HLA Class II Protein Expression Regulation Is Strongly Linked to Cis-Acting SNPs

Allele-specific variability in HLA class I gene expression levels has been associated with many diseases. Although expression variation at the allelic level has not been well-characterised for the HLA class II genes, differential expression of these genes, as marked by single nucleotide polymorphisms (SNPs), has been implicated in the outcome of several diseases. Here, we measured cell surface expression levels of distinct HLA-DR, HLA-DQ and HLA-DP allotypes in 175 healthy European American donors using locus-specific antibodies. We identified allotype-specific variation in the intrinsic cell surface expression levels. To further characterise genetic associations with differential protein expression levels of the HLA class II molecules, we performed a genome-wide association study (GWAS). This showed that surface expression levels of HLA-DR, HLA-DQ and HLA-DP associated most significantly with rs28383323 (p = 3.9 × 10^-10), rs281860696 (p = 2.2 × 10^-5) and rs3128928 (p = 1.3 × 10^-8), respectively. Two SNPs, rs3128927 and rs9277534, were previously reported to associate with HLA-DP protein expression and hepatitis B virus (HBV) recovery/persistence. We show that rs3128928, which resides in the COL11A2P1 pseudogene, associates most significantly with HLA-DP protein expression, whereas the neighbouring rs3128927 associates most significantly with HBV recovery/persistence. Thus, protein expression levels of HLA-DR, DQ and DP appear to be controlled by cis-elements that do not mark specific alleles. This finding may help to distinguish disease associations caused by specific HLA allelic effects vs. protein expression levels.