The –308 G>A SNP of TNFA is a factor predisposing to chronic rhinosinusitis associated with nasal polyposis in aspirin-sensitive Hungarian individuals: conclusions of a genetic study with multiple stratifications

Abstract

Single nucleotide polymorphisms (SNPs) of the tumour necrosis factor alpha (TNFα) gene (TNFA) have been extensively studied and shown to be associated with an increased risk of the development of various chronic inflammatory diseases. Inflammation has been demonstrated to play a central role in the pathogenesis of chronic rhinosinusitis (CRS), and TNFα is a key pro-inflammatory cytokine with important functions in these processes. In order to determine whether the well-known TNFA -308 G>A SNP has a role in a genetic predisposition to CRS in the Hungarian population, we analyzed our genomic collection containing control and CRS patient samples in a case-control study, and compared the genotype and allele frequencies. There was no significant difference in the observed genotype or allele frequencies between the controls and the total CRS group. However, after careful stratification of the patient group on the basis of the observed clinical symptoms, we found a significantly higher carriage rate of the rare A allele-containing genotypes among the CRS patients with nasal polyposis (NP) who also exhibited sensitivity to aspirin (acetylsalicylic acid, ASA(+)). It is concluded that genetic variants of the TNFA gene may affect the risk of CRS in a clinically well-defined group of CRSNP(+)ASA(+) patients in the Hungarian population. Our results also emphasize that the group of CRS patients is not homogenous in that patients exhibiting different clinical symptoms exist. Their carried genetic predisposing factors, and as a result, the exact molecular events leading to the development of various forms of CRS, may also differ.

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

“…Three candidate SNPs have been replicated in separate publications: TNF, [619][620][621][622][623] IL1A, 619,624 and AOAH. 613,618 TNF and IL1A are important proinflammatory cytokines, and AAOH inactivates lipopolysaccharides.…”

TNF-α and IL-1 β Cytokine Gene Polymorphism in Patients with Nasal Polyposis

“…The other important factor is that TNF-α expression is not only controlled by the TNFA gene locus, and the TNFB gene is another important molecular determinant of TNF-α levels (7). The extended linkage group around the TNFA locus might also be a causative factor for the genetic susceptibility for NP development (20).…”

Epigenetic Regulation of Gene Activity in Epithelial Cells of Nasal Mucous Membrane in Patients with Polypous Rhinosinusitis

“…However, despite large cohort studies including several thousand patients, the defective gene of aspirin intolerance has not been found yet [17,24,29].…”

“…The genetic apparatus is not involved. Since the mechanisms of the aforementioned abnormalities are caused by the modification of gene expression without changes in the genome, they are called epigenetic [5,29]. Nowadays epigenetic modification of the genome is considered as changes in gene function which are inherited but do not involve nucleotide sequence abnormalities.…”