Histamine Pharmacogenomics

Genetic polymorphisms for histamine-metabolizing enzymes are responsible for interindividual variation in histamine metabolism and are associated with diverse diseases. Initial reports on polymorphisms of histamine-related genes including those coding for the enzymes histidine decarboxylase (HDC), diamine oxidase (ABP1) and histamine N-methyltransferase (HNMT), as well as histamine receptor genes, often have pointed to polymorphisms that occur with extremely low frequencies or that could not be verified by later studies. In contrast, common and functionally significant polymorphisms recently described have been omitted in many association studies. In this review we analyze allele frequencies, functional and clinical impact and interethnic variability on histamine-related polymorphisms. The most relevant nonsynonymous polymorphisms for the HDC gene are rs17740607 Met31Thr, rs16963486 Leu553Phe and rs2073440 Asp644Glu. For ABP1 the most relevant polymorphisms are rs10156191 Thr16Met, rs1049742 Ser332Phe, and particularly because of its functional effect, rs1049793 His645Asp. In addition the ABP1 polymorphisms rs45558339 Ile479Met and rs35070995 His659Asn are relevant to Asian and African subjects, respectively. For HNMT the only nonsynonymous polymorphism present with a relevant frequency is rs1801105 Thr105Ile. For HRH1 the polymorphism rs7651620 Glu270Gly is relevant to African subjects only. The HRH2 rs2067474 polymorphism, located in an enhancer element of the gene promoter, is common in all populations. No common nonsynonymous SNPs were observed in the HRH3 gene and two SNPs were observed with a significant frequency in the HRH4 gene: rs11665084 Ala138Val and rs11662595 His206Arg. This review summarizes relevant polymorphisms, discusses controversial findings on association of histamine-related polymorphisms and allergies and other diseases, and identifies topics requiring further investigation.