Publications by authors named "Andrew D Paterson"

219 Publications

Anti-microbial antibody response is associated with future onset of Crohn's disease independent of biomarkers of altered gut barrier function, subclinical inflammation, and genetic risk.

Gastroenterology 2021 Jul 19. Epub 2021 Jul 19.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology & Hepatology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: /Aim: Altered host immune reactivity to microbial antigens is hypothesized to trigger the onset of Crohn's disease (CD). We aimed to assess whether increased serum anti-microbial antibody response in asymptomatic first-degree relatives (FDR) of CD patients is an independent risk factor for future CD development.

Methods: We measured host serum antibody response to six microbial antigens at enrollment (Prometheus ELISA test: ASCA IgA/IgG, anti-OmpC, anti-A4-Fla2, anti-FlaX, anti-CBir1) and derived the sum of positive antibodies (AS). We used samples at enrollment of prospectively followed healthy FDRs from a nested case-control cohort of the CCC-GEM Project. Those who later developed CD (n=77) were matched 1:4 by age, sex, follow-up duration, and geographical location with control FDRs remaining healthy (n=307). To address our research aims, we fitted a multivariable conditional logistic regression model and performed causal mediation analysis.

Results: High baseline AS (≥2) (43% of cases, 11% of controls) was associated with higher risk of developing CD (adjusted OR 6.5, 95% CI 3.4-12.7; p<0.001). Importantly, this association remained significant when adjusted for markers of gut barrier function, fecal calprotectin, C-reactive protein, and CD-polygenic risk score, and in subjects recruited more than 3 years before diagnosis. Causal mediation analysis showed that the effect of high AS on future CD development is partially mediated (42%) via preclinical gut inflammation.

Conclusions: Our results suggest that increased anti-microbial antibody responses are associated with risk of future development of CD, independent of biomarkers of abnormal gut barrier function, subclinical inflammation, and CD-related genetic risks. This suggests that anti-microbial antibody responses are an early pre-disease event in the development of CD.
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http://dx.doi.org/10.1053/j.gastro.2021.07.009DOI Listing
July 2021

Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study.

Diabetes Care 2021 Apr 21. Epub 2021 Apr 21.

Biostatistics Center, George Washington University, Rockville, MD.

Objective: The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study.

Research Design And Methods: Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1,371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or nonfatal myocardial infarction [MI] or stroke) and any CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD with adjustment for other factors (including age, lipids, blood pressure, and glycemia).

Results: CAD PRS was strongly associated with the subsequent risk of any CVD (42% and 38% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; < 0.0001) and with the risk of MACE (50% and 40% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; < 0.0001). Several individual single nucleotide polymorphisms were also nominally associated with the risk of any CVD and MACE.

Conclusions: Genetic factors are associated with the risk of subsequent CVD in individuals with T1D above and beyond the effect of established risk factors such as age, lipids, blood pressure, and glycemia.
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http://dx.doi.org/10.2337/dc20-2388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247524PMC
April 2021

Type IV Collagen Variants in CKD: Performance of Computational Predictions for Identifying Pathogenic Variants.

Kidney Med 2021 Mar-Apr;3(2):257-266. Epub 2021 Feb 10.

Division of Nephrology, University Health Network, Toronto, Canada.

Rationale & Objective: Pathogenic variants in type IV collagen have been reported to account for a significant proportion of chronic kidney disease. Accordingly, genetic testing is increasingly used to diagnose kidney diseases, but testing also may reveal rare missense variants that are of uncertain clinical significance. To aid in interpretation, computational prediction (called in silico) programs may be used to predict whether a variant is clinically important. We evaluate the performance of in silico programs for variants.

Study Design Setting & Participants: Rare missense variants in were identified in disease cohorts, including a local focal segmental glomerulosclerosis (FSGS) cohort and publicly available disease databases, in which they are categorized as pathogenic or benign based on clinical criteria.

Tests Compared & Outcomes: All rare missense variants identified in the 4 disease cohorts were subjected to in silico predictions using 12 different programs. Comparisons between the predictions were compared with: (1) variant classification (pathogenic or benign) in the cohorts and (2) functional characterization in a randomly selected smaller number (17) of pathogenic or uncertain significance variants obtained from the local FSGS cohort.

Results: In silico predictions correctly classified 75% to 97% of pathogenic and 57% to 100% of benign variants in public disease databases. The congruency of in silico predictions was similar for variants categorized as pathogenic and benign, with the exception of benign variants, in which disease effects were overestimated. By contrast, in silico predictions and functional characterization classified all 9 pathogenic variants correctly that were obtained from a local FSGS cohort. However, these programs also overestimated the effects of genomic variants of uncertain significance when compared with functional characterization. Each of the 12 in silico programs used yielded similar results.

Limitations: Overestimation of in silico program sensitivity given that they may have been used in the categorization of variants labeled as pathogenic in disease repositories.

