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Introduction
Predictive medicin of Type 2 diabetes complications
Current institution
Publications
Publications (820)
Oxidative stress mediated by reactive oxygen species (ROS) contributes to apoptosis of tubular epithelial cells (TECs) and renal inflammation during acute kidney injury (AKI). Copper Metabolism MURR1 domain-containing 5 (COMMD5/HCaRG) shows strong cytoprotective properties. COMMD5 is highly expressed in proximal tubules (PTs), where it controls cel...
Aim
Whether apolipoproteins (apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 [ApoB/ApoA1] ratio) or very‐low‐density lipoprotein (VLDL) cholesterol are better risk predictors than established lipid risk markers, and whether there are sex differences, is uncertain, both in general populations and in patients with diabetes. Th...
The Action in Diabetes and Vascular disease: preterAx and diamicroN Controlled Evaluation (ADVANCE) trial investigated the effects of intensive blood pressure (BP) lowering using a fixed combination of perindopril-indapamide versus placebo in type 2 diabetes (T2D). The study showed that combination perindopril-indapamide had significant benefits in...
Objective
Context: Early-onset type 2 diabetes (T2D) increases rapidly worldwide, alongside obesity, and carries an excess risk of microvascular complications and early death compared to when it started later in life. We have developed a multi-polygenic risk score (multiPRS) that predicts the risk of major micro- and macrovascular complications of...
X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 f...
Background
Standard measures of blood pressure (BP) do not account for both the magnitude and duration of exposure to elevated BP over time.
Objectives
The purpose of this study was to assess the association between cumulative systolic blood pressure (SBP) load and risk of cardiovascular events in patients with type 2 diabetes.
Methods
A post hoc...
Background and objectives:
Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear.
Design, setting, participants, & measurements:
Data came from th...
Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1...
Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline r...
A Correction to this paper has been published: https://doi.org/10.1007/s00125-021-05544-x
Aims/hypothesis
Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk.
Methods
We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) comp...
The cover image is based on the Original Article Sex differences in risk factors for cognitive decline and dementia, including death as a competing risk, in individuals with diabetes: Results from the ADVANCE trial by Jessica Gong et al., https://doi.org/10.1111/dom.14391.
Background/aim:
Copper metabolism MURR1 domain-containing 5 (COMMD5) is mainly expressed in renal tubules (RTs), where it facilitates re-differentiation of injured RTs. We reported that COMMD5 regulates the expression of epidermal growth factor receptor by participating in its endocytic membrane trafficking, thus inhibiting tumor growth. Here we a...
Objective:
To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Co...
Aims:
The association between diabetes and cognitive decline (CD) and dementia has been well-documented. This study estimated the associations between risk factors and CD/dementia, and the sex differences in these risk factors in individuals with type 2 diabetes, while accounting for the competing risk of death.
Materials and methods:
The Action...
There are limited data on whether estimated glomerular filtration rate (eGFR) variability modifies the risk of future clinical outcomes in type 2 diabetes mellitus (T2DM). We assessed the association between 20‐month eGFR variability and the risk of major clinical outcomes in T2DM amongst 8241 participants in the ADVANCE trial. Variability in eGFR...
Aims:
For relatively old patients with diabetes, current guidelines recommend adjustment of glycaemic goals based on patients' cognitive function, or coexisting chronic illnesses. However, the evidence which supports the efficacy and safety of intensive glucose lowering in older patients with diabetes is scarce.
Materials and methods:
The effect...
Background
ACE2 has been identified as the entry receptor for coronaviruses into human cells, including SARS-COV-2 that causes COVID-19. Since hypertension is a leading comorbidity in non-survivors of COVID-19, we tested for association between ACE2 gene and hypertension in interaction with specific pre-existing conditions known to be associated wi...
Crosstalk between environmental factors, genes and health outcomes is gaining more attention in the pathophysiology of cardiometabolic diseases. The genome and environment convergence is a major focus of personalized medicine that became subject of interest in preventive/predictive healthcare. The collective knowledge related to multifactorial and...
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases...
Aims/hypothesis:
This biomarker study aimed to quantify the association of essential and other plasma fatty acid biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes.
Methods:
A case-cohort study (N = 3576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5...
Background
Creatinine‐based estimated glomerular filtration rate (eGFR) is biased in the setting of obesity and other conditions. Alternative kidney filtration markers may be useful in adults with diabetes, but few studies examined the associations with risk of clinical outcomes.
Methods
In the Action in Diabetes and Vascular Disease: Preterax and...
Aims:
Sex differences in associations between several risk factors and myocardial infarction (MI), including diabetes, have been found in general populations. Whether similar differences are observed in patients with diabetes is unknown.
Materials and methods:
11,065 (42% women) participants with type 2 diabetes in the ADVANCE trial and its post...
