Multiple Superoxide Dismutase 1/Splicing Factor Serine Alanine 15 Variants Are Associated With the Development and Progression
of Diabetic Nephropathy
The Diabetes Control and Complications ...Trial/Epidemiology of Diabetes Interventions and Complications Genetics Study
Hussam Al-Kateb 1 ,
Andrew P. Boright 2 ,
Lucia Mirea 3 4 ,
Xinlei Xie 3 ,
Rinku Sutradhar 3 5 ,
Alireza Mowjoodi 1 ,
Bhupinder Bharaj 1 ,
Michelle Liu 1 ,
Jean M. Bucksa 6 ,
Valerie L. Arends 6 ,
Michael W. Steffes 6 ,
Patricia A. Cleary 7 ,
Wanjie Sun 7 ,
John M. Lachin 7 ,
Paul S. Thorner 8 9 ,
Michael Ho 8 ,
Amy Jayne McKnight 10 ,
A. Peter Maxwell 10 ,
David A. Savage 10 ,
Kenneth K. Kidd 11 ,
Judith R. Kidd 11 ,
William C. Speed 11 ,
Trevor J. Orchard 12 ,
Rachel G. Miller 12 ,
Lei Sun 1 4 ,
Shelley B. Bull 3 4 ,
Andrew D. Paterson 1 4 and
the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group *
1 Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
2 Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
3 Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, Toronto, Ontario, Canada
4 Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada
5 Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada
6 Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
7 The Biostatistics Center, The George Washington University, Rockville, Maryland
8 Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada
9 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
10 Nephrology Research Group, Queen's University of Belfast, Belfast, Northern Ireland, U.K
11 Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
12 University of Pittsburgh, Pittsburgh, Pennsylvania
Address correspondence and reprint requests to Dr. Andrew Paterson, Program in Genetics and Genome Biology, The Hospital for
Sick Children, TMDT Building East Tower, Rm. 15-707, 101 College St., Toronto, Ontario, Canada M5G 1L7. E-mail: andrew.paterson{at}utoronto.ca
Abstract
BACKGROUND— Despite familial clustering of nephropathy and retinopathy severity in type 1 diabetes, few gene variants have been consistently
associated with these outcomes.
RESEARCH DESIGN AND METHODS— We performed an individual-based genetic association study with time to renal and retinal outcomes in 1,362 white probands
with type 1 diabetes from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
(DCCT/EDIC) study. Specifically, we genotyped 1,411 SNPs that capture common variations in 212 candidate genes for long-term
complications and analyzed them for association with the time from DCCT baseline to event for renal and retinal outcomes using
multivariate Cox proportion hazards models. To address multiple testing and assist interpretation of the results, false discovery
rate q values were calculated separately for each outcome.
RESULTS— We observed association between rs17880135 in the 3′ region of superoxide dismutase 1 (SOD1) and the incidence of both severe
nephropathy (hazard ratio HR 2.62 95% CI 1.64–4.18, P = 5.6 × 10 −5 , q = 0.06) and persistent microalbuminuria (1.82 1.29–2.57, P = 6.4 × 10 −4 , q = 0.46). Sequencing and fine-mapping identified additional SOD1 variants, including rs202446, rs9974610, and rs204732, which
were also associated ( P < 10 −3 ) with persistent microalbuminuria, whereas rs17880135 and rs17881180 were similarly associated with the development of severe
nephropathy. Attempts to replicate the findings in three cross-sectional case-control studies produced equivocal results.
We observed no striking differences between risk genotypes in serum SOD activity, serum SOD1 mass, or SOD1 mRNA expression
in lymphoblastoid cell lines.
CONCLUSIONS— Multiple variations in SOD1 are significantly associated with persistent microalbuminuria and severe nephropathy in the DCCT/EDIC
study.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on October 2007. DOI: 10.2337/db07-1059. DCCT clinical trial reg. no. NCT00360815, EDIC clinical trial reg. no. NCT00360893,
clinicaltrials.gov.
