Recipient IL28B polymorphism is an important independent predictor of posttransplant diabetes mellitus in liver transplant patients with chronic hepatitis C

IL28B polymorphisms are strongly associated with response to treatment for HCV infection. IL28B acts on interferon-stimulated genes via the JAK-STAT pathway, which has been implicated in development of insulin resistance. We investigated whether IL28B polymorphisms are associated with posttransplant diabetes mellitus (DM). Consecutive HCV patients who underwent liver transplantation between 1-1995 and 1-2011 were studied. Genotyping of the polymorphism rs12979860 was performed on DNA collected from donors and recipients. Posttransplant DM was screened for by fasting blood glucoses every 1-3 months. Of 221 included patients, 69 developed posttransplant DM (31%). Twenty-two patients with recipient IL28B genotype TT (48%), 25 with IL28B genotype CT (25%) and 22 with IL28B genotype CC (29%) developed posttransplant DM. TT genotype was statistically significantly associated with posttransplant DM over time (log rank p = 0.012 for TT vs. CT and p = 0.045 for TT vs. CC). Multivariate Cox regression analysis correcting for donor age, body mass index, baseline serum glucose, baseline serum cholesterol, recipient age and treated rejection, showed that recipient IL28B genotype TT was independently associated with posttransplant DM (hazard ratio 2.51; 95% confidence interval 1.17-5.40; p = 0.011). We conclude that the risk of developing posttransplant DM is significantly increased in recipients carrying the TT polymorphism of the IL28B gene. An analysis of liver transplant recipients with hepatitis C virus infection finds that the risk of developing posttransplant diabetes mellitus is significantly increased in recipients carrying the TT polymorphism of the IL28B gene

APACHE III outcome prediction in patients admitted to the intensive care unit after liver transplantation: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>The Acute Physiology and Chronic Health Evaluation (APACHE) III prognostic system has not been previously validated in patients admitted to the intensive care unit (ICU) after orthotopic liver transplantation (OLT). We hypothesized that APACHE III would perform satisfactorily in patients after OLT</p> <p>Methods</p> <p>A retrospective cohort study was performed. Patients admitted to the ICU after OLT between July 1996 and May 2008 were identified. Data were abstracted from the institutional APACHE III and liver transplantation databases and individual patient medical records. Standardized mortality ratios (with 95% confidence intervals) were calculated by dividing the observed mortality rates by the rates predicted by APACHE III. The area under the receiver operating characteristic curve (AUC) and the Hosmer-Lemeshow C statistic were used to assess, respectively, discrimination and calibration of APACHE III.</p> <p>Results</p> <p>APACHE III data were available for 918 admissions after OLT. Mean (standard deviation [SD]) APACHE III (APIII) and Acute Physiology (APS) scores on the day of transplant were 60.5 (25.8) and 50.8 (23.6), respectively. Mean (SD) predicted ICU and hospital mortality rates were 7.3% (15.4) and 10.6% (18.9), respectively. The observed ICU and hospital mortality rates were 1.1% and 3.4%, respectively. The standardized ICU and hospital mortality ratios with their 95% C.I. were 0.15 (0.07 to 0.27) and 0.32 (0.22 to 0.45), respectively.</p> <p>There were statistically significant differences in APS, APIII, predicted ICU and predicted hospital mortality between survivors and non-survivors. In predicting mortality, the AUC of APACHE III prediction of hospital death was 0.65 (95% CI, 0.62 to 0.68). The Hosmer-Lemeshow C statistic was 5.288 with a p value of 0.871 (10 degrees of freedom).</p> <p>Conclusion</p> <p>APACHE III discriminates poorly between survivors and non-survivors of patients admitted to the ICU after OLT. Though APACHE III has been shown to be valid in heterogenous populations and in certain groups of patients with specific diagnoses, it should be used with caution – if used at all – in recipients of liver transplantation.</p

Liver transplantation as a new standard of care in patients with perihilar cholangiocarcinoma?:Results from an international benchmark study

Objective: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons.Background: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC.Methods: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014–2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥ 50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter &lt;3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers.Results: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤ 5.2%; comprehensive complication index at 1 year of ≤ 33.7; grade ≥ 3 complication rates ≤ 66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n = 106) (62% vs 32%, P &lt; 0.001).Conclusion: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC.</p

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development