Introduction: We assessed the performance of our newly developed polygenic risk score (PRS) to predict microvascular and macrovascular complications of type 2 diabetes (T2D) in men and women. The PRS is composed of 600 common genomic variants associated to diabetes, cardiovascular and renal diseases and their key risk factors selected from summary...
Introduction
The current screening method for diabetic nephropathy (DN) is based upon detection of albumin in the urine and decline of glomerular filtration rate. The latter usually occurs relatively late in the course of the disease. A polygenic risk score (PRS) was recently developed for early prediction of the risk for type 2 diabetes (T2D) pati...
Despite some controversy, true BRCA1/2 non-carriers are generally considered to be at an average risk for breast and ovarian cancer. Primary care physicians are then expected to encourage their non-carrier patients to adopt cancer screening practices appropriate to women of the same age in the general population. This study aimed to describe breast...
Aims:
To explore whether there is a different strength of association between self-rated health and all-cause mortality in people with type 2 diabetes across three country groupings: nine countries grouped together as 'established market economies'; Asia; and Eastern Europe.
Methods:
The ADVANCE trial and its post-trial follow-up were used in th...
The massive adoption of high-throughput genomics, deep sequencing technologies and big data technologies have made possible the era of precision medicine. However, the volume of data and its complexity remain important challenges for precision medicine research, hindering development in this field. The literature on precision medicine research desc...
Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction can lead to timely intervention and better outcomes. Through summary statistics of meta-analyses of published genome-wide association studies performed in over 1.2 million of individuals, we combined 9 PRS gathering genomic variants associated to...
Aims/hypothesis
Some studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear.
Methods
We us...
Diabetes mellitus (DM) is a heterogeneous group of disorders characterized by persistent hyperglycemia. Its two most common forms are type 1 diabetes (T1D) and type 2 diabetes (T2D), for which genetic and environmental risk factors act in synergy. Because it occurs in children and involves infectious, autoimmune or toxic destruction of the insulin-...
Context
Weight loss is strongly recommended for overweight and obese adults with type 2 diabetes. Unintentional weight loss is associated with increased risk of all-cause mortality, but few studies have examined its association with cardiovascular outcomes in patients with diabetes.
Objective
To evaluate 2-year weight change and subsequent risk of...
Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Ser...
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, includ...
Background and objectives:
Whether combining changes in eGFR and urine albumin-to-creatinine ratio (UACR) is more strongly associated with outcomes compared with either change alone is unknown.
Design, setting, participants, & measurements:
We analyzed 8766 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax an...
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be rel...
Background
Low 1,5‐anhydroglucitol (1,5‐AG) is a marker of glycosuric hyperglycemia. We evaluated 1,5‐AG with clinical outcomes and assessed the effects of glucose‐ and blood pressure‐lowering interventions on change in 1,5‐AG in type 2 diabetes.
Methods
We measured 1,5‐AG in 6,826 stored samples at baseline and a random subsample of 684 participa...
The optimal blood pressure (BP) goal in patients with diabetes mellitus remains controversial. We examined whether benefits and risks of intensified antihypertensive therapy in diabetes mellitus are influenced by either baseline BP or cardiovascular disease (CVD) risk. We studied 10 948 people with diabetes mellitus, at moderate-to-high risk, in th...
Objective:
We investigated the association of genetic variants of EPHA4, a receptor tyrosine kinase, with hypertension, and its role in vascular smooth muscle cell (VSMC) contractility.
Methods:
Data from two human genetic studies, ADVANCE and HCHS/SOL, were analyzed for association of EPHA4 single nucleotide variants (SNVs) with hypertension ri...
The rapid growth of technology in the past couple of decades has paved the way for development of novel techniques that can solve scientific questions at a rate that is far beyond the capability of humans. One such example is the field of Artificial Intelligence (AI) and Machine Learning (ML). AI is a discipline that deals with the study and design...
Genome-wide association studies or GWAS yielded an impressive amount of data that improved the understanding of complex diseases. However, the initial results were deceiving, when the early GWAS of Wellcome Trust, that was successful in reporting many significant associations for several diseases, claimed that no association could be observed for h...
Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in...
BACKGROUND:
The mechanism explaining the inverse association between renal urate and albumin excretion remains unclear. First, we evaluated the impact of candidate variants in the main urate transporter genes (i.e., SLC2A9, SLC22A12, ABCG2) on the association between fractional excretion of uric acid (FEUA) and urinary albumin/creatinine ratio (uAC...
COMMD5/HCaRG is involved in tissue repair, and its low expression is associated with tumorigenicity. Cell growth, migration, and differentiation are controlled by COMMD5. We previously reported that COMMD5 inhibited the growth of renal carcinoma cells by regulating expression or phosphorylation of ErbB members. Here, we demonstrate that COMMD5 is c...
