147-P

Abstract

Gene expression levels are regulated by genetic variants and environmental exposures. HLA gene expression levels have not been analyzed using modern tools. We aimed to initiate a series of experiments to assess the degree of variation and its determinants in classic HLA genes. On 16 IHWG B-LCLs representing common CEHs, we assessed baseline mRNA levels of HLA-B, -DRA and -DQA1 genes by TaqMan assays using GUSB and EIF4EBP2 as the recommended normalizers for B-LCLs. We first confirmed the validity of the experimental system by confirming heat-shock-induced changes in HSPA1B expression. CEH13.1 (B13DR7) had the highest expression level at HLA-B, -DRA and -DQA1, while another DRB1 ∗ 07 haplotype CEH44.3 (B44DR7) has consistently low expression of the same genes. The expression levels of DQA1 showed the greatest variation with hundreds-fold differences among expression levels. The cell lines homozygous for DQA1 ∗ 01 (HLA-DRB1 ∗ 01/08/11:01/13/15) had the highest expression levels along with the HLA-B7:DR7 (DR53) haplotype. The other DR7 haplotypes and the rest of the DR53 haplotypes had much lower DQA1 expression together with the DRB1 ∗ 11:02 and B ∗ 08/B ∗ 18-DR3 haplotypes. The DQA1 3′UTR polymorphism (rs1142316) that splits HLA class II haplotypes in evolutionarily related lineages showed a strong correlation with DQA1 expression levels (average ranking were 7.1 for allele C and 14.7 for allele A; Spearman’s P = 0.007). The most ancient locus in the HLA class II region shows an extra-ordinary level of variation in its expression that correlates with ancestral class II haplotypic lineages and is likely to be relevant in disease associations These findings have important implications in disease association studies. Genome-wide association studies are currently analyzed at single SNP level or for high-resolution HLA-DRB1 alleles. The few existing markers should be supplemented by more refined joint markers of ancestral lineages to extract further information from such studies.