activity. | Korean [55-57] |
| CYSLTR2 | -189 T>C | ||
| COX-2 | -765 G>C | This SNP could affect gene transcriptional activity and contribute to PGD2 production in NERD patients. | Polish [60] |
| ALOX5 | -1708 G>A, 21 C>T, 270 G>A, 1728 G>A | -1708 A allele was associated with NECD/NIUA. | Korean [53, 61] |
| Haplotype (GCGA) was associated with NERD. | |||
| ALOX15 | -272 C>A | NECD/NIUA | Polish [62] |
| TBXA2R | -4684 C>T | This SNP affected gene transcriptional activity. C allele was associated with NERD, while TT genotype was associated with NIUA. | Korean [64, 65] |
| 795 T>C | This SNP was associated with NERD and % fall in FEV1 after aspirin challenge. | Korean [66] | |
| TBXAS1 | 141931T>A | This SNP was associated with NERD in a Korean, and NIUA in a Spanish population. | Korean [67] |
| Spain [68] | |||
| PTGER2 | -616 C>G, -166 G>A | NERD | Korean [65] |
| PTGER3 | -1709 T>A, 173288G>T, 195000A>G | NERD | Korean [65, 70] |
| PTGER4 | -1254 A>G | This SNP could affect gene transcriptional activity and was associated with NERD as well as NECD. | Korean [65, 69] |
| PTGIR | 1915 T>A | NERD | Korean [65] |
| Basophil/mast cell and eosinophil activation | |||
| FCER1G | -237 A>G | This SNP was associated with NERD and increased total IgE serum level in NERD patients. | Korean [72] |
| FCER1A | -344 T>A | This SNP was associated with NECD and increased total IgE serum level in NECD patients. | Korean [72, 73] |
| NERD patients carrying CC/CT genotype had a higher serum level of IgE to staphylococcal enterotoxin A than those with CC genotype. | |||
| HNMT | 939 A>G | This SNP was associated with NECD, could affect HNMT mRNA stability, protein expression, and enzymatic activity of HNMT. | Korean [75] |
| IL-4 | -589 T>C, -33 T>C | These SNPs were associated with NERD and could affect gene transcriptional activity. | Korean [78] |
| IL-13 | -1510 A>C, -1055 C>T | These SNPs were associated with rhinosinusitis in NERD patients. | Korean [79, 80] |
| 110 G>A (Arg 110Gln) | This SNP was associated with increased blood eosinophil count in NERD patients. | Korean [80] | |
| -1111 C>T | This SNP was associated with NERD. | Japanese [81] | |
| Other inflammatory mediators and cytokines | |||
| IL-5Rα | -5993 G>A | This SNP was associated with the production of serum-specific IgE against staphylococca enterotoxin A in NERD patients. | Korean [83] |
| TNF-α | -1031 T>C, -863 C>A | NECD/NIUA | Korean [84] |
| -308 G>A | This SNP was associated with chronic rhinosinusitis and nasal polyposis in NERD. | Hungarian [85] | |
| IL-10 | -819 T>C | NERD | Korean [87] |
| IL-18 | -607 A>C | -607 A>C and the haplotype (CG) were associated with NIUA. The (CG) haplotype increased transcriptional activity and neutrophil chemotaxis. | Korean [86] |
| -137 G>C | |||
| IL-17A | -737 C>T | NERD | Japan [81] |
| IL-17Rα | -1075 A>G, -947 A>G, -50 C>T | Major alleles of these SNPs were associated with NERD, higher IL-17RA mRNA and protein expression in CD14+ peripheral monocytes. | Korean [88] |
| HLA system | |||
| DPB1*0301 | - | This allele was associated with NERD and could interact with TNF-α polymorphisms to increase NERD susceptibility. | Polish [90] |
| Korean [91, 92] | |||
| DPB1 | Rs3128965 | This SNP was associated with NERD, increased airway hyper-responsiveness in aspirin challenge test, and increased secretion of 15-HETE from peripheral blood leukocytes. | Korean [92] |
| Exm537513 | NERD | Korean [94] | |
| DPB1*0401 | - | This allele had a protective role against NERD. | Polish [90] |
| German [93] | |||
| DQB1*0301, DQB1*011 | - | There alleles had a protective role against NERD. | Iran [95] |
| DQB1*0302, DRB1*04 | - | NERD | Iran [95] |
| DQB1*0609 [DRB1*1303 /DQB1*0 609/DPB1*0201] | - | NECD | Korean [96] |
| Cw4, Cw7 | - | These alleles may have a protective role against NECD. | Italian [97] |
| B44 | - | NECD | Italian [97] |
| Other pathways | |||
| ATF6B | Rs2228628, Rs8111 | These SNPs were associated with a decline in %FEV1 after aspirin challenge test. | Korean [98] |
| CYP2C19 | 681 G>A, 636 G>A | NERD | Japan [99] |
| DPP10 | Rs1704175 | This SNP was associated with NERD and the serum level of DPP10 in asthmatic patients. | Korean [100] |
| P2Y12 | 18 C>T | This SNP was associated with platelet P2Y12 expression in NERD patients. | Korean [101] |
| 742 T>A | This SNP was associated with the nasal secretion level of eosinophil cationic protein in NERD patients. | ||
NSAID, nonsteroidal anti-inflammatory drug; SNP, single nucleotide polymorphism; LTC4S, leukotriene C4 synthase; NERD, NSAID-exacerbated respiratory disease; LTE4, leukotriene E4; CYSLTR1, CysLT receptor 1 gene; CYSLTR2, CysLT receptor 2 gene; COX-2, cyclooxygenase 2; PGD2, prostaglandin D2; ALOX5, 5-lipoxygenase; NECD, NSAID-exacerbated cutaneous disease; NIUA, NSAID-induced urticaria/angioedema; TBXA2R, TXA2 receptor gene; FEV1, forced expiratory volume in 1 second; TBXAS1, TBXA1 synthase gene; PTGER, prostaglandin E receptor; PTGIR, prostagladin I receptor; FCER1G, Fc epsilon receptor 1 gamma; IgE, immunoglobulin E; FCER1A, Fc epsilon receptor 1 alpha; HNMT, histamine N-methyltransferase; IL-4, interleukin 4; TNF-α, tumor necrosis factor α; HLA, human leukocyte antigen; 15-HETE, 15-hydroeicosatetraenoic acid; ATF6B, activating transcription factor 6β gene; CYP, cytochrome P450; DPP10, dipeptidyl-peptidase 10 gene.