Genetics and Epigenetics of Aldehyde Dehydrogenase (ALDH2) in Alcohol Related Liver Disease

Alcohol dependence and cirrhosis are key outcomes of excessive alcohol use. We studied the interaction between genetics and epigenetics at the aldehyde dehydrogenase (ALDH2) locus to understand differences in vulnerability to cirrhosis. Individuals were selected according to ICD 10 criteria for Alcohol dependence with Cirrhosis (AUDC+ve, N=116) and Alcohol dependence but without Cirrhosis; (AUDC-ve, N=123) from the clinical services of Gastroenterology and Psychiatry at the St Johns Medical College Hospital (SJMCH). Fibroscan/sonographic evidence was used to rule out fibrosis for the AUDC-ve group. Genomic DNA from blood was used for genotyping at ALDH2 (rs2238151) locus. A subset of the samples was assessed for DNA methylation (AUDC+ve, N=50; AUDC-ve, N=50) at the LINE-1 and ALDH2 CpG loci by pyrosequencing on a PyroMark Q24. LINE1 DNA methylation did not differ between the groups. ALDH2 DNA methylation was significantly lower in AUDC+ve group compared to AUDC-ve group (P <0.001). Lower methylation in T-allele carriers compared to T-allele non-carriers of the ALDH2 locus (rs2238151) was observed in AUDC+ve subjects (P=0.009). Compromised methylation in blood DNA at candidate loci, in those with liver disease in the context of prolonged severe alcohol abuse, could be explored as a biomarker for current pathology, and further progression.