Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation ...only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI.sub.95%:4.440-21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The prevalence of diabetes is increasing globally, and this trend is predicted to continue for future decades. Research is needed to uncover new ways to manage diabetes and its co-morbidities. A ...significant secondary complication of diabetes is kidney disease, which can ultimately result in the need for renal replacement therapy, via dialysis or transplantation. Diabetic kidney disease presents a substantial burden to patients, their families and global healthcare services. This review highlights studies that have harnessed genomic, epigenomic and functional prediction tools to uncover novel genes and pathways associated with DKD that are useful for the identification of therapeutic targets or novel biomarkers for risk stratification. Telomere length regulation is a specific pathway gaining attention recently because of its association with DKD. Researchers are employing both observational and genetics-based studies to identify telomere-related genes associated with kidney function decline in diabetes. Studies have also uncovered novel functions for telomere-related genes beyond the immediate regulation of telomere length, such as transcriptional regulation and inflammation. This review summarises studies that have revealed the potential to harness therapeutics that modulate telomere length, or the associated epigenetic modifications, for the treatment of DKD, to potentially slow renal function decline and reduce the global burden of this disease.
Chronic kidney disease has emerged as a strong cardiovascular risk factor, and in many current guidelines, it is already considered as a coronary heart disease (CHD) equivalent. Routinely, creatinine ...has been used as the main marker of renal function, but recently, cystatin C emerged as a more promising marker. The aim of this study was to assess the comparative cardiovascular and mortality risk of chronic kidney disease (CKD) using cystatin C-based and creatinine-based equations of the estimated glomerular filtration rate (eGFR) in participants of population-based and disease cohorts.
The present study has been conducted within the BiomarCaRE project, with harmonized data from 20 population-based cohorts (n = 76,954) from 6 European countries and 3 cardiovascular disease (CVD) cohorts (n = 4982) from Germany. Cox proportional hazards models were used to assess hazard ratios (HRs) for the various CKD definitions with adverse outcomes and mortality after adjustment for the Systematic COronary Risk Evaluation (SCORE) variables and study center. Main outcome measures were cardiovascular diseases, cardiovascular death, and all-cause mortality.
The overall prevalence of CKD stage 3-5 by creatinine- and cystatin C-based eGFR, respectively, was 3.3% and 7.4% in the population-based cohorts and 13.9% and 14.4% in the disease cohorts. CKD was an important independent risk factor for subsequent CVD events and mortality. For example, in the population-based cohorts, the HR for CVD mortality was 1.72 (95% CI 1.53 to 1.92) with creatinine-based CKD and it was 2.14 (95% CI 1.90 to 2.40) based on cystatin-based CKD compared to participants without CKD. In general, the HRs were higher for cystatin C-based CKD compared to creatinine-based CKD, for all three outcomes and risk increased clearly below the conventional threshold for CKD, also in older adults. Net reclassification indices were larger for a cystatin-C based CKD definition. Differences in HRs (between the two CKD measures) in the disease cohorts were less pronounced than in the population-based cohorts.
CKD is an important risk factor for subsequent CVD events and total mortality. However, point estimates of creatinine- and cystatin C-based CKD differed considerably between low- and high-risk populations. Especially in low-risk settings, the use of cystatin C-based CKD may result in more accurate risk estimates and have better prognostic value.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The impact of the current COVID-19 pandemic has been felt worldwide. Many vulnerable populations rely heavily on peer support provided by individual or collaborative groups. This study aimed to ...evaluate the impact of COVID-19 on groups supporting patients with a rare disease(s). Anecdotally the current pandemic significantly changed the way in which these groups operate and the services they can provide.
A targeted survey was conducted online with rare disease individual or collaborative groups. The results of the survey highlight the challenges individual and collaborative groups are facing during this pandemic and help to identify what support should be put in place to enable them to sustain their much-valued service through these trialing times. Groups have experienced an increase in calls to their helplines as well as followers to their websites and social media feeds. Groups are no longer meeting in person and so online meetings, webinars and zoom chats have become a regular occurrence. Fundraising was highlighted as an area of concern for such groups. It is hoped that this data might be used to highlight the support individual and collaborative groups require while also raising awareness of the value they bring to many.
