Objective: To analyze the occurrence and the functional effects of nonsynonymous single nucleotide polymorphisms in the human diamine oxidase (ABP1) gene.
Methods: Genomic DNA from 134 healthy Caucasian individuals was analyzed for three nonsynonymous single nucleotide polymorphisms in the ABP1 gene. Serum diamine oxidase activity was studied in 37 individuals with known ABP1 genotype.
Results: Variant ABP1 alleles leading to the amino-acid substitutions Thr16Met, Ser332Phe and His645Asp were identified with frequencies of 25.4, 6.3 and 30.6%, respectively. Over 70% of the population (95% confidence interval, 62.4-77.9%) carry at least one amino-acid substitution. Each amino-acid substitution was at Hardy-Weinberg's equilibrium, but linkage disequilibrium between variant alleles was observed. The percentage of individuals carrying simultaneously the three amino-acid substitutions in heterozygosity or homozygosity (9%, 95% confidence interval, 4.2-13.8%) was over three times that expected from a random association (P<0.05). Individuals carrying the 645Asp amino acid displayed lower serum diamine oxidase activity as compared with noncarriers (P<0.001) with a significant gene-dose effect (P<0.05). This was due to an increase in the Michaelis-Menten constant. Individuals heterozygous for 645Asp show Vmax/Km values of 66% and homozygous 51% as compared with noncarriers. The effect of the 16Met variant allele was lower and that of the rarest allele 332Phe was negligible.
Conclusion: Nonsynonymous ABP1 gene polymorphisms are common in humans; they cause relevant functional effects and can be considered as major determinants of variability for human diamine oxidase activity.