Abstract
In this month's issue of Genetic Testing and Molecular Biomarkers, our two leading articles support our quest to publish articles that unite the studies of human genetics with infectious disease biology. In the article by Li et al. “Association of Nucleostemin Polymorphisms with Chronic Hepatitis B Virus Infection in the Chinese Han Population,” the authors demonstrate that chronic hepatitis B virus (CHB) infection—which often leads to liver cancer—is significantly associated with three single nucleotide polymorphisms (SNPs) in the Nucelostemin (NS) gene that is also referred to the G protein nucleolar 3 (GNL3) gene (https://www.ncbi.nlm.nih.gov/gene/26354).
The NS/GNL3 protein has been shown to concentrate in the nucleolus of stem cells and tumor cells and to play a role in cell-cycle progression (Lin et al., 2008). Lin et al. (2019) have posited that NS/GLN3 is a member of a tumor-promoting genome maintenance program required for tumor progression and have demonstrated it possesses multiple features associated with tumorigenesis and that its mechanism of action appears to be supportive of the homologous repair (HR) system of DNA. This is because NS-deficient cells demonstrate a significantly reduced HR activity. Paradoxically, its expression levels display a triphasic phenotype.
Both low and high levels are associated with increased cancerogenic potential in breast cancer, whereas intermediate levels were not (Lin et al., 2019). Thus, the targeting of this gene's polymorphisms for their potential associations with the development of a chronic infectious condition (CHB) that often leads to cancer was well justified. Li et al. found that three of four NS/GNL3 SNPs examined (rs3733039, rs1866268, and rs11177) were significantly associated with CHB in women and that the rs3733039 SNP was significantly associated with CHB when both genders were combined.
Interestingly only the rs1866268 SNP in the male group was significantly associated with CHB after the authors' performance of a Bonferroni correction, however, before the correction for multiple testing, all three markers were significantly associated with both sexes. These gender-based differences in the strengths of the associations for the three SNPs are likely indicative of the fact that although CHB is more prevalent in men than in women, that any nonsex-linked genetic traits that are associated with disease susceptibility (as in the current case) would play a greater role in female susceptibility.
In any event it appears clear that the allelic forms of the NS/GNL3 gene studied herein are involved in the response to HBV infection; this conjecture is supported by the fact that a haplotypic analysis showed a highly significant association between the rs3733039-rs1866268-rs11177 block and CHB.
In our second article this month by Kulmann-Leal et al. “TLR9 2848 G/A Gene Polymorphism in HCV+, HIV+, and HCV+/HIV+ Individuals,” the authors make a preliminary finding that the functional 2848 SNP (G), that is associated with increased TLR9 expression, when present may serve as protective factor against viral infection by HIV and HCV. TLR9 is one of the toll-like receptors that are a class of innate immune genes that encode proteins that recognize conserved features of pathogens, termed PAMP (pathogen-associated molecular pattern). The TLR9 protein is activated by unmethylated CpG dinucleotides (Bauer et al., 2001) that are over-represented in the genomes of bacterial and viral pathogens compared with humans (and other eukaryotes).
In this article, the GG genotype at the 2848 SNP was initially shown to be protective when HIV+/HCV+ individuals were compared with uninfected controls, similarly, the G allele was also found to be associated with protection in multiple comparisons evaluating various groups of singly and doubly infected individuals compared with uninfected controls. Unfortunately, these findings did not hold up after correction for multiple testing. However, the trends are encouraging and the authors and other groups with access to large virally infected populations are encouraged to further pursue these studies.