Aims/hypotheses:
We aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes.
Methods:
We performed a case-cohort study (N = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy...
Cardiovascular and renal complications of T2D represent a human and societal burden. Early detection of susceptibility to complications could help their prevention. Clinical scores are useful to predict hard outcomes but genomic score can be applied earlier than a risk factor based score and thus save morbidity. We have constructed a polygenic risk...
Aims/hypothesisPrevious studies have suggested that the haemoglobin glycation index (HGI) can be used as a predictor of diabetes-related complications in individuals with type 1 and type 2 diabetes. We investigated whether HGI was a predictor of adverse outcomes of intensive glucose lowering and of diabetes-related complications in general, using d...
Background
Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients.
Methods
WHtR was evaluated as a predictor for the risk of CVD and mortality amongst 11 12...
Hypertension Canada provides annually-updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension in adults and children. This year, the adult and pediatric guidelines are combined in one document. The new 2018 pregnancy-specific hypertension guidelines are published separately.
For 2018, 5 new guidel...
A global, interdisciplinary perspective makes it possible to understand the importance and value of precision medicine as an integral part of the personalized medicine movement, itself part of the international contract-based authority movement, whose virtue is to authorize only those forms of intervention that generate fairness as well as clinical...
With the availability of high-throughput genomics technologies and the completion of the Human Genome Project in 2003, we are now in the “postgenomics era.” The concept of precision medicine evolved over time and was popularized only recently. It became a hot topic in the medical community as well as in public sphere due to president Obama's announ...
Background:
In families with a proven BRCA1/2 mutation, women not carrying the familial mutation should follow the cancer screening recommendations applying to women in the general population. In the present study, we evaluated the cancer screening practices of unaffected noncarriers from families with a proven BRCA mutation, and we assessed the r...
Objective:
This study examined the individual and combined effect of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), interleukin-6 (IL-6), and hs-CRP on the prediction of heart failure incidence or progression in patients with type 2 diabetes.
Research design and methods:
A nested case-cohort...
Hypertension-related, calcium-regulated gene (HCaRG/COMMD5) is highly expressed in renal proximal tubules, where it contributes to the control of cell proliferation and differentiation. HCaRG accelerates tubular repair by facilitating re-differentiation of injured proximal tubular epithelial cells, thus improving mouse survival after acute kidney i...
Recent studies demonstrated that in addition to Na+,K+-ATPase inhibition cardiotonic steroids (CTSs) affect diverse intracellular signaling pathways. This study examines the relative impact of [Na+]i/[K+]i-mediated and -independent signaling in transcriptomic changes triggered by the endogenous CTSs ouabain and marinobufagenin (MBG) in human umbili...
EPH kinases and their ligands, ephrins (EFNs), have vital and diverse biological functions. We recently reported that Efnb3 gene deletion results in hypertension in female but not male mice. These data suggest that EFNB3 regulates blood pressure in a sex- and sex hormone-dependent way. In the present study, we conducted a human genetic study to ass...
Hypertension Canada provides annually-updated, evidence-based guidelines for the diagnosis, assessment, prevention, and treatment of hypertension. This year, we introduce 10 new guidelines. Three previous guidelines have been revised and 5 have been removed. Previous age and frailty distinctions have been removed as considerations for when to initi...
Objective:
To measure the placebo-controlled effects of combination therapy on hypotension, treatment discontinuation, and major renal outcomes, according to baseline blood pressure.
Methods:
We conducted an analysis of the action in diabetes and vascular disease: preterax and diamicron-MR controlled evaluation and perindopril protection against...
Background: With the use of next generation sequencing technologies, translational research is becoming a catalyst for the implementation of personalized medicine (PM). To implement PM, we will also need to ensure that sensitive results are shared, used and returned to the participants in compliance with applicable ethical and legal frameworks. Fur...
Artificial Intelligence (AI) is a general term that implies the use of a computer to model intelligent behaviour with minimal human intervention. AI is generally accepted as having started with the invention of robots. The term derives from the Czech word robota, meaning biosynthetic machines used as forced labour. In this field, Leonardo Da Vinci'...
Background:
The prevalence of diabetic nephropathy varies according to ethnicity. Environmental as well as genetic factors contribute to the heterogeneity in the presentation of diabetic nephropathy. Our objective was to evaluate this heterogeneity within the Caucasian population.
Methods:
The geo-ethnic origin of the 3409 genotyped Caucasian ty...
Introduction:
Guidelines do not currently recommend routine systematic hormonal screening for phaeochromocytoma (PHEO) in all/normotensive patients with Neurofibromatosis type 1 (NF1), in contrast to other PHEO predisposing genetic syndromes such as Von Hippel Lindau syndrome and Multiple endocrine neoplasia type 2.
Objectives:
To characterise a...
