[Show abstract][Hide abstract] ABSTRACT: Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate
the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs)
for cancer at 13 anatomical sites.
Full-text · Article · Oct 2015 · JNCI Journal of the National Cancer Institute
[Show abstract][Hide abstract] ABSTRACT: IFN-l4 is a novel type-III interferon with strong clinical significance in humans. Only a subset of individuals— up to 10% of Asians, 50% of Europeans, and 90% of Africans—carry the DG allele of a genetic variant rs368234815-TT/DG and are genetically able to produce IFN-l4 protein. Carriers of the DG allele have impaired ability to clear infection with hepatitis C virus (HCV). IFN-l4 is also predicted to exist and be functionally important in several nonhuman mammals. In this study, we present the first comparative analysis of 12 mammalian IFN-l4 orthologs in a human hepatic cell line, HepG2, which supports signaling of the human IFN-l4. We show that despite differences in protein sequences, functional properties of the recombinant human and nonhuman IFN-l4 proteins are comparable—they are all expressed as predominantly cytoplasmic proteins that are biologically active for induction of interferon signaling. We show that several IFN-l4 orthologs can be detected by Western blotting, flow cytometry, and confocal imaging using a monoclonal antibody developed for the human IFN-l4. Studies of IFN-l4 in animals should help improve our understanding of the biology of this novel clinically important interferon in normal and disease conditions.
Full-text · Article · Aug 2015 · Journal of Interferon & Cytokine Research
[Show abstract][Hide abstract] ABSTRACT: Interferon lambda 4 (IFN-l4) is a novel type-III interferon that can be generated only in individuals carrying a DG frame-shift allele of an exonic genetic variant (rs368234815-DG/TT). The rs368234815-DG allele is strongly associated with decreased clearance of hepatitis C virus (HCV) infection. Here, we further explored the biological function of IFN-l4 expressed in human hepatic cells—a hepatoma cell line HepG2 and fresh primary human hepatocytes (PHHs). We performed live confocal imaging, cell death and proliferation assays, mRNA expression profiling, protein detection, and antibody blocking assays using transient and inducible stable in vitro systems. Not only did we observe significant intracellular retention of IFN-l4 but also detected secreted IFN-l4 in the culture media of expressing cells. Secreted IFN-l4 induced strong activation of the interferon-stimulated genes (ISGs) in IFN-l4-expressing and surrounding cells in transwell assays. Specifically, in PHHs, secreted IFN-l4 induced expression of the CXCL10 transcript and a corresponding pro-inflammatory chemokine, IP-10. In IFN-l4-expressing HepG2 cells, we also observed decreased proliferation and increased cell death. All IFN-l4-induced phenotypes— activation of ISGs, decreased proliferation, and increased cell death—could be inhibited by an anti-IFN-l4-specific antibody. Our study offers new insights into biology of IFN-l4 and its possible role in HCV clearance.
Full-text · Article · Jul 2015 · Journal of Interferon & Cytokine Research
[Show abstract][Hide abstract] ABSTRACT: Interferon lambda 4 gene (IFNL4) encodes IFN-λ4, a new member of the IFN-λ family with antiviral activity. In humans IFNL4 open reading frame is truncated by a polymorphic frame-shift insertion that eliminates IFN-λ4 and turns IFNL4 into a polymorphic pseudogene. Functional IFN-λ4 has antiviral activity but the elimination of IFN-λ4 through pseudogenization is strongly associated with improved clearance of hepatitis C virus (HCV) infection. We show that functional IFN-λ4 is conserved and evolutionarily constrained in mammals and thus functionally relevant. However, the pseudogene has reached moderately high frequency in Africa, America, and Europe, and near fixation in East Asia. In fact, the pseudogenizing variant is among the 0.8% most differentiated SNPs between Africa and East Asia genome-wide. Its raise in frequency is associated with additional evidence of positive selection, which is strongest in East Asia, where this variant falls in the 0.5% tail of SNPs with strongest signatures of recent positive selection genome-wide. Using a new Approximate Bayesian Computation (ABC) approach we infer that the pseudogenizing allele appeared just before the out-of-Africa migration and was immediately targeted by moderate positive selection; selection subsequently strengthened in European and Asian populations resulting in the high frequency observed today. This provides evidence for a changing adaptive process that, by favoring IFN-λ4 inactivation, has shaped present-day phenotypic diversity and susceptibility to disease.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000
bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis.
To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic
subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036
controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide
polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific
effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene
expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy
across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
Full-text · Article · Jul 2014 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Response to pegylated interferon-alpha and ribavirin (IFN-α/RBV) treatment for chronic hepatitis C virus (HCV) infection is
influenced by host genetic factors, but their role for IFN-α–free, direct-acting antiviral (DAA) regimens is unclear. An exonic
deletion allele (IFNL4-ΔG) bolsters the established association with IFN-α/RBV therapy treatment outcome of another IFNL4 variant, rs12979860, which is located upstream of IFNL3 (IL28B). We report that in patients treated with the DAA sofosbuvir along with RBV, IFNL4-ΔG is associated with slower early viral decay, due to slower loss of free virus (P = .039) and decreased drug efficacy (P = .048), suggesting functional relevance of IFN-λ4 in IFN-α–free DAA therapies.
Preview · Article · Dec 2013 · The Journal of Infectious Diseases