John C Martin Foundation.

SUMMARY. The disease burden of hepatitis C virus (HCV) is expected to increase as the infected population ages. A modelling approach was used to estimate the total number of viremic infections, diagnosed, treated and new infections in 2013. In addition, the model was used to estimate the change in the total number of HCV infections, the disease progression and mortality in 2013-2030. Finally, expert panel consensus was used to capture current treatment practices in each country. Using today's treatment paradigm, the total number of HCV infections is projected to decline or remain flat in all countries studied. However, in the same time period, the number of individuals with late-stage liver disease is projected to increase. This study concluded that the current treatment rate and efficacy are not sufficient to manage the disease burden of HCV. Thus, alternative strategies are required to keep the number of HCV individuals with advanced liver disease and liver-related deaths from increasing.

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We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10 −4 ) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10 −13 ), 7q12-21 (combined P = 3.50 × 10 −13 ) and MMEL1 (combined P = 3.15 × 10 −8 ) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases. Note: Supplementary information is available on the Nature Genetics website. COMPETING FINANCIAL INTERESTSThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturegenetics/. Supplementary Fig. 1); for each locus, association signals at P < 1 × 10 −4 were detected for more than one SNP found in the initial GWAS, with the exception of IRF5-TNPO3, a well-recognized autoimmune disease risk locus. The combination of these replication results and our prior genome-wide association data yielded a genetic dataset derived from 1,351 PBC cases and 4,700 controls (Supplementary Methods). NIH Public AccessFifteen SNPs replicated (P < 1.39 × 10 −3 ) after Bonferroni adjustment (Table 1 and Supplementary Table 1). In addition to HLA, IL12A and IL12RB2, genes at the IRF5-TNPO3 locus, at chromosome 17q12-21 (containing IKZF3, ZPBP2, GSDMB and ORMDL3) and at MMEL1 loci showed significant association with PBC in both the replication analysis and in an analysis combining the replication and initial GWAS datasets ( Fig. 1 and Supplementary Fig. 2).Among the PBC loci confirmed by this analysis, the locus at IRF5-TNPO3 (encoding interferon regulatory factor 5 and transportin 3) is of interest because of the integral immunoregulatory roles for IRF5, the prior association of this locus with systemic lupus erythematosus (SLE) 4, 5 , systemic sclerosis 6 and Sjögrens syndrome 7 , and the strong effect of the disease-associated SNP at this locus on disease risk (rs10488631) in the replication (P = 1.13 × 10 −8 , odds ratio (OR) = 1.58) and combined datasets (P = 8.66 × 10 −13 , OR = 1.57). Association of this locus was thus explored, initially by resequencing the IRF5 locus intronic and exonic regions and the 5′ and 3′ flanking regions of IRF5 in genomic pools of 100 subjects so as to delineate the genetic variation across the locus. This analysis confirmed prior reports of 41 polymorphisms across this region, but it failed to identify any new variants. Among these 41 SNPs, two (rs3807135 and rs3834330) failed repeatedly in genotyping assays and four (rs10275092, rs12537192, rs1727172 and rs754280) showed negligible polymorphism. Thus, for finemapping studies, 1,330 cases and 1,833 controls were geno-typed for 35 SNPs across this region. Among the associations identified (Supplementary Ta...

SUMMARY. Detailed, country-specific epidemiological data are needed to characterize the burden of chronic hepatitis C virus (HCV) infection around the world. With new treatment options available, policy makers and public health officials must reconsider national strategies for infection control. In this study of 15 countries, published and unpublished data on HCV prevalence, viraemia, genotype, age and gender distribution, liver transplants and diagnosis and treatment rates were gathered from the literature and validated by expert consensus in each country. Viraemic prevalence in this study ranged from 0.2% in Iran and Lebanon to 4.2% in Pakistan. The largest viraemic populations were in Pakistan (7 001 000 cases) and Indonesia (3 187 000 cases). Injection drug use (IDU) and a historically unsafe blood supply were major risk factors in most countries. Diagnosis, treatment and liver transplant rates varied widely between countries. However, comparison across countries was difficult as the number of cases changes over time. Access to reliable data on measures such as these is critical for the development of future strategies to manage the disease burden.