rs12979860

In 258 chronic hepatitis C patients treated with direct-acting antivirals, VDR FokI rs10735810 T>C SNP was significantly associated with hepatocellular carcinoma (HCC) presence (p=0.013), with all CC genotype carriers remaining HCC-free. Multivariate logistic regression identified age (OR 25.41), ribavirin administration, and IL28B rs12979860 CC genotype as HCC risk factors, while VDR FokI CC genotype was protective.

This association study examined IL28B polymorphisms in 220 Pakistani HCV patients (100 responders, 120 nonresponders) to pegylated interferon-alpha and ribavirin treatment. The rs12980275 AA genotype showed the strongest association with treatment response (62% responders vs 37.5% nonresponders, OR: 4.1, P < 0.0001), followed by rs12979860 CT (OR: 3.0, P < 0.001) and rs8099917 TT (P < 0.032). This was the first report describing rs12980275 association with HCV treatment response in Pakistani patients.

Multicenter study of 293 Japanese patients with HCV genotype 1b found that week 4 HCV RNA reduction is a strong predictor of sustained virologic response (SVR) to peginterferon-ribavirin therapy, with AUROC 0.927 (88% sensitivity, 87% specificity). The IL28B rs8099917 polymorphism and HCV viral factors (core region position 70 and ISDR) significantly influence the optimal cut-off thresholds for SVR prediction; patients with unfavorable TG/GG genotype require markedly lower viral reduction thresholds.

This comprehensive review examines the genetic background of nonalcoholic fatty liver disease (NAFLD), focusing on variants identified by genome-wide association studies (GWAS) and candidate gene studies. The most significant GWAS-identified variants are PNPLA3 rs738409 (I148M), which strongly associates with increased liver steatosis, fibrosis severity, and HCC risk (12-fold increased risk for homozygous carriers), and TM6SF2 rs58542926 (E167K), which increases NASH progression but reduces cardiovascular risk. The review also discusses numerous candidate genes involved in lipid and glucose metabolism and liver injury mechanisms.

This commentary reviews the discovery of a dinucleotide variant ss469415590 (∆G) upstream of IFNL3 on chromosome 19q13.13 that creates a novel interferon-lambda gene IFNL4. The variant is associated with impaired hepatitis C virus clearance, particularly in individuals of African ancestry, and is in high linkage disequilibrium with the previously known rs12979860 SNP. The IFNL4 protein product appears to cause pre-activation of interferon signaling that reduces responsiveness to IFN-α treatment.

IL28B rs12979860 CC genotype independently predicted HBsAg seroclearance in 101 HBeAg-negative genotype D chronic hepatitis B patients treated with interferon (OR 3.9, 95% CI 1.1-13.2, P=0.025). CC carriers had 29% HBsAg clearance rate compared to 13% in CT/TT carriers over 11-year median follow-up, confirming IL28B's predictive value for interferon response in difficult-to-cure HBV infection.

In the HALT-C cohort of 1,319 patients with advanced chronic hepatitis C, elevated baseline gamma-glutamyl transferase (GGT) activity was strongly associated with diminished virological response to interferon-based treatment and with adverse clinical outcomes including hepatic decompensation, death, and fibrosis progression. Notably, IL28B rs12979860 T allele carriers with high GGT had markedly poor treatment response, with only 1 of 56 TT homozygotes in the highest GGT quintile achieving sustained virological response, whereas CC homozygotes showed favorable response rates relatively unaffected by GGT levels.

This methods paper describes a rapid PCR-based test for screening IL28B SNPs (rs12979860 and rs8099917) and characterizes their distribution in a French Canadian injection drug user cohort (N=183). The study found that French Canadians have unusual genetic characteristics: high prevalence of responder genotypes (rs12979860 C/C: 51.4%, rs8099917 T/T: 63.4%) and reduced linkage disequilibrium between the two SNPs (|d'|=0.68, r=0.59), attributed to a founder effect from early French colonization.

