Introduction Genome Wide Association Studies (GWAS) revealed significant associations for SNPs mapping at the REL, GATA3 and TCF3 loci with cHL susceptibility. In this study, we aim to elucidate the susceptibility mechanism of these associations by establishing possible expression quantitative trait loci (eQTL) effects.
Methods EQTL analysis was performed in EBV transformed lymphoblastoid cell lines (LCLs) generated from 96 controls and 70 former cHL patients as well as in three previously published large gene expression studies of HRS cells and total HL tissue samples.
Results An eQTL effect for REL was found using cHL total tissue array data with increased REL expression levels for individuals carrying the homozygous risk allele. No significant effects were observed for the HRS cell data and for the LCLs. For GATA3 a significant association was found in the patient derived LCLs with lower GATA3 levels in LCLs of homozygous risk allele carriers, while no effect was observed for the control LCLs, or the HRS cell and the cHL total tissue array data. Only In the control LCLs lower TCF3 expression levels were found for individuals homozygous for the risk allele. To identify the downstream targets of these three transcription factors we performed gene expression arrays of cHL cell lines infected with shRNA constructs. We identified 1805, 1052, 1602 differentially expressed genes for REL, GATA3 and TCF3, respectively. eQTL analysis of the array data focusing only on these downstream targets is ongoing.
Conclusion For REL, GATA3 and TCF3 we observed an eQTL effect in at least one of the studied groups. For REL and TCF3 the eQTL pattern is consistent with the proposed susceptibility effects of these genes, i.e. higher REL levels stimulating cell growth and lower TCF3 levels supporting the loss-of-B-cell phenotype for the risk alleles. Surprisingly, for the T-helper 2 specific transcription factor GATA3 the risk allele is associated with decreased levels in B-cells, but apparently not in T-cells. Our data support a functional rol for the risk and protective SNP alleles in cHL susceptibility.