Association Analysis ofMember RAS Oncogene FamilyGene Polymorphisms with Aspirin Intolerance in Asthmatic Patients

Abstract

Member RAS oncogene family (RAB1A), a member of the RAS oncogene family, cycles between inactive GDP-bound and active GTP-bound forms regulating vesicle transport in exocytosis. Thus, functional alterations of the RAB1A gene may contribute to aspirin intolerance in asthmatic sufferers. To investigate the relationship between single-nucleotide polymorphisms (SNPs) in the RAB1A gene and aspirin-exacerbated respiratory disease (AERD), asthmatics (n=1197) were categorized into AERD and aspirin-tolerant asthma (ATA). All subjects were diagnosed as asthma on the basis of the Global Initiative for Asthma (GINA) guidelines. AERD was defined as asthmatics showing 15% or greater decreases in forced expiratory volume in one second (FEV(1)) or naso-ocular reactions by the oral acetyl salicylic acid (ASA) challenge (OAC) test. In total, eight SNPs were genotyped. Logistic regression analysis identified that the minor allele frequency of +14444 T>G and +41170 C>G was significantly higher in the AERD group (n=181) than in the ATA group (n=1016) (p=0.0003-0.03). Linear regression analysis revealed a strong association between the SNPs and the aspirin-induced decrease in FEV(1) (p=0.0004-0.004). The RAB1A gene may play a role in the development of AERD in asthmatics and the genetic polymorphisms of the gene have the potential to be used as an indicator of this disease.

Genetic and Epigenetic Components of Aspirin-Exacerbated Respiratory Disease

“…Two SNPs, RAB1A 14444G>T and RAB1A 41170C>G, were associated with aspirin hypersensitivity and the minor allele frequencies of these SNPs were also higher in this group 66 . In addition, the RAB1A 14444TT and RAB1A 41170GG carriers showed a greater decline in FEV1 following oral aspirin challenge, with heterozygotes for both SNPs demonstrating intermediate levels of FEV1 decline 66 . The Ras family GTPases regulate production of inflammatory mediators 67 , and granule release from platelets, eosinophils, and neutrophils requires RAB1A activation 68 .…”

“…RAB1A encodes a Ras family GTPase that may contribute to eosinophilia and immune responses in AERD by regulating vesicle exocytosis in activated immune cells. Eight polymorphisms in the RAB1A gene were analyzed for associations with the risk of AERD in 181 asthmatic subjects with aspirin intolerance and 1016 non-aspirin intolerant asthmatic controls 66 . Two SNPs, RAB1A 14444G>T and RAB1A 41170C>G, were associated with aspirin hypersensitivity and the minor allele frequencies of these SNPs were also higher in this group 66 .…”

“…Eight polymorphisms in the RAB1A gene were analyzed for associations with the risk of AERD in 181 asthmatic subjects with aspirin intolerance and 1016 non-aspirin intolerant asthmatic controls 66 . Two SNPs, RAB1A 14444G>T and RAB1A 41170C>G, were associated with aspirin hypersensitivity and the minor allele frequencies of these SNPs were also higher in this group 66 . In addition, the RAB1A 14444TT and RAB1A 41170GG carriers showed a greater decline in FEV1 following oral aspirin challenge, with heterozygotes for both SNPs demonstrating intermediate levels of FEV1 decline 66 .…”

Genetic basis of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs

“…Functional N-acetyltransferase and CYP2C polymorphisms have recently been analyzed in relation to metamizole metabolic profile [85 && ]. Associations with NERD have been also reported for SNPs in formyl peptide receptor 2, a high-affinity ligand receptor for lipoxins [86], heat shock protein 70 [87], and members of the rat sarcoma viral (RAS) oncogene family [88].…”

Inhibition of RAB1A suppresses epithelial-mesenchymal transition and proliferation of triple-negative breast cancer cells

“…Member of Rab family (4), RAB1A is anchored on the membranes of endoplasmic reticulum (ER) and Golgi by prenylation and functions as controller of vesicle trafficking from ER to Golgi apparatus (5,6). The aberrant expression of RAB1A induces many diseases, such as Parkinson's disease (7), aspirin-exa cerbated respiratory disease (8), cardiomyopathy (9) and cancer (10,11). mTORC1 as a complicated pathway is demonstrated to play various effects on cell survival, cell growth, cell metabolism, cell cycle and is sensitive to rapa mycin (12).…”