This study examined ITPA gene polymorphisms (rs1127354 and rs7270101) in 121 patients with HIV/HCV coinfection (n=63) and HCV monoinfection (n=58) treated with pegIFN/RBV. ITPA deficiency was found protective against hemoglobin reduction >3 g/dl (P=0.020 at week 4 in coinfected patients) and was associated with rapid virologic response at week 4 (P=0.017) in HIV/HCV coinfected patients, but did not improve sustained virologic response.

This study examined IL28B genetic polymorphisms (rs12979860 and rs8099917) and hepatic ISG expression in 68 chronic hepatitis C patients, of whom 47 received interferon-ribavirin treatment. The rs12979860 CC genotype was significantly associated with sustained virological response (SVR; OR=6.29, 95% CI=1.72-23.01, P=0.004) and lower hepatic expression of IFI27, ISG15, and MX1 compared to CT-TT genotypes. IP10 expression was independently associated with SVR and strongly linked to liver fibrosis progression, while silencing of IP10 provided additional predictive value for treatment response.

This study evaluated IL28B SNP polymorphisms (rs12979860 and rs8099917) as predictors of treatment response in 100 Egyptian chronic hepatitis C (genotype 4) patients treated with pegylated interferon and ribavirin. The CC genotype of rs12979860 was associated with 87.2% sustained virological response (SVR) compared to 10% for TT (p<0.001), and rs8099917 TT was associated with 80.4% SVR versus 16.7% for GG, supporting IL28B polymorphisms as important biomarkers for predicting HCV treatment outcomes in genotype 4 patients.

This case-control study investigated the association between IL28B gene polymorphisms and hepatitis B infection in a Chinese population from Yunnan. The authors screened three SNPs (rs12979860, rs8099917, and rs12980275) in 493 HBV-infected individuals and 460 controls. While no significant association was found between IL28B genetic polymorphisms and HBV infection susceptibility, the study identified associations between IL28B variants and leukomonocyte (LYM) levels in HBV-infected individuals, with rs12979860 showing significant differences in mean LYM levels (1.78 vs 2.00, p=0.032).

This prospective study of acute hepatitis C infection in injection drug users (n=29) found that spontaneous viral clearance was predicted by high initial HCV RNA levels (median 7.1 vs 5.4 log10 IU/mL, P=0.002) and the favorable IL-28B rs12979860-C allele. Clearance subjects showed rapid, divergent HVR1 evolution driven by neutralizing antibody responses, while persistence subjects showed slower, convergent evolution, linking host genetics, viral dynamics, and immune pressure to infection outcome.

A comprehensive review of IL28B gene polymorphisms and their impact on drug responses across multiple conditions. The review discusses how three major IL28B SNPs (rs12979860, rs8099917, rs12980275) and seven additional polymorphisms predict treatment response to interferon-based therapies for chronic hepatitis C, hepatitis B, and myeloproliferative neoplasms. IL28B genotypes, particularly the favorable CC genotype at rs12979860 and TT genotype at rs8099917, are associated with higher sustained virologic response (SVR) rates in HCV treatment, with effect sizes showing 3-4.5 fold differences in relapse risk between genotypes.

This study investigated the biological mechanism of the IL28B rs12979860 polymorphism in 88 patients (44 HIV/HCV co-infected, 44 HCV mono-infected). The favorable CC genotype was associated with improved treatment response (SVR ~50% vs 12% in unfavorable genotypes), more rapid viral kinetics (P=0.004 and P=0.036), and higher IFN anti-viral efficiency (95% vs 82%, P=0.007). Gene expression profiling revealed dysregulation of innate immunity pathways in unfavorable genotypes independent of ISG expression.

This study of 643 individuals with acute hepatitis C virus (HCV) infection from nine international prospective cohorts (InC3 Study) evaluated patterns of HCV RNA levels and associated factors. The IFNL3 CC genotype (rs12979860) was independently associated with partial viral control compared to viral plateau (adjusted odds ratio [AOR]: 2.75; 95% CI: 1.08–7.02), while female sex was independently associated with spontaneous HCV clearance compared to partial viral control (AOR: 2.86; 95% CI: 1.04–7.83).

