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.

Keywords: asthma; genetics; histamine.

Figure 1.

Differences observed in the HRH1-17 TT genotype between allergic and nonallergic asthma phenotype. The frequency of the HRH1-17 variant TT genotype between allergic and nonallergic children differed; the homozygous variant genotype was not present in the nonallergic groups (0.06 allergic versus 0 nonallergic children; P = 0.03). N.D. indicates that the genotype was not detected in that group.

Figure 2.

Differences observed in HNMT-464 and HNMT-1639 genotype frequencies between participants with allergic versus nonallergic asthma. The HNMT-464 homozygous variant TT and HNMT-1639 TT genotype frequencies differed between children with allergic and nonallergic asthma: HNMT-464 TT genotype 0.41 allergic versus 0.29 nonallergic, P = 0.04 (after adjustment for race, P = 0.03); HNMT-1639 TT genotype 0.3 allergic versus 0.2 nonallergic after adjustment for race, P = 0.04.

Figure 3.

Differences in genotype frequencies relative to asthma phenotype among stratified African-American and white children. (A) African-American subjects with allergic asthma more commonly possessed the variant homozygous genotype for HRH1-17 (TT = 0.13) than those with nonallergic asthma (TT = 0) (P = 0.04; P = 0.04 from recessive genotype model analysis). The HNMT-1639 TT genotype was more frequent among African-American subjects with allergic asthma than nonallergic asthma (TT = 0.23 allergic asthma versus TT = 0.03 nonallergic asthma; P = 0.03 and P = 0.02 for recessive genotype model analysis). N.D. indicates that the genotype was not detected in that group. (B) In white children the ABP1 4107 GG genotype frequency differed between allergic and nonallergic participants (0.18 nonallergic versus 0.05 allergic; P = 0.04 for both genotype and recessive model genotype analyses).