Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

Abstract

Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2 -resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes -is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (V max /K m ) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30-50% of whom possess the inactive ALDH2*2 mutant allele.

ALDH2 genetic polymorphism and the risk of type II diabetes mellitus in CAD patients

“…23,24 Previous studies showed that ALDH2 activity from either genotype *1/*2 or *2/*2 decreased significantly compared with that of the ALDH2 *1/*1 genotype. 23 Our study showed that 43.2% and 32.7% of CAD patients and subjects without CAD and DM, respectively, had the ALDH2 *2 allele; most subjects with the ALDH2 *2 allele were heterozygous (38.9% in CAD patients and 30.7% in subjects without CAD and DM). Owing to the similar activities of ALDH2 *1/*2 and *2/*2 alleles and the characteristic of genetic polymorphism distribution in the Chinese, we considered ALDH2 genotypes *1/*2 and *2/*2 as a group, which was then compared with genotype *1/*1 in this study.…”

“…Another recent study revealed that the dehydrogenase activities for ALDH2 *2/*2 and *1/*2 were only 2-15% of the ALDH2 *1/*1 activity. 23 Previous studies have shown that oxidative stress was an important consequence of inflammation, and inflammation influenced insulin resistance significantly. 39,40 We hypothesized that ALDH2 from different genotypes might influence insulin resistance, ALDH2 genetic polymorphism and the risk of T2DM in CAD patients F Xu et al FPG and subsequent DM by a different effect on inflammation.…”

“…22 Acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme of alcohol metabolism, shows a significant variation in a single-nucleotide polymorphism (SNP) in East Asians (30-50% with the ALDH2 mutant allele) compared with Caucasians (lower than 5%). 23,24 ALDH2 is mainly located in the mitochondria and is encoded by the ALDH2 gene on chromosome 12. The ALDH2 gene is composed of 13 exons.…”

“…The ALDH2 gene is composed of 13 exons. In exon 12, there is a G-to-A missense mutation in which glutamate at position 504 is replaced by lysine (Glu504Lys); hence, there are two ALDH2 alleles (Glu504 and Lys504, also named *1 and *2, respectively, in many classic papers 23,24 ) and three combinations, namely, *1/*1 (wide-type homozygote), *1/*2 (heterozygote) and *2/*2 (mutant homozygote), in the population.…”

Asian flushing presents opportunities for disease prevention

“…The relative deficiency is responsible for facial flushing, headaches, nausea, dizziness, and cardiac palpitations after alcohol consumption. The ALDH2*2 polymorphism also contributes to variation in efficacy of sublingual nitroglycerin [3]. For allele carriers, the symptoms are a convenient "stopping signal" after alcohol ingestion.…”