A retrospective association study of 206 chronic hepatitis C patients examining whether vitamin D binding protein (GC) gene polymorphisms (rs7041, rs4588) and baseline vitamin D levels predict antiviral response. In difficult-to-treat HCV genotypes, patients with vitamin D >20 ng/mL and the GC wildtype (WT+) diplotype had significantly higher sustained viral response (SVR) rates (65.5% vs 24.0%, p=0.003), with multivariate OR=4.52 (p=0.015) for vitamin D >20 + GC WT+. IL-28B rs12979860 was confirmed as a strong independent predictor of SVR across all genotypes.

This study of 272 Japanese patients with HCV genotype 1b investigated whether early viral dynamics (HCV RNA reduction at 4 and 12 weeks) retain predictive value for sustained virologic response (SVR) when stratified by IL28B polymorphisms (rs8099917, rs12979860). Among patients with favorable TT genotype for rs8099917, ≥3 log10 reduction in HCV RNA at 4 weeks predicted SVR (P<0.0001); conversely, TG/GG genotype patients showed no such prediction. Lack of early virologic response at 12 weeks retained strong predictive value for treatment failure regardless of IL28B genotype.

This study investigates the IL-28B rs12979860 C/T polymorphism as a predictor of liver fibrosis progression in 93 patients with chronic hepatitis C and persistently normal transaminases. The IL-28B rs12979860 T/T genotype and low serum cholesterol (<175 mg/dl) interaction was independently associated with greater fibrosis progression (OR=1.41, p<0.01), confirmed in a cross-sectional cohort of 143 patients.

This study examined 22 HIV/HCV coinfected patients treated with peginterferon/ribavirin to determine whether the IL28B rs12979860 polymorphism (CC favorable vs CT/TT unfavorable genotype) associates with HCV protease NS3 quasispecies diversity. IL28B genotype showed no significant association with baseline NS3 nucleotide or amino acid diversity. The authors found that the IL28B polymorphism is unlikely to negatively impact HCV protease inhibitor efficacy in treatment-experienced coinfected patients.

This study examined how the IL28B rs12979860 SNP polymorphism affects hepatitis C viral evolution during pegylated interferon and ribavirin treatment. Among 33 HCV genotype 1-infected patients, those with the favorable CC genotype showed significantly higher non-synonymous substitution rates (dN values) by day 7 of treatment and more amino acid substitutions in the NS5A region at baseline compared to non-CC patients, despite similar baseline viral loads and genetic diversity.

This is a comprehensive review chapter on liver transplantation in patients with hepatitis C, covering disease pathogenesis post-transplant, diagnostic approaches, and current treatment strategies. The paper discusses the impact of various factors including IL28B genotype on HCV recurrence after transplantation and reviews clinical trial data on direct-acting antiviral (DAA) therapies (sofosbuvir, ledipasvir, daclatasvir, velpatasvir) used in both transplant candidates and post-transplant patients, with sustained viral response rates exceeding 95% in many populations.

This case-control study of 330 subjects (154 HBV-related HCC patients, 86 chronic hepatitis B patients, 43 HBV self-limited infections, and 47 controls) examined three IL28B SNPs for association with hepatitis B-related hepatocellular carcinoma. The CC genotype at rs12979860 was protective (91.5% in controls vs 72.9% in CHB, P=0.01; vs 74.7% in HCC, P=0.01), while T allele carriers had increased HCC risk (χ²=4.44, P=0.04). Gene-gene interactions between rs12979860 and rs12980275 showed an OR of 11.79 (P=0.04), indicating IL28B polymorphisms influence HBV infection progression and HCC susceptibility.