H.A.-K. and A.P.B. contributed equally to this work, and L.M. and X.X. contributed equally to this work.
*
* A complete list of investigators and members of the research group appears in N Engl J Med 353:2643–2653, 2005.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 30, 2007.
Received July 31, 2007.
DIABETES
Gremlin, a cell growth and differentiation factor, promotes the development of diabetic nephropathy in animal models, but whether GREM1 gene variants associate with diabetic nephropathy is unknown. ...We comprehensively screened the 5' upstream region (including the predicted promoter), all exons, intron-exon boundaries, complete untranslated regions, and the 3' region downstream of the GREM1 gene. We identified 31 unique variants, including 24 with a minor allele frequency exceeding 5%, and 9 haplotype-tagging single nucleotide polymorphisms (htSNPs). We selected one additional variant that we predicted to alter transcription factor binding. We genotyped 709 individuals with type 1 diabetes of whom 267 had nephropathy (cases) and 442 had no evidence of kidney disease (controls). Three individual SNPs significantly associated with nephropathy at the 5% level, and two remained significant after adjustment for multiple testing. Subsequently, we genotyped a replicate population comprising 597 cases and 502 controls: this population supported an association with one of the SNPs (rs1129456; P = 0.0003). Combined analysis, adjusted for recruitment center (n = 8), suggested that the T allele conferred greater odds of nephropathy (OR 1.69; 95% CI 1.36 to 2.11). In summary, the GREM1 variant rs1129456 associates with diabetic nephropathy, perhaps explaining some of the genetic susceptibility to this condition.
Genetics of New-Onset Diabetes after Transplantation McCAUGHAN, Jennifer A; McKNIGHT, Amy Jayne; MAXWELL, Alexander P
Journal of the American Society of Nephrology,
05/2014, Letnik:
25, Številka:
5
Journal Article
Recenzirano
Odprti dostop
New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic β-cell dysfunction, as opposed ...to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in β-cell apoptosis. These results corroborate recent clinical evidence implicating β-cell dysfunction in the pathophysiology of new-onset diabetes after transplantation and support the pursuit of therapeutic strategies to protect β cells in the post-transplant period.
Brain tumours are known to have a high mortality and morbidity rate due to their localised and frequent invasive growth. The concept that glioma resistance could originate from the dissimilarity in ...the vulnerability of clonogenic glial stem cells to chemotherapeutic drugs and radiation has driven the scientific community to reexamine the comprehension of glioma growth and strategies that target these cells or modify their stemness.
Based on the enrichment scores of 12 stemness signatures, we identified glioma subtypes in both tumour bulks and single cells by clustering analysis. Furthermore, we comprehensively compared molecular and clinical features among the glioma subtypes.
Consistently, in seven different datasets, hierarchical clustering uncovered three subtypes of glioma, termed Stem-H, Stem-M, and Stem-L, with high, medium, and low stemness signatures, respectively. Stem-H and Stem-L exhibited the most unfavorable and favourable overall and disease-free survival, respectively. Stem-H showed the highest enrichment scores of the EMT, invasion, proliferation, differentiation, and metastasis processes signatures, while Stem-L displayed the lowest. Stem-H harboured a greater proportion of late-stage tumours compared to Stem-L. Moreover, Stem-H manifested higher tumour mutation burden, DNA damage repair and cell cycle activity, intratumour heterogeneity, and a more frequent incidence of TP53 and EGFR mutations than Stem-L. In contrast, Stem-L had higher O6-Methylguanine-DNA Methyltransferase (MGMT) methylation levels.
The classification of glioma based on stemness may offer new insights into the biology of the tumour, as well as more accurate clinical management of the disease.
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•Three glioma subtypes (Stem-H, Stem-M, Stem-L) based on stemness signatures.•Stem-H has the worst survival, and Stem-L has the best outcomes.•Stem-H exhibits high TMB, HRD, and gene mutations.•Single-cell analysis showed consistency with the bulk tumour analysis.
