An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs

Backgrounds & Aims Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC

Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study

107noNonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome and may evolve into hepatocellular carcinoma (HCC). Only scanty clinical information is available on HCC in NAFLD. The aim of this multicenter observational prospective study was to assess the clinical features of patients with NAFLD-related HCC (NAFLD-HCC) and to compare them to those of hepatitis C virus (HCV)-related HCC. A total of 756 patients with either NAFLD (145) or HCV-related chronic liver disease (611) were enrolled in secondary care Italian centers. Survival was modeled according to clinical parameters, lead-time bias, and propensity analysis. Compared to HCV, HCC in NAFLD patients had a larger volume, showed more often an infiltrative pattern, and was detected outside specific surveillance. Cirrhosis was present in only about 50% of NAFLD-HCC patients, in contrast to the near totality of HCV-HCC. Regardless of tumor stage, survival was significantly shorter (P = 0.017) in patients with NAFLD-HCC, 25.5 months (95% confidence interval 21.9-29.1), than in those with HCV-HCC, 33.7 months (95% confidence interval 31.9-35.4). To eliminate possible confounders, a propensity score analysis was performed, which showed no more significant difference between the two groups. Additionally, analysis of patients within Milan criteria submitted to curative treatments did not show any difference in survival between NAFLD-HCC and HCV-HCC (respectively, 38.6 versus 41.0 months, P = nonsignificant) Conclusions: NAFLD-HCC is more often detected at a later tumor stage and could arise also in the absence of cirrhosis, but after patient matching, it has a similar survival rate compared to HCV infection; a future challenge will be to identify patients with NAFLD who require more stringent surveillance in order to offer the most timely and effective treatment. (Hepatology 2016;63:827-838)openopenPiscaglia F.; Svegliati-Baroni G.; Barchetti A.; Pecorelli A.; Marinelli S.; Tiribelli C.; Bellentani S.; Bernardi M.; Biselli M.; Caraceni P.; Domenicali M.; Garuti F.; Gramenzi A.; Lenzi B.; Magalotti D.; Cescon M.; Ravaioli M.; Del Poggio P.; Olmi S.; Rapaccini G.L.; Balsamo C.; Di Nolfo M.A.; Vavassori E.; Alberti A.; Benvegnau L.; Gatta A.; Giacomin A.; Vanin V.; Pozzan C.; Maddalo G.; Giampalma E.; Cappelli A.; Golfieri R.; Mosconi C.; Renzulli M.; Roselli P.; Dell'isola S.; Ialungo A.M.; Risso D.; Marenco S.; Sammito G.; Bruzzone L.; Bosco G.; Grieco A.; Pompili M.; Rinninella E.; Siciliano M.; Chiaramonte M.; Guarino M.; Camma C.; Maida M.; Costantino A.; Barcellona M.R.; Schiada L.; Gemini S.; Lanzi A.; Stefanini G.F.; Dall'aglio A.C.; Cappa F.M.; Suzzi A.; Mussetto A.; Treossi O.; Missale G.; Porro E.; Mismas V.; Vivaldi C.; Bolondi L.; Zoli M.; Granito A.; Malagotti D.; Tovoli F.; Trevisani F.; Venerandi L.; Brandi G.; Cucchetti A.; Bugianesi E.; Vanni E.; Mezzabotta L.; Cabibbo G.; Petta S.; Fracanzani A.; Fargion S.; Marra F.; Fani B.; Biasini E.; Sacco R.; Morisco F.; Caporaso N.; Colombo M.; D'ambrosio R.; Croce L.S.; Patti R.; Giannini E.G.; Loria P.; Lonardo A.; Baldelli E.; Miele L.; Farinati F.; Borzio M.; Dionigi E.; Soardo G.; Caturelli E.; Ciccarese F.; Virdone R.; Affronti A.; Foschi F.G.; Borzio F.Piscaglia, F.; Svegliati-Baroni, G.; Barchetti, A.; Pecorelli, A.; Marinelli, S.; Tiribelli, C.; Bellentani, S.; Bernardi, M.; Biselli, M.; Caraceni, P.; Domenicali, M.; Garuti, F.; Gramenzi, A.; Lenzi, B.; Magalotti, D.; Cescon, M.; Ravaioli, M.; Del Poggio, P.; Olmi, S.; Rapaccini, G. L.; Balsamo, C.; Di Nolfo, M. A.; Vavassori, E.; Alberti, A.; Benvegnau, L.; Gatta, A.; Giacomin, A.; Vanin, V.; Pozzan, C.; Maddalo, G.; Giampalma, E.; Cappelli, A.; Golfieri, R.; Mosconi, C.; Renzulli, M.; Roselli, P.; Dell'Isola, S.; Ialungo, A. M.; Risso, D.; Marenco, S.; Sammito, G.; Bruzzone, L.; Bosco, G.; Grieco, A.; Pompili, M.; Rinninella, E.; Siciliano, M.; Chiaramonte, M.; Guarino, M.; Camma, C.; Maida, M.; Costantino, A.; Barcellona, M. R.; Schiada, L.; Gemini, S.; Lanzi, A.; Stefanini, G. F.; Dall'Aglio, A. C.; Cappa, F. M.; Suzzi, A.; Mussetto, A.; Treossi, O.; Missale, G.; Porro, E.; Mismas, V.; Vivaldi, C.; Bolondi, L.; Zoli, M.; Granito, A.; Malagotti, D.; Tovoli, F.; Trevisani, F.; Venerandi, L.; Brandi, G.; Cucchetti, A.; Bugianesi, E.; Vanni, E.; Mezzabotta, L.; Cabibbo, G.; Petta, S.; Fracanzani, A.; Fargion, S.; Marra, F.; Fani, B.; Biasini, E.; Sacco, R.; Morisco, F.; Caporaso, N.; Colombo, M.; D'Ambrosio, R.; Croce, L. S.; Patti, R.; Giannini, E. G.; Loria, P.; Lonardo, A.; Baldelli, E.; Miele, L.; Farinati, F.; Borzio, M.; Dionigi, E.; Soardo, G.; Caturelli, E.; Ciccarese, F.; Virdone, R.; Affronti, A.; Foschi, F. G.; Borzio, F

Elastography: where are we now?

3noN/AreservedmixedGiuffré, Mauro; Colecchia, Antonio; Crocé, Lory SGiuffré, Mauro; Colecchia, Antonio; Crocé, Lory

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies