The histamine 1 and histamine 2 receptor genes—candidates for schizophrenia and clozapine drug response

Abstract

Introduction There is growing evidence to suggest the involvement of histaminergic pathways in the pathophysiology of schizophrenia. Overactive histamine activity is thought to contribute significantly to deficit symptoms such as apathy and social withdrawal associated with the disorder, while the efficacy of certain atypical antipsychotics may include their action at histamine receptors. By selecting the histamine 1 (H1) and histamine 2 (H2) receptor genes as candidates, the aim of this study was to investigate the possible involvement of these receptors both in schizophrenia and in the clinical response of patients undergoing clozapine treatment.

Method Using single strand conformation polymorphism (SSCP) analysis we screened the complete coding region of each receptor gene for mutations in 50 schizophrenics and 50 unaffected individuals. Automated sequencing was used to confirm the presence and nature of each detected polymorphism.

Results We report here the identification of five previously undescribed H1 receptor polymorphisms (Lys19Asn, Asp349Glu, 1068-A/G, Phe358Δ and Leu449Ser) and a single novel H2 receptor polymorphism (543-G/A). Initial analysis of these polymorphisms in case vs. control association studies revealed a significant increase in distribution of one, the H1Ser449 allele, in our control sample (13/97) compared with the group of schizophrenics (0/90), prompting further analysis of this polymorphism in an extended patient sample population. Overall we observed a trend towards increased frequency of this allele amongst our controls compared with the corresponding group of schizophrenics, though the significance was estimated to be marginal (χ² = 3.94, P = 0.047). Similarly, no conclusive evidence could be found to suggest the involvement of any other H1 and H2 receptor variants in schizophrenia or clozapine response. Further investigation of the five polymorphic H1 loci by haplotype analysis indicated a lack of association between these loci and both schizophrenia and clozapine response.

Conclusions These results suggest that histamine H1 and H2 receptor variants do not bear significant influence on the susceptibility of individuals to schizophrenia, nor do they appear to influence clinical response to clozapine treatment.