Alzheimer's disease and its treatment-yesterday, today, and tomorrow.

Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-ß (Aß) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aß monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aß will benefit the majority of subjects with AD that the anti-Aß MABs are unlikely to be the "magic bullet". A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.

Treatment of hypoplastic left heart syndrome: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: This meta-analysis aimed to consolidate existing data from randomised controlled trials on hypoplastic left heart syndrome. METHODS: Hypoplastic left heart syndrome specific randomised controlled trials published between January 2005 and September 2021 in MEDLINE, EMBASE, and Cochrane databases were included. Regardless of clinical outcomes, we included all randomised controlled trials about hypoplastic left heart syndrome and categorised them according to their results. Two reviewers independently assessed for eligibility, relevance, and data extraction. The primary outcome was mortality after Norwood surgery. Study quality and heterogeneity were assessed. A random-effects model was used for analysis. RESULTS: Of the 33 included randomised controlled trials, 21 compared right ventricle-to-pulmonary artery shunt and modified Blalock-Taussig-Thomas shunt during the Norwood procedure, and 12 regarded medication, surgical strategy, cardiopulmonary bypass tactics, and ICU management. Survival rates up to 1 year were superior in the right ventricle-to-pulmonary artery shunt group; this difference began to disappear at 3 years and remained unchanged until 6 years. The right ventricle-to-pulmonary artery shunt group had a significantly higher reintervention rate from the interstage to the 6-year follow-up period. Right ventricular function was better in the modified Blalock-Taussig-Thomas shunt group 1-3 years after the Norwood procedure, but its superiority diminished in the 6-year follow-up. Randomised controlled trials regarding medical treatment, surgical strategy during cardiopulmonary bypass, and ICU management yielded insignificant results. CONCLUSIONS: Although right ventricle-to-pulmonary artery shunt appeared to be superior in the early period, the two shunts applied during the Norwood procedure demonstrated comparable long-term prognosis despite high reintervention rates in right ventricle-to-pulmonary artery shunt due to pulmonary artery stenosis. For medical/perioperative management of hypoplastic left heart syndrome, further randomised controlled trials are needed to deliver specific evidence-based recommendations.

Investigation of the optimal medium and application strategy for foot-and-mouth disease vaccine antigen production.

AIMS: For the effective production of 146S particles, which determines foot-and-mouth disease (FMD) vaccine efficacy, we aimed to identify the optimal medium that is easy-to-use, productive and economically affordable for the large-scale production of FMD vaccine. METHODS AND RESULTS: Nine combinations of cell growth media and replacement media were tested for virus propagation. Apart from the replacement strategy, we tested a simple addition strategy involving the addition of 30% v/v of fresh medium to the total spent medium using the Cellvento BHK-200 (Vento). Unlike other tested media that produced poor yields of 146S particles when the spent media were not eliminated, Vento exhibited high productivity with the 30% addition strategy. CONCLUSIONS: Considering its lower price and media consumption compared to those of other media that require media replacement, the 30% addition strategy of Vento is highly effective. Furthermore, owing to its simple application strategy, it makes the scale-up process easy and helps in saving the time and labour involved in spent media removal. SIGNIFICANCE AND IMPACT OF THE STUDY: Through the first comparative assessment of commercial media for the 146S particle recovery, this study suggests the best practical medium for the industrial-scale production of FMD vaccines.

Oxytocin alleviates cellular senescence through oxytocin receptor-mediated extracellular signal-regulated kinase/Nrf2 signalling.

