rs7770370 — HLA-DPB1

HLA-DPB1 rs7770370 — A Gatekeeper Haplotype for Hepatitis B Immunity

When the hepatitis B virus enters the body, the immune system must decide within weeks whether to mount a clearing response or allow the infection to persist for life. That decision hinges heavily on HLA class II antigen presentation¹¹ HLA class II antigen presentation
The process by which antigen-presenting cells — dendritic cells, macrophages, B cells — display viral peptide fragments on MHC class II molecules to CD4+ T helper cells, initiating adaptive immunity. rs7770370 sits within the HLA-DPB1 gene on chromosome 6p21 and marks a haplotype block that controls how efficiently the immune system presents HBV antigens. The G allele at this position tags a low-expression HLA-DP haplotype — carriers produce fewer HLA-DP antigen-presenting complexes, mount weaker T-cell responses to HBV, and face significantly higher odds of chronic infection and vaccine non-response.

The Mechanism

HLA-DP is a heterodimeric surface receptor composed of an alpha chain (HLA-DPA1) and a beta chain (HLA-DPB1), expressed on antigen-presenting cells including the Kupffer cells and dendritic cells of the liver. It binds viral peptide fragments in its groove and displays them to CD4+ T helper cells²² CD4+ T helper cells
The immune cells that coordinate both antibody production by B cells and activation of CD8+ cytotoxic T cells — the two arms of adaptive immunity needed to clear HBV. rs7770370 is an intronic variant in HLA-DPB1 that does not change the protein sequence — instead, it acts as a tag SNP³³ tag SNP
A marker in strong linkage disequilibrium with the functional haplotype; it doesn't cause the effect itself but reliably identifies carriers of the causally relevant low-expression haplotype for a haplotype including the eQTL variants rs3077 (HLA-DPA1 3′ UTR) and rs9277535 (HLA-DPB1 3′ UTR), both of which directly reduce HLA-DP mRNA expression. The G allele at rs7770370 co-segregates with the G allele at rs3077 and the A allele at rs9277535 — the combination associated with the lowest HLA-DPA1 and HLA-DPB1 surface density on liver antigen-presenting cells. With fewer HLA-DP molecules available, HBV peptide display to CD4+ T cells is impaired, T-helper activation is blunted, antibody production against the HBV surface antigen (anti-HBs) is reduced, and cytotoxic T-cell killing of infected hepatocytes is diminished.

The Evidence

Wu et al. (2015)⁴⁴ Wu et al. (2015)
SNP rs7770370 in HLA-DPB1 loci as a major genetic determinant of response to booster hepatitis B vaccination. J Gastroenterol Hepatol performed the first GWAS specifically focused on rs7770370, studying 15- to 18-year-olds who had received primary HBV vaccination in infancy but failed to maintain protective antibody levels. Among HLA-DP candidate SNPs in a 47 kb block, rs7770370 was the sentinel signal: AA homozygotes had an adjusted odds ratio of just 0.095 (CI 0.030–0.307) for vaccine non-response relative to GG homozygotes — a greater than 10-fold difference — while AG heterozygotes showed a 2-fold advantage (OR 0.524). This quantified the G allele as the dominant genetic driver of long-term vaccine failure in this population.

Roh et al. (2016)⁵⁵ Roh et al. (2016)
HLA-DP variants and hepatitis B vaccine responsiveness in Korean infants. Vaccine extended the finding to 290 infants (the primary vaccination setting), showing that the AA genotype was associated with vaccine response (relative risk 2.5, p=0.033) and with high-titer response specifically (RR 2.7, p<0.001). The A allele was significantly more frequent in responders (p<0.01), confirming the genotype predicts immunogenicity from the very first vaccination series.

For chronic HBV infection susceptibility, Huang et al. (2020)⁶⁶ Huang et al. (2020)
Taiwan Biobank GWAS of 15,352 HBV-exposed participants. Aliment Pharmacol Ther identified rs7770370 as the single most significant HLA class II signal for HBV chronicity (P=2.73×10⁻³⁵, Pcorrected <8.6×10⁻⁸). The HLA-DPB1*05:01 allele — in strong LD with the G allele — conferred OR 1.61 (CI 1.29–2.01) for chronic HBV. In a Thai GWAS, Ashouri et al. (2022)⁷⁷ Ashouri et al. (2022)
Genome-wide Association Study for Chronic Hepatitis B in the Thai Population. Front Genet independently replicated the association (p=7.71×10⁻¹⁰, OR=0.49 for the protective A allele). The association is present across Asian, European, and mixed-ancestry cohorts, though the G allele is far more common in populations with historically high HBV endemicity — about 46–54% in East Asians and Africans versus only 13% in Europeans — a pattern consistent with ongoing selection pressure from the virus.

Practical Actions

The key clinical implication is twofold: vaccine response and infection susceptibility. G-allele carriers — especially GG homozygotes — are at substantially higher risk of failing to develop protective antibodies after standard HBV vaccination, and of progressing to chronic infection if exposed. The appropriate actions are checking post-vaccination antibody titres and, for those with exposure risk, baseline serology and follow-up for signs of chronicity.

For those already identified with chronic HBV infection, the HLA-DP haplotype also predicts treatment response dynamics — AA haplotype carriers have better HBsAg seroclearance during nucleot(s)ide analogue therapy, making genotype relevant to hepatologist treatment planning.

Interactions

rs7770370 is part of the same HLA-DP haplotype block as rs3077 (HLA-DPA1 3′ UTR) and rs9277535 (HLA-DPB1 3′ UTR). These three variants tag a low-expression haplotype that produces reduced HLA-DPA1 and HLA-DPB1 mRNA. The combined protective haplotype (A allele at rs3077 and A allele at rs9277535) shows a stronger additive protective effect against chronic HBV (OR 0.57 in Indonesian replication, CI 0.36–0.92) than either variant alone. Profiling all three SNPs together provides the most complete picture of HLA-DP expression and HBV susceptibility in a given individual. Each additional G allele across this haplotype incrementally reduces HLA-DP surface density and immune clearance capacity.