Several studies have provided compelling evidence implicating the Wnt signalling pathway in the pathogenesis of diabetic nephropathy. Gene expression profiles associated with renal fibrosis have been ...attenuated through Wnt pathway modulation in model systems implicating Wnt pathway members as potential therapeutic targets for the treatment of diabetic nephropathy. We assessed tag and potentially functional single nucleotide polymorphisms (SNPs; n = 31) in four key Wnt pathway genes (CTNNB1, AXIN2, LRP5 and LRP6) for association with diabetic nephropathy using a case-control design.
SNPs were genotyped using Sequenom or Taqman technologies in 1351 individuals with type 1 diabetes (651 cases with nephropathy and 700 controls without nephropathy). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK, to compare allele and haplotype frequencies in cases and controls. Adjustment for multiple testing was performed by permutation testing.
Following logistic regression analysis adjusted by collection centre, duration of T1D, and average HbA1c as covariates, a single SNP in LRP6 (rs1337791) was significantly associated with DN (OR = 0.74; CI: 0.57-0.97; P = 0.028), although this was not maintained following correction for multiple testing. Three additional SNPs (rs2075241 in LRP6; rs3736228 and rs491347 both in LRP5) were marginally associated with diabetic nephropathy, but none of the associations were replicated in an independent dataset. Haplotype and subgroup analysis (according to duration of diabetes, and end-stage renal disease) also failed to reveal an association with diabetic nephropathy.
Our results suggest that analysed common variants in CTNNB1, AXIN2, LRP5 and LRP6 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes or other members of the Wnt pathway, from involvement in the pathogenesis of diabetic nephropathy as our study had limited power to detect variants with small effect size.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This exploratory study aimed to gain an understanding of carer reported experiences derived specifically from persons caring for someone with a rare disease. The survey took place online on the ...SmartSurvey platform from November 2019 to January 2020. The facilitated workshop took place in Bangor Carnegie Library, Northern Ireland. To be eligible to participate in the online survey respondents had to be adults caring for someone with a rare disease. Fifty‐seven respondents took part, 15.8% male, 84.2% female. Thirty‐two attendees were part of the facilitated workshop. While carers reported several positive aspects of their caring role, the majority of comments highlighted challenges such as sub‐optimal interactions with healthcare professionals, insufficient (or absent) emotional, psychological and social support, lack of financial support and lack of awareness of existing support services. It is important that strategies are put in place to ensure that carers are given the time they need to care for themselves, and that awareness is raised of what support options are available for carers of people with a rare disease(s) from health and social care providers, charities or support groups.
IntroductionThe development of next generation sequencing technology has enabled cost-efficient, large scale, multiple ‘omic’ analysis, including epigenomic, genomic, metabolomic, phenomic, proteomic ...and transcriptomic research. These integrated approaches hold significant promise for rare disease research, with the potential to aid biomarker discovery, improve our understanding of disease pathogenesis and identify novel therapeutic targets. In this paper we outline a systematic approach for a scoping review designed to evaluate what primary research has been performed to date on multi-omics and rare disease.Methods and analysisThis protocol was designed using the Joanna Briggs Institute methodology for scoping reviews. Databases to be searched will include: MEDLINE, EMBASE, PubMed, Web of Science, Scopus and Google Scholar for primary studies relevant to the key terms ‘multi-omics’ and ‘rare disease’, published prior to 30th December 2018. Grey literature databases GreyLit and OpenGrey will also be searched, as well as reverse citation screening of relevant articles and forward citation searching using Web of Science Cited Reference Search Tool. Data extraction will be performed using customised forms and a narrative synthesis of the results will be presented.Ethics and disseminationAs a secondary analysis study with no primary data generated, this scoping review does not require ethical approval. We anticipate this review will highlight a gap in rare disease research and provide direction for novel research. The completed review will be submitted for publication in peer-reviewed journals and presented at relevant conferences discussing rare disease research and/or molecular strategies.
