Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation. PTDM prevalence varies due to different diabetes definitions. Consensus guidelines for the diagnosis ...of PTDM have been published based on random blood glucose levels, glycated hemoglobin (HbA1c), and oral glucose tolerance test (OGTT). The task of diagnosing PTDM continues to pose challenges, given the potential for diabetes to manifest at different time points after transplantation, thus demanding constant clinical vigilance and repeated testing. Interpreting HbA1c levels can be challenging after renal transplantation. Pre-transplant risk factors for PTDM include obesity, sedentary lifestyle, family history of diabetes, ethnicity (e.g., African-Caribbean or South Asian ancestry), and genetic risk factors. Risk factors for PTDM include immunosuppressive drugs, weight gain, hepatitis C, and cytomegalovirus infection. There is also emerging evidence that genetic and epigenetic variation in the organ transplant recipient may influence the risk of developing PTDM. This review outlines many known risk factors for PTDM and details some of the pathways, genetic variants, and epigenetic features associated with PTDM. Improved understanding of established and emerging risk factors may help identify people at risk of developing PTDM and may reduce the risk of developing PTDM or improve the management of this complication of organ transplantation.
Chronic kidney disease (CKD) is a major global health problem with an increasing prevalence partly driven by aging population structure. Both genomic and environmental factors contribute to this ...complex heterogeneous disease. CKD heritability is estimated to be high (30-75%). Genome-wide association studies (GWAS) and GWAS meta-analyses have identified several genetic loci associated with CKD, including variants in
, solute carriers, and E3 ubiquitin ligases. However, these genetic markers do not account for all the susceptibility to CKD, and the causal pathways remain incompletely understood; other factors must be contributing to the missing heritability. Less investigated biological factors such as telomere length; mitochondrial proteins, encoded by nuclear genes or specific mitochondrial DNA (mtDNA) encoded genes; structural variants, such as copy number variants (CNVs), insertions, deletions, inversions and translocations are poorly covered and may explain some of the missing heritability. The sex chromosomes, often excluded from GWAS studies, may also help explain gender imbalances in CKD. In this review, we outline recent findings on molecular biomarkers for CKD (telomeres, CNVs, mtDNA variants, sex chromosomes) that typically have received less attention than gene polymorphisms. Shorter telomere length has been associated with renal dysfunction and CKD progression, however, most publications report small numbers of subjects with conflicting findings. CNVs have been linked to congenital anomalies of the kidney and urinary tract, posterior urethral valves, nephronophthisis and immunoglobulin A nephropathy. Information on mtDNA biomarkers for CKD comes primarily from case reports, therefore the data are scarce and diverse. The most consistent finding is the A3243G mutation in the
gene, mainly associated with focal segmental glomerulosclerosis. Only one GWAS has found associations between X-chromosome and renal function (rs12845465 and rs5987107). No loci in the Y-chromosome have reached genome-wide significance. In conclusion, despite the efforts to find the genetic basis of CKD, it remains challenging to explain all of the heritability with currently available methods and datasets. Although additional biomarkers have been investigated in less common suspects such as telomeres, CNVs, mtDNA and sex chromosomes, hidden heritability in CKD remains elusive, and more comprehensive approaches, particularly through the integration of multiple -"omics" data, are needed.
