Genetic variation within the histamine pathway among patients with asthma--a pilot study

Abstract

Objective: Histamine is an important mediator in the pathophysiology of asthma. We have previously reported that HRH1 is differentially expressed among those with asthma compared to those without asthma. Single histamine-related genes have also been associated with asthma. We aimed to evaluate known single nucleotide polymorphisms (SNPs) in genes along the histamine biotransformation and response pathway, and determine their association with asthma and HRH1 mRNA expression.

Methods: We enrolled children and adults (n = 93) with/without asthma who met inclusion/exclusion criteria. Genotyping was performed for nine known SNPs in the HDC, HRH1, HRH4, HNMT and ABP1 genes. HRH1 mRNA expression was determined on RNA from buccal tissue. General linear model, Fisher's exact test and Chi-square test were used to determine differences in allele, genotype and haplotype frequency between subjects with and without asthma and differential HRH1 mRNA expression relative to genotype. Statistical significance was determined by p < 0.05.

Results: No difference was observed in genotype/allele frequency for the nine SNPs between subjects with and without asthma. The HNMT-1639C/-464C/314C/3'UTRA haplotype was more frequently observed in those without asthma than those with asthma (p = 0.03). We also observed genetic differences relative to race and gender. HNMT 314 genotype CT was more frequent in males with asthma compared to those without asthma (p = 0.04).

Conclusions: Histamine pathway haplotype was associated with a diagnosis of asthma in our cohort but allele and genotype were not. Subgroup evaluations may also be important. Further studies are needed to determine the potential biological/clinical significance of our findings.

Keywords: ABP1; HDC; HNMT; HRH 1; HRH4; mRNA expression; single nucleotide polymorphisms.

Figure 1

Comparison of the variant allele frequency of single nucleotide polymorphisms ABP1 47C→T, HNMT 314C→T, and HDC 92C→T between African American and Caucasian participants * p<0.05, *** p<0.001

Figure 2

Comparison of genotype frequencies between males and females for HRH1 -17C→T and ABP1 47C→T Panel A: Comparison of ABP1 47 genotype frequency between males and females; ABP1 47 TT genotype more common in females p=0.004 Panel B: Comparison of HRH1-17 genotype frequency between males and females; HRH1-17 genotype more common in females (not present in males) p =0.049

Figure 2

Comparison of genotype frequencies between males and females for HRH1 -17C→T and ABP1 47C→T Panel A: Comparison of ABP1 47 genotype frequency between males and females; ABP1 47 TT genotype more common in females p=0.004 Panel B: Comparison of HRH1-17 genotype frequency between males and females; HRH1-17 genotype more common in females (not present in males) p =0.049

Figure 3

Comparison of HNMT 314C→T genotype between those with and without asthma among male participants. The CT genotype was not represented among males without asthma p=0.04

Figure 4

Comparison of Log HRH1 mRNA expression of relative to ABP1 995C→T genotypes in subjects 12 years or older. Subjects with ABP1 995 genotypes containing variant allele T (CT and TT) conferred increased HRH1 expression with an observed dose response for these genotypes. p=0.04