Phenotyping aldehyde metabolism in humans uncovers novel genetic mutations in aldehyde dehydrogenase 2

Inefficient aldehyde metabolism by an aldehyde dehydrogenase 2 (ALDH2) genetic variant, ALDH2*2 (rs671), increases the risk of esophageal cancer with alcohol consumption. Here we tested the hypothesis that additional genetic differences in ALDH2 besides ALDH2*2 exist resulting in inefficient acetaldehyde metabolism after alcohol consumption. Human volunteers were recruited who self-reported flushing after alcohol. The first stage recruited East Asians and the second stage non-East Asians. After phone screening and ALDH2 sequencing, volunteers were subjected to an alcohol challenge (0.25g/kg). Physiological parameters and breath acetaldehyde levels were assessed. Twenty-six participants were given an alcohol challenge. In the first stage, when comparing the ALDH2*1/*2 genotype to ALDH2*1/*1 genotype, tachycardia (104{+/-}3* versus 73{+/-}4 beats per minute), increases in facial skin temperature (99.6{+/-}0.4* versus 95.9{+/-}0.50F), and increases in breath acetaldehyde (peak: 2.1{+/-}0.4* versus 0.2{+/-}0.3ppm, n=8/group, *p<0.01) occurred after alcohol consumption. In the second stage, heterozygotes for an ALDH2 intron variant (rs4646777, G>A) caused increases in facial skin temperature (98{+/-}1* versus 94{+/-}10F, n=4, *p<0.01) without tachycardia or acetaldehyde accumulation after alcohol consumption. Subjects self-identifying as non-East Asian genotyped with an ALDH2*1/*2 variant also displayed a characteristic ALDH2*1/*2 phenotype after alcohol consumption. Further, ALDH2 point mutations rs747096195 (R101G) and rs190764869 (R114W) showed reduced acetaldehyde metabolism and increases in facial skin temperature after an alcohol challenge relative to wild type ALDH2 subjects. Taken together, we developed a method to non-invasively phenotype genetic differences for ALDH2 in humans including quantifying aldehyde metabolism in single subjects. We also discovered genetic differences besides ALDH2*2 that cause inefficient aldehyde metabolism. Brief SummaryWe developed a method to phenotype genetic differences in ALDH2 and we discovered novel ALDH2 mutations that result in inefficient acetaldehyde metabolism after alcohol consumption.