Increased albuminuria indicates underlying glomerular pathology and is associated with worse renal disease outcomes, especially in diabetic kidney disease. Many single nucleotide polymorphisms ...(SNPs), associated with albuminuria, could be potentially useful to construct polygenic risk scores (PRSs) for kidney disease. We investigated the diagnostic accuracy of SNPs, previously associated with albuminuria-related traits, on albuminuria and renal injury in the UK Biobank population, with a particular interest in diabetes. Multivariable logistic regression was used to evaluate the influence of 91 SNPs on urine albumin-to-creatinine ratio (UACR)-related traits and kidney damage (any pathology indicating renal injury), stratifying by diabetes. Weighted PRSs for microalbuminuria and UACR from previous studies were used to calculate the area under the receiver operating characteristic curve (AUROC).
-rs1801239 and
-rs116772905 were associated with all the UACR-derived phenotypes, in both the overall and non-diabetic cohorts, but not with kidney damage. Several SNPs demonstrated different effects in individuals with diabetes compared to those without. SNPs did not improve the AUROC over currently used clinical variables. Many SNPs are associated with UACR or renal injury, suggesting a role in kidney dysfunction, dependent on the presence of diabetes in some cases. However, individual SNPs or PRSs did not improve the diagnostic accuracy for albuminuria or renal injury compared to standard clinical variables.
The global prevalence of diabetic nephropathy is rising in parallel with the increasing incidence of diabetes in most countries. Unfortunately, up to 40 % of persons diagnosed with diabetes may ...develop kidney complications. Diabetic nephropathy is associated with substantially increased risks of cardiovascular disease and premature mortality. An inherited susceptibility to diabetic nephropathy exists, and progress is being made unravelling the genetic basis for nephropathy thanks to international research collaborations, shared biological resources and new analytical approaches. Multiple epidemiological studies have highlighted the clinical heterogeneity of nephropathy and the need for better phenotyping to help define important subgroups for analysis and increase the power of genetic studies. Collaborative genome-wide association studies for nephropathy have reported unique genes, highlighted novel biological pathways and suggested new disease mechanisms, but progress towards clinically relevant risk prediction models for diabetic nephropathy has been slow. This review summarises the current status, recent developments and ongoing challenges elucidating the genetics of diabetic nephropathy.
Rare ophthalmic conditions often cause degenerative vision loss which leads to loss of independence, ability to work and ultimately quality life. Differential methylation is an epigenomic marker that ...is a feature of several diseases, including eye conditions. This review will aim to elucidate the extent to which differential methylation has been identified in rare ophthalmic conditions.
A systematic review will be conducted of articles found in the electronic databases MEDLINE, EMBASE, PubMed and Cochrane Library of Systematic Reviews. Grey literature databases GreyLit and OpenGrey will be searched for relevant unpublished sources. Reference lists of articles which meet eligibility criteria will also be screened for forward and reverse citations. Eligibility criteria will include quantitative articles published, before July 2018, written in English and featuring analysis of differential methylation in rare ophthalmic disorders. Studies will be screened firstly by title, abstract and keywords and then by full text for any remaining sources, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data extraction of key characteristics will be completed using customised forms. Methodological rigour will be assessed using customised forms modelled on the Joanna Briggs Institute critical appraisal forms.
This systematic review will enable us to identify if differential methylation can be used to characterise rare ophthalmic disease, which could have crucial implications for improving the accuracy and speed of diagnosis, identifying novel therapeutic targets to reduce or prevent vision loss and overall improving understanding of rare ophthalmic disease.
PROSPERO CRD42018094231.
The challenges in diagnosis of rare renal conditions can negatively impact patient prognosis, quality of life and result in significant healthcare costs. Differential methylation is emerging as an ...important biomarker for rare diseases and should be evaluated for rare renal conditions.
