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Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations, and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR = 25, P =2.9 × 10−14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Primary open-angle glaucoma (POAG) is the major type of glaucoma. To discover genetic markers associated with POAG, we examined a total of 1,575 Japanese subjects in a genome-wide association study (stage 1) and a subsequent study (stage 2). Both studies were carried out at a single institution. In the stage 1 association study, we compared SNPs between 418 POAG patients and 300 control subjects. First, low-quality data were eliminated by a stringent filter, and 331,838 autosomal SNPs were selected for analysis. Poorly clustered SNPs were eliminated by a visual assessment, leaving 255 that showed a significant deviation (P < 0.001) in the allele frequency comparison. In the stage 2 analysis, we tested these 255 SNPs for association in DNA samples from a separate group of 409 POAG and 448 control subjects. High-quality genotype data were selected and used to calculate the combined P values of stages 1 and 2 by the Mantel-Haenszel test. These analyses yielded 6 SNPs with P < 0.0001. All 6 SNPs showed a significant association (P < 0.05) in stage 2, demonstrating a confirmed association with POAG. Although we could not link the SNPs to the annotated gene(s), it turned out that we have identified 3 genetic loci probably associated with POAG. These findings would provide the foundation for future studies to build on, such as for the metaanalysis, to reveal the molecular mechanism of the POAG pathogenesis.diagnosis ͉ SNP ͉ GWAS ͉ meta-analysis ͉ glaucoma genetics

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

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Exfoliation syndrome (XFS) is the commonest recognizable cause of open angle glaucoma world-wide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) on 1,484 patients and 1,188 controls from Japan, and followed up the most significant findings on a further 6,901 patients and 20,727 controls from 17 countries across 6 continents. We discovered a significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (Odds ratio [OR] = 1.16, P = 3.36 × 10−11). Although overwhelming association at the LOXL1 locus was confirmed, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on ethnic grouping (In Japanese: ORA-allele= 9.87, P = 2.13 × 10−217; In non-Japanese: ORA-allele= 0.49, P = 2.35 × 10−31). Our findings represent the first genetic locus outside of LOXL1 which surpasses genome-wide significance for XFS, and provides insight into the biology and pathogenesis of the disease.

Ribavirin (RBV) is a potential partner of interferon (IFN)-based therapy for patients with chronic hepatitis C. However, to date, its anti-hepatitis C virus (HCV) mechanism remains ambiguous due to the marginal activity of RBV on HCV RNA replication in HuH-7-derived cells, which are currently used as the only cell culture system for robust HCV replication. We investigated the anti-HCV activity of RBV using novel cell assay systems. The recently discovered human hepatoma cell line, Li23, which enables robust HCV replication, and the recently developed Li23-derived drug assay systems (ORL8 and ORL11), in which the genome-length HCV RNA (O strain of genotype 1b) encoding renilla luciferase efficiently replicates, were used for this study. At clinically achievable concentrations, RBV unexpectedly inhibited HCV RNA replication in ORL8 and ORL11 systems, but not in OR6 (an HuH-7-derived assay system). The anti-HCV activity of RBV was almost cancelled by an inhibitor of equilibrative nucleoside transporters. The evaluation of the anti-HCV mechanisms of RBV proposed to date using ORL8 ruled out the possibility that RBV induces error catastrophe, the IFN-signaling pathway or oxidative stress. However, we found that the anti-HCV activity of RBV was efficiently cancelled with guanosine, and demonstrated that HCV RNA replication was notably suppressed in inosine monophosphate dehydrogenase (IMPDH)-knockdown cells, suggesting that the antiviral activity of RBV is mediated through the inhibition of IMPDH. In conclusion, we demonstrated for the first time that inhibition of IMPDH is a major antiviral target by which RBV at clinically achievable concentrations inhibits HCV RNA replication.

BackgroundTo date, only a small portion of the genetic variation for primary open-angle glaucoma (POAG), the major type of glaucoma, has been elucidated.Methods and Principal FindingsWe examined our two data sets of the genome-wide association studies (GWAS) derived from a total of 2,219 Japanese subjects. First, we performed a GWAS by analyzing 653,519 autosomal common single-nucleotide polymorphisms (SNPs) in 833 POAG patients and 686 controls. As a result, five variants that passed the Bonferroni correction were identified in CDKN2B-AS1 on chromosome 9p21.3, which was already reported to be a significant locus in the Caucasian population. Moreover, we combined the data set with our previous GWAS data set derived from 411 POAG patients and 289 controls by the Mantel-Haenszel test, and all of the combined variants showed stronger association with POAG (P<5.8×10−10). We then subdivided the case groups into two subtypes based on the value of intraocular pressure (IOP)—POAG with high IOP (high pressure glaucoma, HPG) and that with normal IOP (normal pressure glaucoma, NPG)—and performed the GWAS using the two data sets, as the prevalence of NPG in Japanese is much higher than in Caucasians. The results suggested that the variants from the same CDKN2B-AS1 locus were likely to be significant for NPG patients.Conclusions and SignificanceIn this study, we successfully identified POAG-associated variants in the CDKN2B-AS1 locus using a Japanese population, i.e., variants originally reported as being associated with the Caucasian population. Although we cannot rule out that the significance could be due to the differences in sample size between HPG and NPG, the variants could be associated specifically with the vulnerability of the optic nerve to IOP, which is useful for investigating the etiology of glaucoma.