In an effort to accelerate the identification of susceptibility genes in diabetic nephropathy, the first genome-wide fluorescence-based DNA microsatellite (n=6000) association screen was performed, ...using pools of genomic DNA derived from Irish patients with (cases; n=200) and without (controls; n=200) type 1 diabetic nephropathy. Allele image profiles were generated for 5353 (89.2%) microsatellite markers for both case and control pools. Allele counts (estimated from allele image profiles) were compared in case versus control groups, and empirical P values were generated. Markers then were ranked on the basis of their empirical P values (lowest to highest). Repeat PCR amplification and electrophoresis of pooled samples were performed systematically on ranked markers until the 50 most associated markers with consistent results were identified. DNA samples that composed the pools then were genotyped individually for these markers. Two markers on chromosome 10, D10S558 (Pcorrected=0.005) and D10S1435 (Pcorrected=0.016), revealed statistically significant associations with diabetic nephropathy. An additional four markers (D6S281, D4S2937, D2S291, and D17S515) also are worthy of further investigation. Relevant functional candidate genes have been identified in the vicinity of these markers, demonstrating the feasibility of low-resolution genome-wide microsatellite association screening to identify possible candidate genes for diabetic nephropathy.
Genetic polymorphisms and kidney transplant outcomes Chand, Sourabh; McKnight, Amy Jayne; Borrows, Richard
Current opinion in nephrology and hypertension,
2014-November, Letnik:
23, Številka:
6
Journal Article
Recenzirano
PURPOSE OF REVIEWGene polymorphism studies are growing at a quasiexponential rate and aim to improve immediate and long-term outcomes in renal transplantation. This review highlights recent evidence ...and potential future directions for genetic research studies.
RECENT FINDINGSStudies are largely based on immunity, inflammation and pharmacogenetics, investigating mostly ‘surrogate’ outcomes with sometimes conflicting results. However, the last 12 months has also heralded the emergence of important genome-wide association studies on transplantation, more robust replicated multicentre analyses of candidate gene variants, meta-analyses, and an increasing interest in copy number variation and donor genetics.
SUMMARYThese studies set the scene for further investigation, aiming to understand pathways of disease and biomarkers of risk, and are leading to a greater understanding of the biology of transplantation. Future studies will require focus on donor : recipient and gene : environment interactions, and an integrated approach of ‘transplantomics’ to evaluate long-term outcomes in multinational collaborations.
BackgroundChronic kidney disease (CKD) is defined by abnormalities in kidney structure and/or function present for more than 3 months. Worldwide, both the incidence and prevalence rates of CKD are ...increasing. The renin-angiotensin-aldosterone system (RAAS) regulates fluid and electrolyte balance through the kidney. RAAS activation is associated with hypertension, which is directly implicated in causation and progression of CKD. RAAS blockade, using drugs targeting individual RAAS mediators and receptors, has proven to be renoprotective.ObjectivesTo assess genomic variants present within RAAS genes, ACE, ACE2, AGT, AGTR1, AGTR2 and REN, for association with CKD.Design and data sourcesA systematic review and meta-analysis of observational research was performed to evaluate the RAAS gene polymorphisms in CKD using both PubMed and Web of Science databases with publication date between the inception of each database and 31 December 2018. Eligible articles included case–control studies of a defined kidney disease and included genotype counts.Eligibility criteriaAny paper was removed from the analysis if it was not written in English or Spanish, was a non-human study, was a paediatric study, was not a case–control study, did not have a renal disease phenotype, did not include data for the genes, was a gene expression-based study or had a pharmaceutical drug focus.ResultsA total of 3531 studies were identified, 114 of which met the inclusion criteria. Genetic variants reported in at least three independent publications for populations with the same ethnicity were determined and quantitative analyses performed. Three variants returned significant results in populations with different ethnicities at p<0.05: ACE insertion, AGT rs699-T allele and AGTR1 rs5186-A allele; each variant was associated with a reduced risk of CKD development.ConclusionsFurther biological pathway and functional analyses of the RAAS gene polymorphisms will help define how variation in components of the RAAS pathway contributes to CKD.
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