Limitations of lymphoblastoid cell lines for functional analysis of SNPs

Single nucleotide polymorphisms (SNPs) are widely linked to the susceptibility and penetrance of diseases. SNP rs886205 (A/G) located in the aldehyde dehydrogenase 2 (ALDH2) promoter is associated with esophageal carcinoma in alcohol-dependent patients. Previously, we found an interaction of the SNP with the methylation of promoter regions as well as the protein levels of ALDH2 in alcohol-dependent patients. To study the DNA-protein interactions involved in rs886205 mediated regulation of ALDH2, we chose lymphoblastoid cell lines harboring AA/GA/GG genotype and acquired two for each genotype from National Human Genome Research Institute repository. We measured the promoter methylation of ALDH2 by using bisulfite sequencing and quantified protein expression of ALDH2 by western blot to compare the cell lines with the previous findings in patients.

DNA methylation showed significant differences not only based on genotype but also due to the different background of the cells owing to their origin from different individuals. Although ALDH2 protein expression seemed to be driven by the rs886205 genotype, results were not in consensus with data from the patient cohorts. Our findings show the limitations of the usage of lymphoblastoid cell lines due to the unavoidable background genetic differences that may influence the effect of SNP.