Genetic risk factors for chronic kidney disease (CKD) are being identified through international collaborations. By comparison, epigenetic risk factors for CKD have only recently been considered ...using population-based approaches. DNA methylation is a major epigenetic modification that is associated with complex diseases, so we investigated methylome-wide loci for association with CKD. A total of 485,577 unique features were evaluated in 255 individuals with CKD (cases) and 152 individuals without evidence of renal disease (controls). Following stringent quality control, raw data were quantile normalized and β values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls with resultant P values adjusted for multiple testing. Genes with significantly increased and decreased levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways in Partek Genomics Suite. Twenty-three genes, where more than one CpG per loci was identified with P
adjusted
< 10
−8
, demonstrated significant methylation changes associated with CKD and additional support for these associated loci was sought from published literature. Strong biological candidates for CKD that showed statistically significant differential methylation include CUX1, ELMO1, FKBP5, INHBA-AS1, PTPRN2, and PRKAG2 genes; several genes are differentially methylated in kidney tissue and RNA-seq supports a functional role for differential methylation in ELMO1 and PRKAG2 genes. This study reports the largest, most comprehensive, genome-wide quantitative evaluation of DNA methylation for association with CKD. Evidence confirming methylation sites influence development of CKD would stimulate research to identify epigenetic therapies that might be clinically useful for CKD.
New onset diabetes after transplantation (NODAT) is a serious complication following solid organ transplantation. There is a genetic contribution to NODAT and we have conducted comprehensive ...meta-analysis of available genetic data in kidney transplant populations.
Relevant articles investigating the association between genetic markers and NODAT were identified by searching PubMed, Web of Science and Google Scholar. SNPs described in a minimum of three studies were included for analysis using a random effects model. The association between identified variants and NODAT was calculated at the per-study level to generate overall significance values and effect sizes.
Searching the literature returned 4,147 citations. Within the 36 eligible articles identified, 18 genetic variants from 12 genes were considered for analysis. Of these, three were significantly associated with NODAT by meta-analysis at the 5% level of significance; CDKAL1 rs10946398 p = 0.006 OR = 1.43, 95% CI = 1.11-1.85 (n = 696 individuals), KCNQ1 rs2237892 p = 0.007 OR = 1.43, 95% CI = 1.10-1.86 (n = 1,270 individuals), and TCF7L2 rs7903146 p = 0.01 OR = 1.41, 95% CI = 1.07-1.85 (n = 2,967 individuals).
Evaluating cumulative evidence for SNPs associated with NODAT in kidney transplant recipients has revealed three SNPs associated with NODAT. An adequately powered, dense genome-wide association study will provide more information using a carefully defined NODAT phenotype.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Patients with rare diseases face unique challenges in obtaining a diagnosis, appropriate medical care and access to support services. Whole genome and exome sequencing have increased identification ...of causal variants compared to single gene testing alone, with diagnostic rates of approximately 50% for inherited diseases, however integrated multi-omic analysis may further increase diagnostic yield. Additionally, multi-omic analysis can aid the explanation of genotypic and phenotypic heterogeneity, which may not be evident from single omic analyses.
This scoping review took a systematic approach to comprehensively search the electronic databases MEDLINE, EMBASE, PubMed, Web of Science, Scopus, Google Scholar, and the grey literature databases OpenGrey / GreyLit for journal articles pertaining to multi-omics and rare disease, written in English and published prior to the 30th December 2018. Additionally, The Cancer Genome Atlas publications were searched for relevant studies and forward citation searching / screening of reference lists was performed to identify further eligible articles. Following title, abstract and full text screening, 66 articles were found to be eligible for inclusion in this review. Of these 42 (64%) were studies of multi-omics and rare cancer, two (3%) were studies of multi-omics and a pre-cancerous condition, and 22 (33.3%) were studies of non-cancerous rare diseases. The average age of participants (where known) across studies was 39.4 years. There has been a significant increase in the number of multi-omic studies in recent years, with 66.7% of included studies conducted since 2016 and 33% since 2018. Fourteen combinations of multi-omic analyses for rare disease research were returned spanning genomics, epigenomics, transcriptomics, proteomics, phenomics and metabolomics.
This scoping review emphasises the value of multi-omic analysis for rare disease research in several ways compared to single omic analysis, ranging from the provision of a diagnosis, identification of prognostic biomarkers, distinct molecular subtypes (particularly for rare cancers), and identification of novel therapeutic targets. Moving forward there is a critical need for collaboration of multi-omic rare disease studies to increase the potential to generate robust outcomes and development of standardised biorepository collection and reporting structures for multi-omic studies.