This association study of 732 chronic hepatitis C patients examined polymorphisms in the TOMM40-APOE genomic region. rs7412 was significantly associated with serum apolipoprotein E levels (p=2.3×10⁻¹¹), explaining 7% of variance. Among IL28B-CC patients (n=196), rs429358 and TOMM40 '523' polymorphisms together explained 12% of variance in apolipoprotein B levels. Patients homozygous for APOE e3 isoform showed >2-fold increased odds of F2-F4 hepatic fibrosis (p=1.8×10⁻⁵), independent of lipid levels.

This study examined ITPA gene polymorphisms (rs1127354) and their influence on hemoglobin decreases during triple therapy with pegylated interferon, ribavirin, and telaprevir in 61 Japanese patients with hepatitis C virus genotype 1. Patients with the CC genotype at rs1127354 experienced significantly greater hemoglobin reductions (Δ-3.5 ± 1.1 g/dL at week 4, P=0.001) compared to CA/AA genotypes, required more RBV dose reductions during the first 12 weeks (52% vs 65% of target dose, P=0.039), and had higher risk for severe anemia (OR=36.8 for hemoglobin <11 g/dL). SVR rates were comparable between genotypes (71% vs 67%, P=0.736), demonstrating that with careful monitoring and dose adjustment, effective HCV treatment can be achieved despite genetic predisposition to RBV-induced anemia.

This case-control study of 272 hepatitis C patients from the VIRAHEP-C cohort demonstrates that pretreatment serum IP-10 (interferonγ inducible protein-10) is independently and additively predictive of sustained virological response (SVR) to peginterferon and ribavirin when combined with IL28B genotype (rs12979860). Combining IL28B genotype with pretreatment IP-10 significantly improves prediction of treatment response (ROC AUC 0.80 vs 0.70 for genotype alone), particularly in non-CC genotype carriers.

A prospective follow-up study of 4,639 chronic hepatitis C patients treated with pegylated interferon and ribavirin examined hepatocellular carcinoma (HCC) incidence and clinical predictors. Among 3,939 patients with sustained virological response (SVR), 155 developed HCC at an incidence of 6.9 per 1,000 person-years compared to 21.6 per 1,000 person-years in 700 patients with non-sustained response (NSVR). HCC risk was reduced 0.37-fold (HR 0.37, 95% CI 0.22-0.63) in SVR patients without cirrhosis and 0.54-fold (HR 0.54, 95% CI 0.31-0.92) in those with cirrhosis relative to NSVR. Post-treatment elevated α-fetoprotein levels were significantly associated with increased HCC risk in a dose-response manner.

This study examined IL-28B genetic variation and spontaneous hepatitis C virus clearance using multiple- and single-source cohorts. IL-28B protective haplotypes were strongly associated with HCV clearance (OR=2.1 [95% CI 1.6-3.0] in multiple-source cohort, OR=3.9 [95% CI 1.5-10.2] in single-source cohort; P=6×10⁻⁹). The protective haplotypes were in perfect linkage (r²=1.0) with the nonsynonymous coding variant rs8103142, and homozygosity for the rs12979860 C allele predicted the protective haplotype status.

This association study examined the role of interleukin 28B (IL28B) polymorphism (rs12979860) in hepatitis C virus (HCV) vertical transmission and spontaneous clearance in infected children. Among 145 mothers and 171 infants, high maternal HCV viral load (>600,000 IU/mL; OR=7.3) was the only independent predictor of transmission, while IL28B status was not associated with HCV vertical transmission risk. However, IL28B CC genotype in children was independently associated with spontaneous clearance of HCV genotype-1 (OR=17.5), whereas non-CC genotypes (CT/TT) showed predominantly chronic infection (78% vs. 17-22% spontaneous clearance, P=0.04).

This is a special issue of the Italian medical journal BeAdfiles (September 2012) dedicated to genetic conditioning in HIV and hepatitis virus infections. It reviews the major genetic polymorphisms that influence disease progression, treatment response, and drug toxicity in HIV and chronic hepatitis B and C infections, with particular emphasis on IL28B polymorphisms (rs809917 and others) predicting HCV treatment response to interferon-alpha and ribavirin therapy, and ITPA gene variants protecting against ribavirin-induced anemia. The issue also covers pharmacogenetic markers (CYP2B6, ABCB1, HLA-B*5701) and their clinical applications in antiretroviral therapy.

