On the basis of findings for both genome-wide mRNA expression and allelic expression imbalance, it seems that SNPs rs3077 and rs9277535 are strongly associated with regulation of HLA-DPA1
, respectively. Previous studies found that these SNPs were highly associated with chronic HBV infection.2, 3
Together, these independent studies strongly implicate lower expression of HLA-DPA1
with increased risk of chronic HBV.
HLA-DPA1 and HLA-DPB1 are expressed on the surface of antigen-presenting cells. In the liver, expression of these proteins is likely to be limited to a small population of Kupffer cells, the resident macrophages of the liver. Kupffer cells are derived from blood monocytes, and we observed evidence for AEI in both monocytes and liver samples. We found that mRNA expression of both HLA-DPA1
was low in total human liver tissue, suggesting that it might be limited to a specific sub-population of cells. We attempted to quantify protein expression in lysates from total liver tissue, but failed to detect a measurable signal (data not shown). Similarly, HLA-DPA1 and HLA-DPB1 protein expression was undetectable in liver tissue examined by antibody-based proteomic methods.11
It is intriguing that the genetic risk variants associated with chronic hepatitis B affect expression of the alpha (DPA) and beta (DPB) chains of the same antigen-presenting complex, as this suggests that insufficient expression of either or both of these chains might result in the same phenotype.
Kamatani et al.2
reported that chronic hepatitis B was associated with haplotypes comprised of rs3077-G, rs9277535-G and certain structural variants of HLA-DPA1
Our findings do not exclude a role for structural variants of HLA-DPA1
in chronic hepatitis B, as viral control of HBV could be affected by both regulatory and structural variants. For example, functional variants of MBL2
, which has an important role in host defense against HIV-1 and other infectious agents, include both regulatory and structural variants.12
On a genome-wide basis, rs3077 is the variant most strongly associated with risk of chronic hepatitis B and the variant most strongly associated with expression of HLA-DPA1.
It seems highly likely, therefore, that expression of HLA-DPA1
has a role in the clearance of HBV. Similarly, the association of rs9277535 with chronic HBV and with HLA-DPB1
expression suggests that HLA-DPB1
expression also contributes to chronic HBV infection.
Kamatani et al.2
noted that the HBV risk alleles for rs3077 and rs9277535 are more common in Asians than Europeans (fitting the global pattern for the epidemiology of chronic hepatitis B). LD patterns in this genomic region are very similar for populations of Asian or European ancestry groups (), indicating that the relationships between SNPs in this region are comparable between these two ancestral groups even though the allele frequencies differ.
We could not determine why the rs3077 and rs9277535 variants are associated with decreased mRNA expression of HLA-DPA1
in liver, but variants within the 3′ UTR may affect mRNA stability through binding of regulatory factors or regulation by microRNAs.13
SNP rs3077 was found to be associated with methylation level of HLA-DPB1
in adult cerebellum samples studied by Zhang et al.14
(see Supplementary Table 5 of that paper). It may also be noteworthy that rs9277535 was linked to two different copy-number variation regions in European HapMap subjects.15
We did not observe any obvious factors that could explain differential expression of HLA-DPA1
mRNA, but future studies should address this question.
SNPs rs3077and rs9277535 have been associated with other diseases. The rs9277535 variant has been linked to primary biliary cirrhosis.16
Both rs3077 and rs9277535 have been associated with rheumatoid arthritis,17
although other SNPs in the major histocompatibility complex class II region were more strongly associated with that disease.
In conclusion, genetic variants previously associated with chronic hepatitis B2
are also associated with decreased expression of an antigen-presenting complex that consists of HLA-DPA1
chains. Together, these independent studies strongly implicate lower expression of HLA-DPA1
as a factor for increased risk of chronic hepatitis B. Other recent studies have demonstrated a relationship between expression of HLA-C
and control of HIV.18, 19
It is possible, therefore, that HLA expression has a role in control of a range of viruses. More broadly, our findings lend support to the concept that SNPs identified through an integrated genomic approach can provide both confirmation and functional insights for disease associations.6, 20
If greater expression of HLA-DPA1
facilitate clearance of HBV infection, development of therapies that increase expression of these genes might aid in treatment of chronic hepatitis B.