Many people living and working with rare diseases describe consistent difficulties accessing appropriate information and support. In this study an evaluation of the awareness of rare diseases, ...alongside related information and educational resources available for patients, their families and healthcare professionals, was conducted in 2018-2019 using an online survey and semi-structured interviews with rare disease collaborative groups (charities, voluntary and community groups) active across Northern Ireland (NI).
This study had 2 stages. Stage 1 was an online survey and stage 2 involved semi-structured interviews both with rare disease collaborative groups in Northern Ireland. The surveys and interviews were used to locate existing resources as well as identify gaps where the development of further resources would be appropriate.
Ninety-nine rare disease collaborative groups engaged with the survey with 31 providing detailed answers. Resources such as information, communication, 'registries', online services, training and improvements to support services were queried. Excellent communication is an important factor in delivering good rare disease support. Training for health professionals was also highlighted as an essential element of improving support for those with a rare disease to ensure they approach people with these unique and challenging diseases in an appropriate way. Carers were mentioned several times throughout the study; it is often felt they are overlooked in rare disease research and more support should be in place for them. Current care/support for those with a rare disease was highlighted as inadequate. Nine semi-structured interviews were conducted with rare disease collaborative groups. Reoccurring themes included a need for more effective information and communication, training for health professionals, online presence, support for carers, and involvement in research.
All rare disease collaborative groups agreed that current services for people living and working with a rare disease are not adequate. An important finding to consider in future research within the rare disease field is the inclusion of carers perceptions and experiences in studies. This research provides insight into the support available for rare diseases across Northern Ireland, highlights unmet needs, and suggests approaches to improve rare disease support.
Diabetic kidney disease (DKD), also known as diabetic nephropathy, is the leading cause of renal impairment and end-stage renal disease. Patients with diabetes are at risk for DKD because of poor ...control of their blood glucose, as well as nonmodifiable risk factors including age, ethnicity, and genetics. This genome-wide association study (GWAS) was conducted for the first time in the Emirati population to investigate possible genetic factors associated with the development and progression of DKD. We included data on 7,921,925 single nucleotide polymorphism (SNPs) in 258 cases of type 2 diabetes mellitus (T2DM) who developed DKD and 938 control subjects with T2DM who did not develop DKD. GWAS suggestive results (P < 1 × 10
) were further replicated using summary statistics from three cohorts with T2DM-induced DKD (Bio Bank Japan data, UK Biobank, and FinnGen Project data) and T1DM-induced DKD (UK-ROI cohort data from Belfast, UK). When conducting a multiple linear regression model for gene-set analyses, the CNR2 gene demonstrated genome-wide significance at 1.46 × 10
. SNPs in CNR2 gene, encodes cannabinoid receptor 2 or CB2, were replicated in Japanese samples with the leading SNP rs2501391 showing a P
= 9.3 × 10
, and odds ratio = 0.67 in association with DKD associated with T2DM, but not with T1DM, without any significant association with T2DM itself. The allele frequencies of our cohort and those of the replication cohorts were in most cases markedly different. In addition, we replicated the association between rs1564939 in the GLRA3 gene and DKD in T2DM (P = 0.016, odds ratio = 0.54 per allele C). Our findings suggest evidence that cannabinoid signalling may be involved in the development of DKD through CB2, which is expressed in different kidney regions and known to be involved in insulin resistance, inflammation, and the development of kidney fibrosis.