BACKGROUND: Oxytocin (OT) is a neuropeptide hormone that has many beneficial biological effects, including protection against age-related disorders. However, less is known about its role in intrinsic skin ageing, which is accelerated by an increase in senescent cell fraction in skin tissue. OBJECTIVES: To investigate the novel function and the underlying mechanism of OT in preventing cellular senescence in normal human dermal fibroblasts (NHDFs) isolated from the skin of female donors of different ages. METHODS: NHDFs from young and old donors were exposed to conditioned medium from senescent or control NHDFs in the presence or absence of 10 nmol L-1 OT for 3 days, and were continuously subcultured for 12 days. Subsequently, various age-associated signs of senescence including decreased proliferation rate, elevated p16 and p21 levels, and positivity for senescence-associated ß-galactosidase expression were examined. RESULTS: We found that OT suppressed senescence-associated secretory phenotype-induced senescence in NHDFs, and its effect depended on the age of the donor's NHDFs. The inhibitory effects of OT required signalling by OT receptor-mediated extracellular signal-regulated kinase/Nrf2 (nuclear factor erythroid 2-related factor 2). The age-dependent antisenescence effects of OT are closely related to hypermethylation of the OT receptor gene (OXTR). CONCLUSIONS: Our findings bring to light the role of OT in the prevention of skin ageing, which might allow development of new clinical strategies. What's already known about this topic? Senescent keratinocytes and fibroblasts accumulate with age in the skin and contribute to the loss of skin function and integrity during ageing. Senescent cells secrete senescence-associated secretory phenotype (SASP), which includes the release of proinflammatory cytokines such as interleukin (IL)-6 and IL-1, chemokines, extracellular matrix-remodelling proteases and growth factors. The neuropeptide oxytocin (OT) and its receptor (OXTR) have protective effects against various age-related disorders. What does this study add? OT suppressed SASP-induced cellular senescence in normal human dermal fibroblasts (NHDFs), depending on the age of the NHDFs' donor. The inhibitory effects of OT on cellular senescence required OXTR-mediated phosphorylation of extracellular signal-regulated kinase, which enhanced nuclear localization of Nrf2, a vital factor in the antioxidant defence system. The age-specific antisenescent effects of OT were closely related to hypermethylation of OXTR. What is the translational message? Our results suggest that OT and OXTR agonists could be clinically promising agents for the improvement of age-associated skin ageing, especially in women.

IFN-free therapy is associated with restoration of type I IFN response in HIV-1 patients with acute HCV infection who achieve SVR.

Interferon (IFN)-free direct-acting antiviral agents (DAAs) have revolutionized chronic hepatitis C virus (HCV) treatment; early studies suggest excellent efficacy in acute HCV. However, changes in innate immune responses during DAA therapy for acute HCV are unknown. We studied interferon-stimulated gene (ISG) expression and related cytokines/chemokines in HIV-infected patients with acute HCV receiving sofosbuvir plus ribavirin (SOF+RBV) as part of the A5327 clinical trial. ISG expression was determined from PBMCs, and circulating cytokines/chemokines were quantified from serum from study participants. The overall sustained virologic response (SVR) was 57%; all treatment failures were due to virologic relapse. Apart from NOS2a, baseline ISG/chemokine/cytokine levels were similar irrespective of treatment outcome. Downregulation of ISGs was observed at treatment week four and end of treatment (EOT), implicating HCV in establishing elevated ISGs early during HCV infection. Levels of many of these ISGs increased at post-treatment week 12 (PTW12) in relapsers only, coinciding with recurrent HCV RNA. Eleven ISGs were differentially expressed in responders vs relapsers. On-treatment viral suppression was also associated with a reduction in IP-10, CXCL11 and MIP-1ß levels. In contrast, circulating IFN-α levels were significantly higher at EOT and PTW12 in responders vs relapsers. Upregulation of peripheral ISG expression is established early in the course of HCV infection during acute HCV infection, but did not predict subsequent treatment outcome with SOF+RBV. ISGs were downregulated during therapy and increased post-therapy in relapsers. IFN-α levels were higher in responders at EOT/PTW12, suggesting that impaired type I IFN production/secretion may contribute to relapse.

Selective Release System for Antioxidative and Anti-Inflammatory Activities Using H2O2-Responsive Therapeutic Nanoparticles.

