Mannose Binding Lectin Genotypes Influence Recovery from Hepatitis B Virus Infection

Abstract

Mannose binding lectin (MBL) is a central component of the innate immune response and thus may be important for determining hepatitis B virus (HBV) persistence. Since single-nucleotide polymorphisms (SNPs)in the gene encoding MBL (mbl2) alter the level of functional MBL, we hypothesized that mbl2 genotypes are a determinant of HBV persistence or recovery from viral infection. We tested this hypothesis by using a nested case control design with 189 persons with HBV persistence matched to 338 individuals who had naturally recovered from HBV infection. We determined genotypes of two promoter and three exon 1 SNPs in mbl2 and grouped these genotypes according to the amount of functional MBL production. We found that the promoter SNP ؊221C, which leads to deficient MBL production, was more common in those subjects with viral persistence (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.01 to 1.89; P ‫؍‬ 0.04). Those subjects homozygous for the combination of promoter and exon 1 genotypes associated with the highest amount of functional MBL had significantly increased odds of recovery from infection (OR, 0.55; 95% CI, 0.37 to 0.84; P ‫؍‬ 0.005). Conversely, those homozygous for the combination of promoter and exon 1 genotypes which produce the lowest amount of functional MBL were more likely to have viral persistence (OR, 1.76; 95% CI, 1.02 to 3.01; P ‫؍‬ 0.04). These data are consistent with the hypothesis that functional MBL plays a central role in the pathogenesis of acute hepatitis B.Chronic hepatitis B infection affects 400 million people and is the most common cause of cirrhosis and hepatocellular carcinoma worldwide. Although most adults recover from acute hepatitis B virus (HBV) infection, it is not fully understood why some develop chronic hepatitis B. The strength and breadth of the host immune response are important (3, 30), and recent data from chimpanzees and transgenic mice suggest that differences in innate immunity affect recovery from HBV infection (11,16).Mannose binding lectin (MBL) plays a central role in the innate immune response (32). mbl2, which encodes MBL, is located on chromosome 10 and consists of four exons (Fig. 1). Several single-nucleotide polymorphisms (SNPs) in the gene's promoter and in exon 1 that ultimately reduce the level of functional MBL have been described (8). Reduced MBL concentrations have been linked with diminished responses to several infectious diseases, including human immunodeficiency virus (HIV) infection and recurrent infections, and higher levels have been linked with inflammatory outcomes such as vascular complications of diabetes mellitus (5, 12, 24, 29). Although one exon 1 SNP has been associated with HBV persistence (31), this gene and its functionally different haplotypes have not been comprehensively examined in persons infected with HBV.We hypothesized that the mbl2 SNPs that reduce functional MBL levels would be found more often in persons with HBV persistence and vice versa. To test this hypothesis, we determined genotypes of the promoter SNPs at Ϫ5...

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