Meta-analysis of 67 studies involving 20,163 patients for sustained virologic response (SVR) and 10 studies with 3,554 patients for spontaneous clearance (SC). IL28B polymorphisms showed strong associations with HCV clearance: rs12979860 (CC favorable) demonstrated similar associations across HCV genotypes and ethnicities (OR ~3.2-3.6), while rs8099917 (TT favorable) showed stronger effects in East Asians (OR ~6.3 vs 3.4 in Caucasians) and rs12980275 (AA favorable) had OR of 3.95 overall. All three SNPs showed genotype-dependent effects with HCV-1/4 having 3-fold higher ORs than HCV-2/3.

In 133 chronic hepatitis C patients, the IL28B rs12979860 CC protective genotype was inversely associated with hepatic expression of interferon-stimulated genes (ISGs) that promote antiviral responses (ISG15: p=1.42E-12, MxA: p=6.40E-11) and positively associated with expression of genes that suppress antiviral signaling (A20: p=0.00107, Zc3h12a: p=0.00129). The rs12979860 genotype was significantly associated with HCV treatment response to peginterferon-ribavirin therapy, suggesting it affects treatment outcomes through altered intrahepatic ISG expression patterns.

This study examined the IL-28b gene polymorphism (rs8099917) in 183 liver transplant patients with recurrent hepatitis C virus infection, analyzing 605 protocol liver biopsies. The G allele was significantly associated with higher histological grades of inflammation (median grade 3.0 for GG, 2.5 for GT, 2.0 for TT; p<0.001), elevated aminotransferase levels (ALT p=0.001, AST p=0.003), and lack of response to interferon-based antiviral therapy (p<0.001). The G allele was significantly less frequent among successfully treated patients and was not present in the GG genotype among responders, suggesting IL-28b polymorphisms may serve as markers for graft inflammation severity and predictors of antiviral treatment failure.

Population genetics study investigating IFNL3/IFNL4 interferon gene polymorphisms in 669 HCV patients and 1,520 healthy controls across Caucasian and Mongoloid ethnic groups in Russia and Mongolia. Spontaneous HCV viral clearance was significantly more frequent in the Mongoloid population, with protective genotypes: CC genotype at rs12979860, TT genotype at rs8099917, and TT/TT genotype at rs368234815.

Two functional ITPA gene variants (rs1127354 and rs7270101) were strongly protective against ribavirin-induced hemolytic anemia in 238 HCV genotype 2/3 patients treated with pegylated interferon and ribavirin (P=10^-6 and P=10^-7 respectively; combined P=10^-11). Despite protection from anemia, ITPA variants did not decrease the need for ribavirin dose reduction or improve sustained virological response.

Comprehensive review of genetic background in nonalcoholic fatty liver disease (NAFLD). The PNPLA3 I148M variant (rs738409 C>G) is identified as a major genetic player strongly associated with increased liver fat content, NASH development, fibrosis severity, and HCC risk. The TM6SF2 E167K variant (rs58542926) emerges as another key contributor to NAFLD pathogenesis and disease progression. Multiple additional GWAS-identified variants and candidate genes are reviewed for their roles in NAFLD susceptibility and progression.

This retrospective cohort study of 189 HCV-infected liver transplant recipients examined the association between IL28B genotype (rs12979860) and treatment response and clinical outcomes. Recipient IL28B CC genotype was associated with sustained virological response (SVR) rates of 58% versus 0% in TT genotype (OR=3.43, P=0.0062), and delayed histological recurrence. Donor IL28B genotype similarly predicted SVR (59% in CC vs 0% in TT, OR=4.00, P=0.0071), with optimal outcomes in CC donor-to-CC recipient transplants achieving 86% SVR.

