Searching for "monogenic diabetes" in dogs using a candidate gene approach

BACKGROUND: Canine diabetes is a common endocrine disorder with an estimated breed-related prevalence ranging from 0.005% to 1.5% in pet dogs. Increased prevalence in some breeds suggests that diabetes in dogs is influenced by genetic factors and similarities between canine and human diabetes phenotypes suggest that the same genes might be associated with disease susceptibility in both species. Between 1-5% of human diabetes cases result from mutations in a single gene, including maturity onset diabetes of the adult (MODY) and neonatal diabetes mellitus (NDM). It is not clear whether monogenic forms of diabetes exist within some dog breeds. Identification of forms of canine monogenic diabetes could help to resolve the heterogeneity of the condition and lead to development of breed-specific genetic tests for diabetes susceptibility. RESULTS: Seventeen dog breeds were screened for single nucleotide polymorphisms (SNPs) in eighteen genes that have been associated with human MODY/NDM. Six SNP associations were found from five genes, with one gene (ZFP57) being associated in two different breeds. CONCLUSIONS: Some of the genes that have been associated with susceptibility to MODY and NDM in humans appear to also be associated with canine diabetes, although the limited number of associations identified in this study indicates canine diabetes is a heterogeneous condition and is most likely to be a polygenic trait in most dog breeds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2052-6687-1-8) contains supplementary material, which is available to authorized users

The UK DNA banking network: a “fair access” biobank

The UK DNA Banking Network (UDBN) is a secondary biobank: it aggregates and manages resources (samples and data) originated by others. The network comprises, on the one hand, investigator groups led by clinicians each with a distinct disease specialism and, on the other hand, a research infrastructure to manage samples and data. The infrastructure addresses the problem of providing secure quality-assured accrual, storage, replenishment and distribution capacities for samples and of facilitating access to DNA aliquots and data for new peer-reviewed studies in genetic epidemiology. ‘Fair access’ principles and practices have been pragmatically developed that, unlike open access policies in this area, are not cumbersome but, rather, are fit for the purpose of expediting new study designs and their implementation. UDBN has so far distributed >60,000 samples for major genotyping studies yielding >10 billion genotypes. It provides a working model that can inform progress in biobanking nationally, across Europe and internationally

Molecular analysis of HLA-DQB1 alleles in childhood common acute lymphoblastic leukaemia.

Epidemiological studies suggest that childhood common acute lymphoblastic leukaemia (c-ALL) may be the rare outcome of early post-natal infection with a common infectious agent. One of the factors that may determine whether a child succumbs to c-ALL is how it responds to the candidate infection. Since immune responses to infection are under the partial control of (human leucocyte antigen) HLA genes, an association between an HLA allele and c-ALL could provide support for an infectious aetiology. To define the limit of c-ALL susceptibility within the HLA region, we have compared HLA-DQB1 allele frequencies in a cohort of 62 children with c-ALL with 76 newborn controls, using group-specific polymerase chain reaction (PCR) amplification, and single-strand conformation polymorphism (SSCP) analysis. We find that a significant excess of children with c-ALL type for DQB1*05 [relative risk (RR): 2.54, uncorrected P=0.038], and a marginal excess with DQB1*0501 (RR: 2.18; P=0.095). Only 3 of the 62 children with c-ALL have the other susceptibility allele, DPB1*0201 as well as DQB1*0501, whereas 15 had one or the other allele. This suggests that HLA-associated susceptibility may be determined independently by at least two loci, and is not due to linkage disequilibrium. The combined relative risk of the two groups of children with DPB1*0201 and/or DQB1*0501 is 2.76 (P=0.0076). Analysis of amino acids encoded by exon 2 of DQB1 reveal additional complexity, with significant (P<0.05) or borderline-significant increases in Gly26, His30, Val57, Glu66-Val67 encoding motifs in c-ALL compared with controls. Since these amino acids are not restricted to DQB1*0501, our results suggest that, as with DPB1, the increased risk of c-ALL associated with DQB1 is determined by specific amino acid encoding motifs rather than by an individual allele. These results also suggest that HLA-associated susceptibility to c-ALL may not be restricted to the region bounded by DPB1 and DQB1

Paleo-landscapes of the Northern Patagonian Massif, Argentina

Fil: Aguilera, Emilia Yolanda. Instituto de Geomorfología y Suelos (IGS). Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Rabassa, Jorge. Laboratorio de Geomorfología y Cuaternario. CADIC. Universidad Nacional de Tierra del Fuego; ArgentinaFil: Aragón, Eugenio. Centro de Investigaciones Geológicas (CIG). Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; Argentin

Efficient Computation of Casimir Interactions between Arbitrary 3D Objects

We introduce an efficient technique for computing Casimir energies and forces between objects of arbitrarily complex 3D geometries. In contrast to other recently developed methods, our technique easily handles non-spheroidal, non-axisymmetric objects and objects with sharp corners. Using our new technique, we obtain the first predictions of Casimir interactions in a number of experimentally relevant geometries, including crossed cylinders and tetrahedral nanoparticles.Comment: 4 pages, 4 figure

Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds

Abstract: Background: Canine diabetes mellitus (DM) is a common endocrine disease in domestic dogs. A number of pathological mechanisms are thought to contribute to the aetiopathogenesis of relative or absolute insulin deficiency, including immune-mediated destruction of pancreatic beta cells. DM risk varies considerably between different dog breeds, suggesting that genetic factors are involved and contribute susceptibility or protection. Associations of particular dog leucocyte antigen (DLA) class II haplotypes with DM have been identified, but investigations to date have only considered all breeds pooled together. The aim of this study was to analyse an expanded data set so as to identify breed-specific diabetes-associated DLA haplotypes. Methods: The 12 most highly represented breeds in the UK Canine Diabetes Register were selected for study. DLA-typing data from 646 diabetic dogs and 912 breed-matched non-diabetic controls were analysed to enable breed-specific analysis of the DLA. Dogs were genotyped for allelic variation at DLA-DRB1, -DQA1, -DQB1 loci using DNA sequence-based typing. Genotypes from all three loci were combined to reveal three-locus DLA class II haplotypes, which were evaluated for statistical associations with DM. This was performed for each breed individually and for all breeds pooled together. Results: Five dog breeds were identified as having one or more DLA haplotype associated with DM susceptibility or protection. Four DM-associated haplotypes were identified in the Cocker Spaniel breed, of which one haplotype was shared with Border Terriers. In the three breeds known to be at highest risk of DM included in the study (Samoyed, Tibetan Terrier and Cairn Terrier), no DLA haplotypes were found to be associated with DM. Conclusions: Novel DLA associations with DM in specific dog breeds provide further evidence that immune response genes contribute susceptibility to this disease in some cases. It is also apparent that DLA may not be contributing obvious or strong risk for DM in some breeds, including the seven breeds analysed for which no associations were identified

COVID-19 Vaccination and Diabetes Mellitus: How Much Has It Made a Difference to Outcomes Following Confirmed COVID-19 Infection?

Introduction: Since early 2020 the whole world has been challenged by the SARS-CoV-2 virus (COVID-19), its successive variants and the associated pandemic caused. We have previously shown that for people living with type 2 diabetes (T2DM), the risk of being admitted to hospital or dying following a COVID-19 infection progressively decreased through the first months of 2021. In this subsequent analysis we have examined how the UK COVID-19 vaccination programme impacted differentially on COVID-19 outcomes in people with T1DM or T2DM compared to appropriate controls. Methods: T1DM and T2DM affected individuals were compared with their matched controls on 3:1 ratio basis. A 28-day hospital admission or mortality was used as the binary outcome variable with diabetes status and vaccination for COVID-19 as the main exposure variables. Results: A higher proportion of T1DM individuals vs their controls was found to be vaccinated at the point of their first recorded positive COVID-19 test when compared to T2DM individuals vs their controls. Regarding the 28-day hospital admission rate, there was a greater and increasing protective effect of subsequent vaccination dosage (one, two or three) in mitigating the effects of COVID-19 infection versus no vaccination in T1DM than in T2DM individuals when compared with matched controls. Similar effects were observed in T2DM for death. Across both diabetes and non-diabetes individuals, those at greater socio-economic disadvantage were more likely to test positive for COVID-19 in the early phase of the pandemic. For T2DM individuals socio-economic disadvantage was associated with a greater likelihood of hospital admission and death, independent of vaccination status. Age and male sex were also independently associated with 28-day hospital admission in T2DM and to 28-day mortality, independent of vaccination status. African ethnicity was also an additional factor for hospital admission in people with T2DM. Conclusion: A beneficial effect of COVID-19 vaccination was seen in mitigating the harmful effects of COVID-19 infection; this was manifest in reduced hospital admission rate in T1DM individuals with a lesser effect in T2DM when compared with matched controls, regarding both hospital admission and mortality. Socio-economic disadvantage influenced likelihood of COVID-19 confirmed infection and the likelihood of hospital admission/death independent of the number of vaccinations given in T2DM

Functional gene group analysis indicates no role for heterotrimeric G proteins in cognitive ability

Previous functional gene group analyses implicated common single nucleotide polymorphisms (SNPs) in heterotrimeric G protein coding genes as being associated with differences in human intelligence. Here, we sought to replicate this finding using five independent cohorts of older adults including current IQ and childhood IQ, and using both gene- and SNP-based analytic strategies. No significant associations were found between variation in heterotrimeric G protein genes and intelligence in any cohort at either of the two time points. These results indicate that, whereas G protein systems are important in cognition, common genetic variation in these genes is unlikely to be a substantial influence on human intelligence differences