We developed nanoparticles that were degraded by H2O2, a reactive oxygen species (ROS), to study a drug delivery system that targets damaged skin cells with oxidative stress and inflammation. In this study, tyrosol-incorporated copolyoxalate (TPOX) was synthesized by using 1,4-cyclohexanedimethanol, 4-(2-hydroxyethyl)phenol (tyrosol), and oxalyl chloride (Mw ∼ 8835 Da). In vitro drug release behavior was assessed by loading nile red, a lipophilic fluorescent material such as quercetin, into the TPOX nanoparticles. The results indicated that the release of TPOX nanopaticles depended on the H2O2 concentration, but was pH-independent. We confirmed that TPOX nanoparticles under oxidative conditions in oxidative- or inflammatory-damaged cells selectively released entrapped nile red through the degradation by H2O2 for contributing to antioxidant and anti-inflammatory effects. For application, we prepared and evaluated the cytoprotective effect of quercetin-loaded TPOX (QTPOX) nanoparticles against oxidative and inflammatory stress. They showed a strong cytoprotective effect against H2O2-induced cell damage in HaCaT and RAW 264.7 cells. Also, QTPOX nanoparticles inhibited the main factors of LPS-induced inflammation, including iNOS, COX-2, IL-1, TNF-α, and NO production. These results suggest that QTPOX as H2O2-responsive therapeutic nanoparticles is highly potent and versatile as drug delivery system through selective and intensive drug release mechanism for the treatment of abnormal and inflammatory skin diseases.

Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections.

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r2=0.98-1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml-1 of IL-18 after adjusting for covariates (rs80011693; rs111311302 ß=-0.06, P-value=2.7 × 10-4). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections.

Ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic hepatitis C and bleeding disorders.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. AIM: We evaluated the efficacy and safety of ledipasvir-sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1-4 infection and an inherited bleeding disorder. METHODS: Ledipasvir-sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. RESULTS: The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. CONCLUSION: Treatment with ledipasvir-sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

Analysis of resistance-associated substitutions in acute hepatitis C virus infection by deep sequencing across six genotypes and three continents.

Several direct-acting antivirals (DAAs) have been approved for the treatment of chronic hepatitis C virus (HCV) infections, opening the door to highly effective interferon-free treatment regimens. Resistance-associated substitutions (RASs) have been reported both in treatment-naïve patients and following treatment with protease (NS3), phosphoprotein (NS5A) and polymerase (NS5B) inhibitors. The prevalence of naturally occurring RASs in untreated HCV-infected individuals has mostly been analysed in those infected with genotype 1 (GT1), in the late phase of infection, and only within limited regions of the genome. Furthermore, the geographic distribution of RASs remains poorly characterized. In this study, we used next-generation sequencing to analyse full-length HCV genomes for the prevalence of RASs in acute HCV infections identified in nine international prospective cohorts. RASs were analysed in 179 participants infected with all six major HCV genotypes (GT1-GT6), and the geographic distribution of RASs was assessed in 107 GT1a and GT3a samples. While RASs were detected at varied frequencies across the three genomic regions, and between genotypes, RASs relevant to multiple DAAs in the leading IFN-free regimens were rarely detected in combination. Low-frequency RASs (<10% of the viral population) were also shown to have a GT-specific distribution. The main RASs with geographic associations were NS3 Q80K in GT1a samples and NS5B N142T in GT3a. These data provide the backdrop for prospective surveillance of RASs during DAA treatment scale-up.

Phylogenetic analysis of full-length, early infection, hepatitis C virus genomes among people with intravenous drug use: the InC3 Study.

Cross-continental phylogenetic analysis is important to understand subtle molecular differences of currently circulating hepatitis C virus (HCV) subtypes. Existence of such differences can be crucial in pursuing a universal hepatitis C vaccine. We characterized molecular epidemiology of early HCV infections identified across nine cohorts [North America (n=4), Australia (n=4) and Europe (n=1)] in the International Collaborative of Incident HIV and Hepatitis C in Injecting Cohorts (InC3 ). One hundred and ninety-two full-length HCV genomes were amplified from plasma of incident infections and subjected to next generation sequencing to establish the largest cross-continental, full-length acute HCV genomic data set available to date. Genomes from the most common subtypes (1a: n=94, 2b: n=15 and 3a: n=68) were used in phylogenetic analysis. Using full genome trees, 78 sequences (44%) were found to lie within 29 phylogenetic clusters/pairs defined on the basis of molecular similarity of consensus sequences. Of these, 26 each had exclusively Australian or North American sequences indicating a strong geographical bias for molecular similarity. On further analysis of behavioural and demographic associations, binary logistic regression analysis showed that older age and non-Caucasian ethnicity were significantly associated with clustering. HCV probably evolves in micro-epidemics within geographically isolated communities.

