Host Genetic Variant in CXCL16 May Be Associated With Hepatitis B Virus–Related Acute Liver Failure

摘要

Hepatitis B virus (HBV) infection affects 1.25 million persons in the United States and approximately 250 million persons worldwide.1Schweitzer A. et al.Lancet. 2015; 386: 1546-1555Abstract Full Text Full Text PDF PubMed Scopus (1804) Google Scholar In persons exposed to HBV as adults, chronic infection is uncommon (<10%), but increases the risk for cirrhosis and hepatocellular carcinoma. The remainder of cases experience spontaneous clearance of HBV with acute self-limited hepatitis. However, in fewer than 1% of cases, acute infection with HBV can cause acute liver failure (ALF) with unfavorable outcomes.2Reuben A. et al.Ann Intern Med. 2016; 164: 724-732Crossref PubMed Scopus (204) Google Scholar The factors that contribute to a chronic or fulminant course, rather than self-limited and resolving hepatitis, remain poorly understood. Efforts to identify unique molecular signatures in the hepatitis B genome responsible for HBV ALF have been unrewarding to date despite early evidence that unique precore mutations may be associated with ALF.3Liang T.J. et al.N Engl J Med. 1991; 324: 1705-1709Crossref PubMed Scopus (430) Google Scholar Host genetic analysis of chronic HBV has been performed only in individuals of Asian descent and examination of exome arrays of patients with HBV ALF have not been published. By comparing 2 extreme phenotypes, HBV ALF with chronic HBV infection in adults of European descent, we evaluated exome arrays to explore the host factors underlying the wide-ranging response to HBV infection. All of the study participants were white and of European descent. Fifty participants with chronic HBV were identified. Initially, 14 cases of HBV ALF were identified and underwent exome array testing. Two additional HBV ALF patients were identified later and only underwent polymerase chain reaction for rs2277680. The shared control population comprised 2963 patients with exome chip data. The additional populations explored with polymerase chain reaction genotyping for rs2277680 included 16 patients with acute hepatitis B without ALF (non-ALF aHB) and 4 acute-on-chronic HBV reactivations leading to HBV ALF (CHBV ALF) cases (Figure 1). The exome array results with P < 1 × 10-4 were reviewed to find exploratory genes for future study. No polymorphisms met the threshold for exome-wide significance (P < 5 × 10-7). When comparing the HBV ALF population with the general population controls, rs147992634 in LAMB4, rs9894429 in NPLOC4, and rs1195569 in RIMBP2 had increased minor allele frequencies in the HBV ALF patients, and rs2277680 and rs1050998 in chemokine ligand 16 (CXCL16) had decreased minor allele frequencies and met the prespecified threshold of P < 1 × 10-4, but not exome-wide significance (Supplementary Table 1). When comparing the adult-acquired chronic hepatitis B (CHB) population with the control population, 14 loci were identified with a P < 1 × 10-4 for rs58022607, rs201682692, rs72669494, rs2199291, rs73134074, rs57168946, rs1000960, rs11539377, rs143596619, rs56195264, rs7192086, rs45602538, rs73365341, and rs9668527 (Supplementary Table 2), however, again, none met the threshold for exome-wide significance. When comparing the HBV ALF population with the CHB population only rs62417812 in MANEA and rs3849969 in SEC24C were associated with P < 1 × 10-4, but not exome-wide significance (Supplementary Table 3, Supplementary Table 4, Supplementary Table 5). We evaluated the published literature regarding the aforementioned candidate genes. MANEA and SEC24C, which catalyze the release of oligosaccharides in the Golgi and are involved in vesicle trafficking, respectively, did not have a clear putative impact on HBV pathogenesis. CXCL16 is a chemokine that interacts with chemokine receptor CXCR6 and is induced by inflammatory cytokines. Natural killer T (NKT) cells are recruited to the hepatic sinusoids in response to the secretion of CXCL16, which is produced by multiple intrahepatic cells. We subsequently focused on t