Background:
Peripheral arterial disease (PAD) is known to be associated with high cardiovascular risk, but the individual impact of PAD presentations on risk of macrovascular and microvascular events has not been reliably compared in patients with type 2 diabetes. We aimed to evaluate the impact of major PAD, and its different presentations, on th...
Objective:
We have previously reported the genetic determinants of unmet renal needs in Type 2 Diabetic (T2D) patients of the ADVANCE study (Abstract 0105-PD, IDF - World Diabetes Congress, Vancouver, 2015). We report here the external validation of several of these loci. An improved knowledge of the genetics linked to worsening diabetic nephropat...
Objective:
We have previously reported distinct genetic architectures of renal impairment in T2D patients of Slavic and Celtic origins participating in the ADVANCE trial (J Hypertens. 2015 Jun;33 Suppl 1:e3). Further analysis suggests that the major driver of the difference in the prevalence of T2D complications between Slavic and Celtic groups is...
Objective:
Epidermal growth factor receptor (EGFR) signaling plays a dual role in hypertension-induced kidney damage. EGFR is critically involved in angiotensin II-induced renal lesions and fibrosis but is also engaged in kidney tissue repair. Consequently, targeting EGFR in renal diseases is complex because even if inhibition of EGFR activity wou...
BACKGROUND
The impact of metabolic phenotypes on the association of uricemia with urinary albumin/creatinine ratio (uACR) remains unresolved. We evaluated the association between serum uric acid and uACR in persons with 0, and 1–2 metabolic syndrome (MetS) components and determined the modification effects of visceral adiposity index (VAI), mean ar...
Ephrin B2 (EFNB2) is a ligand for erythropoietin-producing hepatocellular kinases (EPH), the largest family of receptor tyrosine kinases. It has critical functions in many biological systems, but is not known to regulate blood pressure. We generated mice with a smooth muscle cell (SMC)-specific deletion of EFNB2 and investigated its roles in blood...
Background: With the use of next generation sequencing technologies, translational research is becoming a catalyst for the implementation of personalized medicine (PM). To implement PM, we will also need to ensure that sensitive results are shared, used and returned to the participants in compliance with applicable ethical and legal frameworks. Fur...
Background
Vascular stiffness and advanced chronic kidney disease (CKD) are strong determinants of higher central blood pressure (BP) and are associated with high cardiovascular morbidity and mortality. Whether mild-to-moderate CKD is associated with higher central BP independently of other comorbid conditions remains uncertain.
Methods
We evaluat...
Genome wide association studies (GWAS) are a widely used approach in genetic research to identify genes or genetic variants involved in human diseases. Each GWAS examines millions of unique single nucleotide polymorphisms (SNPs) for their association to phenotypic traits and diseases. In the context of identifying complex associations in large pati...
Objective:
The associations of discontinuation of the study medication on major outcomes were assessed in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Trial.
Methods:
ADVANCE was a factorial randomized controlled trial of blood pressure lowering (a fixed combination of perindopril and indapamide vs...
With increased involvement of genetic data in most epidemiological investigations, gene–environment (G × E) interactions now
stand as a topic, which must be meticulously assessed and thoroughly understood. The level, mode, and outcomes of interactions
between environmental factors and genetic traits have the capacity to modulate disease risk. These...
Objective:
The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Released Controlled Evaluation (ADVANCE) trial reported that intensive glucose control prevents end-stage kidney disease (ESKD) in patients with type 2 diabetes, but uncertainty about the balance between risks and benefits exists. Here, we examine the long-term...
Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent...
Hypertension Canada's CHEP Guidelines Task Force provides annually-updated, evidence-based recommendations to guide the diagnosis, assessment, prevention, and treatment of hypertension. This year, we present four new recommendations, as well as revisions to two previous recommendations. In the diagnosis and assessment of hypertension, automated off...
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new a...
Supplementary Figures 1-7, Supplementary Tables 1-21, Supplementary Note 1 and Supplementary References
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new a...
Background:
Bilateral macronodular adrenal hyperplasia (BMAH) is a rare cause of Cushing's syndrome (CS) and its familial clustering has been described previously. Recent studies identified that ARMC5 mutations occur frequently in BMAH, but the relation between ARMC5 mutation and the expression of aberrant G-protein-coupled receptor has not been e...
Objective: To measure the impact of complications on summary measures of health-related quality of life among people with type 2 diabetes. Methods: Patients participating in the Action in Diabetes and Vascular Disease:Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial were administered a health-related quality-of-life questionnaire, th...
Over 30 years ago, preimplantation genetic diagnosis (PGD) was developed to help couples at risk of transmitting a serious genetic disease to their offspring. Today, the range of medical and non-medical uses of PGD has expanded considerably and some raise much controversy. This is the case, for example, with In-Vitro Fertilization to select embryos...