Metabolic Syndrome Is not an Independent Risk Factor for Hearing Impairment.

OBJECTIVE: We aimed to investigate the association between metabolic syndrome (MS) and hearing impairment (HI) using nationally representative data from Korean adults. DESIGN, SETTING AND PARTICIPANTS: A total of 16,799 subjects (≥19 years old; 7,170 men and 9,629 women) who underwent pure tone audiometry testing were included in the analysis. Data were obtained from the fifth Korea National Health and Nutrition Examination Survey (2010-2012). Subjects were divided into two groups according to the presence of MS. RESULTS: Among the subjects with MS, 47% had HI. Logistic regression analysis revealed that MS was not an independent risk factor for HI, although increased fasting plasma glucose (OR 1·4, 95% CI: 1·1-1·8) was independently associated with HI. In addition, older age, male sex, very low body mass index (≤17·5 kg/m2), lower education level, smoking history, and occupational noise exposure were independently associated with HI. For low-frequency HI, independent risk factors included older age, lower educational level, lower economic status, and very low BMI (≤17·5 kg/m2). For high-frequency HI, independent risk factors included older age, male sex, lower educational level, lower economic status, increased blood pressure, lower high-density lipoprotein cholesterol, and smoking history. CONCLUSIONS: MS itself was not an independent risk factor for HI, and, among the individual metabolic components, only increased fasting plasma glucose was independently associated with HI.

Clinical impact of treatment timing for chronic hepatitis C infection: a decision model.

Recent advances in the treatment of hepatitis C virus (HCV) infection have led to the availability of both highly efficacious interferon-containing and interferon-sparing regimens. However, the use of such therapies faces restrictions due to high costs. For patients who are medically eligible to receive interferon, the choice between the two will likely be impacted by preferences surrounding interferon, severity of disease, coverage policies and out-of-pocket costs. We developed a decision model to quantify the trade-offs between immediate, interferon-containing therapy and delayed, interferon-free therapy for patients with chronic, genotype 1 HCV infection. We projected the quality-adjusted life expectancy stratified by the presence or absence of cirrhosis for four strategies: (i) no treatment; (ii) immediate, one-time treatment with an interferon-containing regimen; (iii) immediate treatment as above with the opportunity for retreatment in patients who fail to achieve sustained virologic response with interferon-free therapy in 1 year; and (iv) delayed therapy with interferon-free therapy in 1 year. When compared to one-time immediate treatment with the interferon-containing regimen, delayed treatment with the interferon-free regimen in 1 year resulted in longer life expectancy, with a 0.2 quality-adjusted life year (QALY) increase in noncirrhotic patients, and a 1.1 QALY increase in patients with cirrhosis. This superiority in health benefits was lost when wait time for interferon-free therapy was greater than 3-3.2 years. In this modelling analysis, interferon-free therapy resulted in superior health benefits compared to immediate therapy with interferon until wait time exceeded 3-3.2 years. Such data can inform decision-making regarding treatment initiation for HCV as healthcare financing evolves.

Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort.

Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high-risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co-infected. SVR among those with HCV mono-infection was 64% by intention to treat; SVR was 68% among HCV/HIV co-infection. Independent predictors of SVR in HCV mono-infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85-0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13-4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03-4.12, P = 0.041) and age ≥40 years (vs <30: aOR 2.92, 95% CI 1.31-6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype-1 infection. Interferon-based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision-making.

A longitudinal study of hepatitis C virus testing and infection status notification on behaviour change in people who inject drugs.