Chronic kidney disease (CKD) has a prevalence of approximately 10% in adult populations. CKD can progress to end-stage renal disease (ESRD) and this is usually fatal unless some form of renal ...replacement therapy (chronic dialysis or renal transplantation) is provided. There is an inherited predisposition to CKD with several genetic risk markers now identified. The UMOD gene has been associated with CKD of varying aetiologies. An AmpliSeq next generation sequencing panel was developed to facilitate comprehensive sequencing of the UMOD gene, covering exonic and regulatory regions. SNPs and CpG sites in the genomic region encompassing UMOD were evaluated for association with CKD in two studies; the UK Wellcome Trust Case-Control 3 Renal Transplant Dysfunction Study (n = 1088) and UK-ROI GENIE GWAS (n = 1726). A technological comparison of two Ion Torrent machines revealed 100% allele call concordance between S5 XL™ and PGM™ machines. One SNP (rs183962941), located in a non-coding region of UMOD, was nominally associated with ESRD (p = 0.008). No association was identified between UMOD variants and estimated glomerular filtration rate. Analysis of methylation data for over 480,000 CpG sites revealed differential methylation patterns within UMOD, the most significant of these was cg03140788 p = 3.7 x 10-10.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
By definition a rare disease affects fewer than 1 in 2,000 people but collectively 1 in 17 people are affected at some time in their lives. Rare disease patients often describe feeling isolated and ...unsupported. The needs of individuals living with rare disease(s) are not well met globally and have not been specifically explored in Northern Ireland.
An online survey was conducted in spring of 2017, focused on information and communication needs, to identify overarching themes. Databases were searched to place responses in an international context.
There were 240 survey respondents with four overarching themes identified: sources of information; medical care; rare disease community; and public awareness. Thirty relevant papers resulted from the literature search. A coordinated and transparent approach for improved medical care is needed where researchers, practitioners, and policy makers work with patients, carers, and rare disease advocates to ensure a fully considered rare disease strategy is implemented. In line with that developed by many other countries, a physical or virtual Northern Ireland reference network or center of excellence for rare diseases would provide an important strategic link. Sustainable funding, resources for rare disease charities, and more cross-border working would help build a local rare disease community. Major challenges highlighted include finding the right health and social care information. The internet was the most regularly accessed, and perceived as the easiest way, to source information on rare disease. Improved signposting to accredited information, ideally by the creation of a locally relevant online information hub, a local rare disease registry that can integrate with international systems, a local rare disease coordinator, and improving public awareness are urgent needs.
Aligned to internationally reported outcomes, practical issues for future development based on the voices of individuals living, and working with a rare condition are described. It is essential that ongoing research evaluates changes to ensure that the best possible structures and mechanisms are put in place to improve communication and information systems for those affected by a rare condition(s).
Risk preference is a complex trait governed by psycho-social, environmental and genetic determinants. We aimed to examine how an individual's risk preference associates with their epigenetic profile.
...Risk preferences were ascertained by asking participants of the Northern Ireland COhort for the Longitudinal study of Ageing to make a series of choices between hypothetical income scenarios. From these, four risk preference categories were derived, ranging from risk-averse to risk-seeking. Illumina's Infinium High-Density Methylation Assay was used to evaluate the status of 862,927 CpGs.
Risk preference and DNA methylation data were obtained for 1,656 individuals. The distribution of single-site DNA methylation levels between risk-averse and risk-seeking individuals was assessed whilst adjusting for age, sex and peripheral white cell counts. In this discovery cohort, 55 CpGs were identified with significantly different levels of methylation (p≤x10
−5
) between risk-averse and risk-seeking individuals when adjusting for the maximum number of covariates. No CpGs were significantly differentially methylated in any of the risk preference groups at an epigenome-wide association level (p<9x10
−8
) following covariate adjustment.
Protein-coding genes NWD1 and LRP1 were among the genes in which the top-ranked dmCpGs were located for all analyses conducted. Mutations in these genes have previously been linked to neurological conditions.
Epigenetic modifications have not previously been linked to risk-aversion using a population cohort, but may represent important biomarkers of accumulated, complex determinants of this trait. Several striking results from this study support further analysis of DNA methylation as an important link between measurable biomarkers and health behaviours.
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