Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma

Abstract

Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n = 10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P < 0.05 and false-positive report probability. After correction for race differences in genotype were observed, HRH1-17 TT (6% allergic versus 0% nonallergic; P = 0.04), HNMT-464 TT (41% allergic versus 29% nonallergic; P = 0.04), and HNMT-1639 TT (30% allergic versus 20% nonallergic; P = 0.04) were overrepresented among children with allergic asthma. Genotype differences specifically among the African-American children were also observed: HRH1-17 TT (13% allergic versus 0% nonallergic; P = 0.04) and HNMT-1639 TT (23% allergic versus 3% nonallergic; P = 0.03) genotypes were overrepresented among African-American children with allergic asthma. Our study suggests that genetic variation within the histamine pathway may be associated with an allergic versus nonallergic asthma phenotype. Further studies are needed to determine the functional significance of identified SNPs and their impact on antihistamine response in patients with asthma and allergic disease.

Genetic Variation in the Histamine Production, Response, and Degradation Pathway Is Associated with Histamine Pharmacodynamic Response in Children with Asthma

“…Our current findings suggest that the variant may result in decreased expression/function of the enzyme leading to histamine accumulation and exaggerated response to histamine which we observed in our study. We previously found that HNMT -1639 was associated with the allergic asthma phenotype in African American children (Anvari et al, 2015). Therefore, this SNP may have significance in disease pathophysiology and severity particularly among specific racial groups.…”

“…We also conducted a stratified analysis among the two major racial groups included in the study (African American and Caucasian) due to our previous findings that histamine genotype was most strongly associated with allergic asthma phenotype in African American children (Anvari et al, 2015). Furthermore, the contributions of histamine to disease are particularly important to understand among African American children due to increased asthma prevalence, morbidity, and mortality in this group when compared to other racial groups as well as an increased prevalence of the allergic asthma phenotype (Akinbami, 2006).…”

“…We did not observe an association between histamine genetic variation and non-phenotyped asthma. However, histamine pathway genotype was associated with the allergic asthma phenotype (Anvari et al, 2015; Raje et al, 2015). As 50–80% of those with asthma are reported to have allergic asthma, understanding the contributions of histamine and genetic variation within the histamine pathway are important.…”

“…Single nucleotide polymorphisms (SNP) in these genes have been associated with asthma and allergic disease in children and adults of different racial and ethnic populations. We have previously observed that variants in HRH1 and HNMT were associated with allergic asthma in children and specifically among African American children (Anvari et al, 2015). Although, several SNPs have been associated with allergic disease and asthma, the functional relevance of the majority of variants is unknown.…”

Population pharmacokinetic/pharmacodynamic modeling of histamine response measured by histamine iontophoresis laser Doppler

“…Early investigation of Laser Doppler flowimetry have revealed minimal differences related to age and race [18]. Presumed race related differences may instead be related to observed genetic variation in the histamine production, response, and degradation pathway [19]. The advanced model provides a much more precise way to describe the variability of histamine response in population and suggests broader application of HILD method in allergy pharmacodynamic research.…”