Progression of liver fibrosis in HIV/HCV genotype 1 co-infected patients is related to the T allele of the rsI2979860 polymorphism of the IL28B gene

<p>Abstract</p> <p>Objective</p> <p>HIV/HCV co-infection is characterised by accelerated progression of liver disease. Recently, the rsl2979860 C/T polymorphism in the <it>IL28B </it>gene has been linked to progression towards cirrhosis in HCV mono-infected patients and to treatment response of HCV-infection in HIV/HCV co-infected patients. Our aim was to clarify by non-invasive techniques if this polymorphism affects fibrosis progression in HIV/HCV co-infection.</p> <p>Methods</p> <p>In a cross-sectional design, liver stiffness (transient elastography), surrogate markers of liver fibrosis (APRI and FIB-4 scores) and rsl2979860 genotypes were analysed in 84 HCV/H1V co-infected patients. <it>IL28B </it>genotypes were determined by real-time PCR using a light cycler. In 56 HIV/HCV co-infected patients we also studied progression of fibrosis in relation to rsl2979860 C/T genotypes over two years.</p> <p>Results</p> <p>82% of the patients were on HAART (74% without detectable HI viremia) and 67% were haemophiliacs, respectively. HCV genotype 1 was present in 62%. Cross-sectional median liver stiffness was 7.4 kPa and correlated with APRI and FIB-4 scores (r = 0.6 each, p < 0.001). Frequencies of <it>IL28B </it>genotypes were: CC 50%, CT 43% and TT 7%. In the cross-sectional analysis liver stiffness values were not different between the various <it>IL28B</it>-genotypes. Upon follow-up under HAART carriers of a C allele did not show further progression, while liver stiffness significantly increased in HIV/HCV co-infected patients with the T allele (p = 0.047).</p> <p>Conclusion</p> <p>Although progression of liver fibrosis was low under HAART in our cohort, progression was more pronounced in HIV/HCV genotype 1 co-infected patients with the T allele.</p

TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients

<p>Abstract</p> <p>Background</p> <p>Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (<it>DR4</it>) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed <it>DR4 </it>mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC.</p> <p>Methods</p> <p>Frequencies of <it>DR4 </it>gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population.</p> <p>Results</p> <p>Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. <it>DR4 </it>variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 10⁶ IU/ml vs. 1.81 ± 0.23 × 10⁶ IU/ml, p = 0.049).</p> <p>Conclusions</p> <p>The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C.</p

Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers

BACKGROUND & AIMS: Carriage of rs738409:G in patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with PNPLA3 rs738409:G. This study explores the risk-associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including: 1,031 with alcohol-related cirrhosis and HCC; 1,653 with alcohol-related cirrhosis without HCC; 2,588 alcohol misusers with no liver disease; and 899 healthy controls. Genetic associations with the risks for alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for both cirrhosis (OR 0.79 [95% CI 0.72-0.88], p=8.13×10-6) and HCC (OR 0.77 [95% CI 0.68-0.89], p=2.27×10-4), while carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR 1.70 [95% CI 1.54-1.88], p=1.52x10-26) and HCC (OR 1.77 [95% CI 1.58-1.98], p=2.31×10-23). These associations remained significant after adjusting for age, sex, body mass index, type II diabetes mellitus and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women but the protective effect against the subsequent development of HCC was only observed in men (p=1.72×10-4; ORallelic, 0.75; 95% CI, 0.64-0.87). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population

Erratum: PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease (Am J Gastroenterol 110:846-856(2015) DOI: 10.1038/ajg.2015.137)

Erratum for PNPLA3 Gene Polymorphism Is Associated With Predisposition to and Severity of Alcoholic Liver Disease. [Am J Gastroenterol. 2015

Genetic Analyses Reveal a Role for Vitamin D Insufficiency in HCV-Associated Hepatocellular Carcinoma Development.

BACKGROUND: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODOLOGYPRINCIPAL FINDINGS: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99-1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12-2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13-1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P&gt;0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P&gt;0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis. CONCLUSIONSSIGNIFICANCE: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis

Genetic association analyses reveal a role for vitamin D insufficiency in hepatitis C virus-associated hepatocellular carcinoma development

Background: V itamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. Methods: Associations between t he r isk o f HCV-related HCC development and CYP2R1 , GC, and DHCR7 genotypes, which are genetic determinants of reduced 25-OH-vitamin D3 (25[OH]D3) serum levels, were determined. Results: A t otal of 5604 HCV-infected patients, 1279 with a nd 4325 without progression to HCC, w ere identified. The well-known association between 25(OH)D3 s erum levels and variations in CYP2R1 ( rs1993116, rs10741657), GC ( rs2282679), a nd DHCR7 ( rs7944926, rs12785878) g enotypes was also apparent in patients w ith chronic hepatitis C. The same genotypes of t hese single nucleotide polymorphisms (SNPs), w hich are associated with reduced 25(OH)D3 s erum levels, were significantly associated with HCV-associated HCC (P=0.07 [OR=1.13] for CYP2R1 , P=0.007 [OR=1.56] for GC, P=0.003 [OR=1.42] for DHCR7; ORs for risk genotypes). In contrast, no association between t hese genetic variations and the o utcome of antiviral therapy with pegylated interferon-α and ribavirin ( P&gt;0.2 for e ach SNP) or liver fibrosis progression rate (P&gt;0.2 for each SNP) was observed, s uggesting a specific influence o f the genetic d eterminants of 25(OH)D3 s erum levels o n hepatocarcinogenesis. Conclusions: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related HCC development. Controlled clinical trials to assess the benefit of vitamin D supplementation in HCVinfected patients with advanced liver fibrosis or cirrhosis are warranted