Retrospective study of 1,713 treatment-naive hepatitis C virus (HCV) genotype 3 patients developing and validating a clinical prediction score for sustained virologic response (SVR) to peginterferon alfa-2a/ribavirin therapy. The prediction score incorporating age, bodyweight, cirrhosis status, ALT level, platelet count, and HCV RNA achieved 87% SVR rate in patients with score ≥8. IL28B variants rs12979860 (CC) and rs8099917 (TT) were associated with virological response but not included in the final model due to data limitations.

This functional association study investigated IL28B genotype as a determinant of intrahepatic interferon-stimulated gene (ISG) expression in 61 chronic hepatitis C patients. The protective IL28B CC genotype (rs12979860) was associated with significantly lower expression of ISGs (e.g., ISG15 3.9-fold lower, MX1 2.6-fold lower, p < 10⁻⁵) and higher expression of immunomodulatory genes like CXCL9 (3.3-fold). Treatment response was associated with IL28B genotype (p = 0.0054), though the non-synonymous variant Lys70Arg (rs8103142) showed no functional differences in vitro, suggesting non-coding regulatory variants drive the association.

This clinical observational study of 29 Serbian patients with chronic hepatitis C genotype 1b examined how HCV core amino acid substitutions, IL28B rs12979860 polymorphism, and RASSF1A/p16 methylation predict response to pegylated interferon/ribavirin therapy. HCV core substitutions at position 75 combined with CT/TT IL28B genotypes predicted non-response (P=0.023), while substitutions at position 91 with CC IL28B genotype predicted sustained virologic response (P=0.030). The combined analysis of core protein variants, IL28B genotype, and epigenetic modifications significantly improved prediction of treatment response and disease progression.

A prospective cohort study of 163 individuals with recent hepatitis C virus (HCV) infection found that IL28B rs8099917 TT genotype independently predicted spontaneous HCV clearance (AHR 3.78, 95% CI 1.04-13.76, p=0.044) with 32% clearance in TT homozygotes versus 5% in GG/GT carriers. However, IL28B genotype did not impact treatment response (SVR 62% TT vs 64% GG/GT, p=0.884), suggesting IL28B may be useful for determining treatment timing but not for predicting response to therapy.

Association study of 746 chronic hepatitis C patients found that the rs12979860 CC genotype (interferon lambda/IL28B region) was associated with significantly higher LDL cholesterol (p=8.9×10⁻¹⁰), total cholesterol (p=6.0×10⁻⁴), and apolipoprotein B (p=1.3×10⁻⁶) levels compared to CT/TT genotypes. The rs12979860 genotype accounted for 5% of variation in LDL cholesterol and may reflect differences in endogenous interferon response to HCV infection.

This case-control study in 110 Croatian intravenous drug users with chronic hepatitis C found that rs1800795-IL6 C allele was significantly associated with sustained virological response (SVR) to pegylated interferon-alpha/ribavirin treatment (OR 2.15, 95% CI 1.16-4.68, p=0.019 after adjustment). Additionally, rs12979860-IL28B CC genotype showed a protective effect against chronic HCV acquisition (27% in patients vs 49% in population controls, p<0.001), suggesting a role in spontaneous HCV clearance.

A case-control study in a Russian population (285 type 1 diabetes patients, 300 controls) examining 58 SNPs across 47 genes involved in fibrogenesis, endothelial dysfunction, and inflammation. Seven SNPs showed significant association with T1D susceptibility: rs3765124 (ADAMDEC1 AA genotype, OR=1.79, p=0.004), rs1007856 (ITGB5 TT genotype, OR=1.67, p=0.015), rs20579 (LIG1 CC genotype, OR=1.86, p=0.004), rs12980602 (IFNL2 allele C, OR=1.49, p=0.029), rs4986819 (PARP4 allele C, OR=1.52, p=0.044), rs1143674 (ITGA4 GG genotype, OR=2.06, p=0.002), and rs679620 (MMP3 AA genotype, OR=2.03, p=0.008).