Human HistamineN-Methyltransferase Pharmacogenetics: Common Genetic Polymorphisms that Alter Activity

Abstract

Histamine N-methyltransferase (HNMT) catalyzes a major pathway in histamine metabolism. Levels of HNMT activity in humans are regulated by inheritance. We set out to study the molecular basis for this genetic regulation. Northern blot analysis showed that HNMT is highly expressed in the kidney, so we determined levels of enzyme activity and thermal stability in 127 human renal biopsy samples. DNA was isolated from 12 kidney samples with widely different HNMT phenotypes, and exons of the HNMT gene were amplified with the polymerase chain reaction. In these 12 samples, we observed a C314T transition that resulted in a Thr105Ile change in encoded amino acid, as well as an A939G transition within the 3'-untranslated region. All remaining renal biopsy samples then were genotyped for these two variant sequences. Frequencies of the alleles encoding Thr105 and Ile105 in the 114 samples studied were 0.90 and 0.10, respectively, whereas frequencies for the nucleotide A939 and G alleles were 0.79 and 0.21, respectively. Kidney samples with the allele encoding Ile105 had significantly lower levels of HNMT activity and thermal stability than did those with the allele that encoded Thr105. These observations were confirmed by transient expression in COS-1 cells of constructs that contained all four alleles for these two polymorphisms. COS-1 cells transfected with the Ile105 allele had significantly lower HNMT activity and immunoreactive HNMT protein than did those transfected with the Thr105 allele. These observations will make it possible to test the hypothesis that genetic polymorphisms for HNMT may play a role in the pathophysiology of human disease.

Lack of association of histamine-N-methyltransferase (HNMT) polymorphisms with asthma in the Indian population

“…An earlier study identified the C314T polymorphism as the functional variant within this gene (Preuss et al 1998). This polymorphism has previously been shown to reduce the enzymatic activity (Preuss et al 1998) and to represent a risk for asthma in the Caucasian population (Yan et al 2000a). Yan et al (2000a) found a significant increase in Fig.…”

“…In our initial genotyping, the A595G was found to be nonpolymorphic (N=200). Similarly, this variant was also not detected in the study conducted in the Caucasian population (Preuss et al 1998). For the C314T SNP, the distribution of the 314A and 314T alleles was found to be similar in cases and controls (LR v 2 =0.22, d.f.=1, P=0.64).…”

“…Furthermore, when we stratified the patient samples into mild, moderate, and severe on the basis of FEV 1 values (FEV 1 ‡80% predicted classified as mild, 60-80% as moderate, and £ 60% as severe disease), no difference was observed with respect to the distribution of alleles/ genotypes in the three groups (data not shown). An earlier study identified the C314T polymorphism as the functional variant within this gene (Preuss et al 1998). This polymorphism has previously been shown to reduce the enzymatic activity (Preuss et al 1998) and to represent a risk for asthma in the Caucasian population (Yan et al 2000a).…”

“…A functional single nucleotide polymorphism (SNP), C314T, has been identified in the HNMT gene that results in an amino acid change (Thr105Ile). The 314T (Ile105) allele was associated with decreased levels of HNMT enzymatic activity (Preuss et al 1998). Therefore, the presence of the 314T allele might result in reduced histamine metabolism and may influence the susceptibility to develop bronchial hyperresponsiveness (BHR), a hallmark of asthma.…”

Phase II Drug Metabolism

“…HNMT is widely expressed in human tissues; the greatest expression is in the liver and kidney, but also in the spleen, colon, prostate, ovary, brain, bronchi, and trachea (Maintz & Novak, 2007). Common genetic polymorphisms for HNMT might be related to a possible role for individual variation in histamine metabolism in the pathophysiology of diseases such as allergy, asthma, peptic ulcer disease, and some neuropsychiatric illnesses (Preuss et al, 1998). Phenylethanolamine N-methyltransferase (PNMT) plays a role in neuroendocrine and blood pressure regulation in the central nervous system.…”