A comprehensive systematic review of methylation and rare renal disorders was conducted by searching the electronic databases MEDLINE, EMBASE, PubMed, Cochrane Library, alongside grey literature from GreyLit and OpenGrey databases, for publications published before September 2018. Additionally, the reference lists of the included papers were searched. Data was extracted and appraised including the primary focus, measurement and methodological rigour of the source. Eligibility criteria were adapted using the inclusion criteria from 'The 100,000 Genomes Project' and The National Registry of Rare Kidney Diseases, with additional focus on methylation.
Thirteen full text articles were included in the review. Diseases analysed for differential methylation included glomerular disease, IgA nephropathy, ADPKD, rare causes of proteinuria, congenital renal agenesis, and membranous nephropathy.
Differential methylation has been observed for several rare renal diseases, highlighting its potential for improving molecular characterisation of these disorders. Further investigation of methylation following a standardised reporting structure is necessary to improve research quality. Multi-omic data will provide insights for improved diagnosis, prognosis and support for individuals living and working with rare renal diseases.
Patients with type 1 diabetes are more at risk of coronary artery disease than the general population. Although evidence points to a genetic risk there have been no study investigating genetic risk ...factors of coronary artery disease specific to individuals with type 1 diabetes. To identify low frequency and common genetic variations associated with coronary artery disease in populations of individuals with type 1 diabetes.
A two-stage genome wide association study was conducted. The discovery phase involved the meta-analysis of three genome-wide association cohorts totaling 434 patients with type 1 diabetes and coronary artery disease (cases) and 3123 T1D individuals with no evidence of coronary artery disease (controls). Replication of the top association signals (p < 10
) was performed in five additional independent cohorts totaling 585 cases and 2612 controls.
One locus (rs115829748, located upstream of the MAP1B gene) reached the statistical threshold of 5 × 10
for genome-wide significance but did not replicate. Nevertheless, three single nucleotide polymorphisms provided suggestive evidence for association with coronary artery disease in the combined studies: CDK18 rs138760780 (OR = 2.60 95% confidence interval 1.75-3.85, p = 2.02 × 10
), FAM189A2 rs12344245 (OR = 1.85 1.41-2.43, p = 8.52 × 10
) and PKD1 rs116092985 (OR = 1.53 1.27-1.85, p = 1.01 × 10
). In addition, our analyses suggested that genetic variations at the ANKS1A, COL4A2 and APOE loci previously found associated with coronary artery disease in the general population could have stronger effects in patients with type 1 diabetes.
This study suggests three novel candidate genes for coronary artery disease in the subgroup of patients affected with type 1 diabetes. The detected associations deserve to be definitively validated in additional epidemiological studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of chromosome Y in chronic kidney disease (CKD) remains unknown, as chromosome Y is typically excluded from genetic analysis in CKD. The complex, sex-specific presentation of CKD could be ...influenced by chromosome Y genetic variation, but there is limited published research available to confirm or reject this hypothesis. Although traditionally thought to be associated with male-specific disease, evidence linking chromosome Y genetic variation to common complex disorders highlights a potential gap in CKD research. Chromosome Y variation has been associated with cardiovascular disease, a condition closely linked to CKD and one with a very similar sexual dimorphism. Relatively few sources of genetic variation in chromosome Y have been examined in CKD. The association between chromosome Y aneuploidy and CKD has never been explored comprehensively, while analyses of microdeletions, copy number variation, and single-nucleotide polymorphisms in CKD have been largely limited to the autosomes or chromosome X. In many studies, it is unclear whether the analyses excluded chromosome Y or simply did not report negative results. Lack of imputation, poor cross-study comparability, and requirement for separate or additional analyses in comparison with autosomal chromosomes means that chromosome Y is under-investigated in the context of CKD. Limitations in genotyping arrays could be overcome through use of whole-chromosome sequencing of chromosome Y that may allow analysis of many different types of genetic variation across the chromosome to determine if chromosome Y genetic variation is associated with CKD.
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