Common Variants in CLDN2 and MORC4 Genes Confer Disease Susceptibility in Patients with Chronic Pancreatitis

A recent genome-wide association study (GWAS) identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10^-09; rs12008279—OR 1.56, P = 1.53 x 10^-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10^-09; rs6622126—OR 1.75, P = 4.04x10^-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10^-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10^-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.     

Naturally Occurring Autoantibodies against Tau Protein Are Reduced in Parkinson's Disease Dementia

ResultsPDD patients had significantly decreased nAbs-tau serum levels compared to PDND patients (p = 0.007), whereas the serum titers of nAbs-αS and nAbs-Aβ were unchanged. For all three nAbs, no significant differences in avidity were found between PDD and PDND cohorts. However, within both patient groups, nAbs-tau showed lowest avidity to their antigen, followed by nAbs-αS, and nAbs-Aβ. Though, due to a high interassay coefficient of variability and the exclusion of many samples below the limit of detection, conclusions for nAbs-Aβ are only conditionally possible.ConclusionWe detected a significantly decreased nAbs-tau serum level in PDD patients, indicating a potential linkage between nAbs-tau serum titer and cognitive deficits in PD. Thus, further investigation in larger samples is justified to confirm our findings.     

Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a,Randomized, Double-Blind,Placebo-Controlled Research in Japanese Patients

Objective

Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS.

Design

A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial.

Methods

The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1^st endpoint) and upon completion or discontinuation of the study (2^nd endpoint) of the dosing.

Results

Statistics analyses revealed a marginal BRC treatment efficacy with P≦20%to placebo by 1^st and 2^nd endpoint analysis. In the 1^st endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2^nd endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence.

Conclusions

BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment.

Trial Registration

UMIN Clinical Trials UMIN000008527     

The sheep genome reference sequence: a work in progress

Until recently, the construction of a reference genome was performed using Sanger sequencing alone. The emergence of next-generation sequencing platforms now means reference genomes may incorporate sequence data generated from a range of sequencing platforms, each of which have different read length, systematic biases and mate-pair characteristics. The objective of this review is to inform the mammalian genomics community about the experimental strategy being pursued by the International Sheep Genomics Consortium (ISGC) to construct the draft reference genome of sheep (Ovis aries). Component activities such as data generation, sequence assembly and annotation are described, along with information concerning the key researchers performing the work. This aims to foster future participation from across the research community through the coordinated activities of the consortium. The review also serves as a ‘marker paper’ by providing information concerning the pre-publication release of the reference genome. This ensures the ISGC adheres to the framework for data sharing established at the recent Toronto International Data Release Workshop and provides guidelines for data users.     

Coronavirus and Paramyxovirus Shedding by Bats in a Cave and Buildings in Ethiopia

EcoHealth - Bats are important hosts of zoonotic viruses with pandemic potential, including filoviruses, MERS-Coronavirus (CoV), SARS-CoV -1, and likely SARS-CoV-2. Viral infection and transmission...     

African Glucose-6-Phosphate Dehydrogenase Alleles Associated with Protection from Severe Malaria in Heterozygous Females in Tanzania

X-linked Glucose-6-phosphate dehydrogenase (G6PD) A- deficiency is prevalent in sub-Saharan Africa populations, and has been associated with protection from severe malaria. Whether females and/or males are protected by G6PD deficiency is uncertain, due in part to G6PD and malaria phenotypic complexity and misclassification. Almost all large association studies have genotyped a limited number of G6PD SNPs (e.g. G6PD202 / G6PD376), and this approach has been too blunt to capture the complete epidemiological picture. Here we have identified 68 G6PD polymorphisms and analysed 29 of these (i.e. those with a minor allele frequency greater than 1%) in 983 severe malaria cases and controls in Tanzania. We establish, across a number of SNPs including G6PD376, that only female heterozygotes are protected from severe malaria. Haplotype analysis reveals the G6PD locus to be under balancing selection, suggesting a mechanism of protection relying on alleles at modest frequency and avoiding fixation, where protection provided by G6PD deficiency against severe malaria is offset by increased risk of life-threatening complications. Our study also demonstrates that the much-needed large-scale studies of severe malaria and G6PD enzymatic function across African populations require the identification and analysis of the full repertoire of G6PD genetic markers.