BACKGROUND: Hepatitis C virus (HCV) testing and counselling have the potential to impact individual behaviour and transmission dynamics at the population level. Evidence of the impact of an HCV-positive status notification on injection risk reduction is limited. The objective of our study was to (1) assess drug and alcohol use and injection risk behaviours following notification; (2) to compare behaviour change in people who inject drugs (PWID) who received a positive test result and those who remained negative; and (3) to assess the effect of age on risk behaviour. METHODS: Data from the International Collaboration of Incident HIV and HCV Infection in Injecting Cohorts (InC3 Study) were analysed. Participants who were initially HCV seronegative were followed prospectively with periodic HCV blood testing and post-test disclosure and interview-administered questionnaires assessing drug use and injection behaviours. Multivariable generalised estimating equations were used to assess behavioural changes over time. RESULTS: Notification of an HCV-positive test was independently associated with a small increase in alcohol use relative to notification of a negative test. No significant differences in postnotification injection drug use, receptive sharing of ancillary injecting equipment and syringe borrowing postnotification were observed between diagnosis groups. Younger PWID receiving a positive HCV test notification demonstrated a significant increase in subsequent alcohol use compared with younger HCV negative. CONCLUSIONS: The proportion of PWID reporting alcohol use increased among those receiving an HCV-positive notification, increased the frequency of alcohol use postnotification, while no reduction in injection drug use behaviours was observed between notification groups. These findings underscore the need to develop novel communication strategies during post-test notification to improve their impact on subsequent alcohol use and risk behaviours.

Factors associated with hepatitis C virus RNA levels in early chronic infection: the InC3 study.

Improved understanding of natural history of hepatitis C virus (HCV) RNA levels in chronic infection provides enhanced insights into immunopathogenesis of HCV and has implications for the clinical management of chronic HCV infection. This study assessed factors associated with HCV RNA levels during early chronic infection in a population with well-defined early chronic HCV infection. Data were from an international collaboration of nine prospective cohorts studying acute HCV infection (InC(3) study). Individuals with persistent HCV and detectable HCV RNA during early chronic infection (one year [±4 months] postinfection) were included. Distribution of HCV RNA levels during early chronic infection was compared by selected host and virological factors. A total of 308 individuals were included. Median HCV RNA levels were significantly higher among males (vs females; 5.15 vs 4.74 log IU/mL; P < 0.01) and among individuals with HIV co-infection (vs no HIV; 5.89 vs 4.86; P = 0.02). In adjusted logistic regression, male sex (vs female, adjusted odds ratio [AOR]: 1.93; 95%CI: 1.01, 3.69), interferon lambda 4 (IFNL4) rs12979860 CC genotype (vs TT/CT; AOR: 2.48; 95%CI: 1.42, 4.35), HIV co-infection (vs no HIV; AOR: 3.27; 95%CI: 1.35, 7.93) and HCV genotype G2 (vs G3; AOR: 5.40; 95%CI: 1.63, 17.84) were independently associated with high HCV RNA levels (>5.6 log IU/mL = 400 000 IU/mL). In conclusion, this study demonstrated that IFNL4 rs12979860 CC genotype, male sex, HIV co-infection and HCV genotype G2 are associated with high HCV RNA levels in early chronic infection. These factors exert their role as early as one year following infection.

Genome-wide association study of hepatitis C virus- and cryoglobulin-related vasculitis.

The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10(-9)). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region.

Admixture analysis of spontaneous hepatitis C virus clearance in individuals of African descent.

Hepatitis C virus (HCV) infects an estimated 3% of the global population with the majority of individuals (75-85%) failing to clear the virus without treatment, leading to chronic liver disease. Individuals of African descent have lower rates of clearance compared with individuals of European descent and this is not fully explained by social and environmental factors. This suggests that differences in genetic background may contribute to this difference in clinical outcome following HCV infection. Using 473 individuals and 792,721 single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS), we estimated local African ancestry across the genome. Using admixture mapping and logistic regression, we identified two regions of interest associated with spontaneous clearance of HCV (15q24, 20p12). A genome-wide significant variant was identified on chromosome 15 at the imputed SNP, rs55817928 (P=6.18 × 10(-8)) between the genes SCAPER and RCN. Each additional copy of the African ancestral C allele is associated with 2.4 times the odds of spontaneous clearance. Conditional analysis using this SNP in the logistic regression model explained one-third of the local ancestry association. Additionally, signals of selection in this area suggest positive selection due to some ancestral pathogen or environmental pressure in African, but not in European populations.