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Abstract
BackgroundHistamine-metabolizing enzymes (N-methyltransferase and amiloride binding protein 1) are responsible for histamine degradation, a biogenic amine involved in allergic inflammation. Genetic variants of HNMT and ABP1 genes were found to be associated with altered enzyme activity. We hypothesized that alleles leading to decreased enzyme activity and, therefore, decreased inactivation of histamine may be responsible for altered susceptibility to asthma.MethodsThe aim of this study was to analyze polymorphisms within the HNMT and ABP1 genes in the group of 149 asthmatic children and in the group of 156 healthy children. The genetic analysis involved four polymorphisms of the HNMT gene: rs2071048 (-1637T/C), rs11569723 (-411C/T), rs1801105 (Thr105Ile = 314C/T) and rs1050891 (1097A/T) and rs1049793 (His645Asp) polymorphism for ABP1 gene. Genotyping was performed with use of PCR-RFLP. Statistical analysis was performed using Statistica software; linkage disequilibrium analysis was done with use of Haploview software.ResultsWe found an association of TT genotype and T allele of Thr105Ile polymorphism of HNMT gene with asthma. For other polymorphisms for HNMT and ABP1 genes, we have not observed relationship with asthma although the statistical power for some SNPs might not have been sufficient to detect an association. In linkage disequilibrium analysis, moderate linkage was found between -1637C/T and -411C/T polymorphisms of HNMT gene. However, no significant differences in haplotype frequencies were found between the group of the patients and the control group.ConclusionsOur results indicate modifying influence of histamine N-methyltransferase functional polymorphism on the risk of asthma. The other HNMT polymorphisms and ABP1 functional polymorphism seem unlikely to affect the risk of asthma.
Highlights
Histamine-metabolizing enzymes (N-methyltransferase and amiloride binding protein 1) are responsible for histamine degradation, a biogenic amine involved in allergic inflammation
A common C314T polymorphism leading to Thr105Ile substitution was discovered by Preuss et al [2] and it was found that less common T allele was associated with decreased histamine is metabolized by two enzymes: N-methyltransferase (HNMT) enzyme activity [2,3]
The main finding of this study is an association of 314C/T polymorphism of HNMT gene with asthma in the Polish population of pediatric patients which may confirm that impaired histamine metabolism caused by reduced activity of HNMT is involved in asthma pathogenesis
Summary
Histamine-metabolizing enzymes (N-methyltransferase and amiloride binding protein 1) are responsible for histamine degradation, a biogenic amine involved in allergic inflammation. Released histamine is metabolized by two enzymes: N-methyltransferase (HNMT) and diamine oxidase (amiloride binding protein 1, ABP1). Other functional SNP T939C (rs1050891) is located in the 3’ untranslated region of the gene and correlates with HNMT activity, as Kim et al [4] showed that the C allele correlated with increased stability of transcripts containing the HNMT 3’ untranslated region and increased enzyme activity. Both polymorphisms are in strong linkage disequilibrium. Other SNPs from the 5’-flanking region (-1637T/C, -463T/C, -411C/T) as well as 3’UTR (939A/G and 1097A/T) of HNMT gene have been identified [5], their functionality has not been elucidated yet
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