Conclusions: Our results suggest that in silico predictions are sensitive but not specific to assign variant pathogenicity, with misclassification of benign variants and variants of uncertain significance. Thus, we do not recommend in silico programs but instead recommend pursuing more objective levels of evidence suggested by medical genetics guidelines.
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http://dx.doi.org/10.1016/j.xkme.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039416PMC
February 2021

Nuclear genome-wide associations with mitochondrial heteroplasmy.

Sci Adv 2021 Mar 17;7(12). Epub 2021 Mar 17.

Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

The role of the nuclear genome in maintaining the stability of the mitochondrial genome (mtDNA) is incompletely known. mtDNA sequence variants can exist in a state of heteroplasmy, which denotes the coexistence of organellar genomes with different sequences. Heteroplasmic variants that impair mitochondrial capacity cause disease, and the state of heteroplasmy itself is deleterious. However, mitochondrial heteroplasmy may provide an intermediate state in the emergence of novel mitochondrial haplogroups. We used genome-wide genotyping data from 982,072 European ancestry individuals to evaluate variation in mitochondrial heteroplasmy and to identify the regions of the nuclear genome that affect it. Age, sex, and mitochondrial haplogroup were associated with the extent of heteroplasmy. GWAS identified 20 loci for heteroplasmy that exceeded genome-wide significance. This included a region overlapping mitochondrial transcription factor A (), which has multiple roles in mtDNA packaging, replication, and transcription. These results show that mitochondrial heteroplasmy has a heritable nuclear component.
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http://dx.doi.org/10.1126/sciadv.abe7520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968846PMC
March 2021

Population-based studies reveal an additive role of type IV collagen variants in hematuria and albuminuria.

Pediatr Nephrol 2021 Feb 26. Epub 2021 Feb 26.

Institute of Medical Sciences, University of Toronto, Toronto, Canada.

Specific variants in genes that encode the α3α4α5 chains of type IV collagen cause Alport syndrome (AS), which encompass a clinical spectrum from isolated hematuria to multisystem disease affecting sight, hearing and kidney function. The commonest form is X-linked Alport syndrome (XLAS; COL4A5) with autosomal AS (COL4A3 and COL4A4) comprising a minority of cases. While historic data estimates the frequency of AS at 1:5000-10,000, recent population-based genetic studies suggest the prevalence is considerably higher. Genome-wide association studies (GWAS) have been performed in the Icelandic (deCODE) and UK (UK Biobank) populations, demonstrating an association of type IV collagen gene variants with AS relevant kidney traits. In the Icelandic population, 1 in 600 carries a 2.5-kb COL4A3 coding deletion or a COL4A3 missense variant (rs200287952[A], Gly695Arg), both of which are strongly associated with hematuria and albuminuria (P values = 1.9 × 10 to 2.5 × 10). In the UK Biobank, COL4A4 rs35138315 (Ser969X; carrier frequency 0.13%) is strongly associated with both hematuria and albuminuria (P = 1.5 × 10). Thus, the frequency for autosomal AS is 5-16 times higher than the historic prevalence of all forms of the disorder. Furthermore, COL4A4 rs3518315 (Ser969X) is also a reported founder mutation in families with autosomal dominant focal and segmental glomerulosclerosis and autosomal recessive forms of AS. This supports an additive mode of inheritance for specific variants, wherein a number of copies of a mutation influence disease severity in a cumulative fashion. These studies did not include the X chromosome, excluding analysis of COL4A5, which represents an area for future study.
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http://dx.doi.org/10.1007/s00467-021-04934-yDOI Listing
February 2021

Risk Factors for Longitudinal Resting Heart Rate and Its Associations With Cardiovascular Outcomes in the DCCT/EDIC Study.

Diabetes Care 2021 May 25;44(5):1125-1132. Epub 2021 Feb 25.

University of Tennessee Health Science Center, Memphis, TN.

Objective: Individuals with diabetes have higher resting heart rate compared with those without, which may be predictive of long-term cardiovascular disease (CVD) risk. Using data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, we evaluated whether the beneficial effect of intensive versus conventional diabetes therapy on heart rate persisted, the factors mediating the differences in heart rate between treatment groups, and the effects of heart rate on future CVD risk.

Research Design And Methods: Longitudinal changes in heart rate, from annual electrocardiograms over 22 years of EDIC follow-up, were evaluated in 1,402 participants with type 1 diabetes. Linear mixed models were used to assess the effect of DCCT treatment group on mean heart rate over time, and Cox proportional hazards models were used to estimate the effect of heart rate on CVD risk during DCCT/EDIC.

Results: At DCCT closeout, 52% of participants were male and mean ± SD age was 33 ± 7 years, diabetes duration 12 ± 5 years, and HbA 7.4 ± 1.2% (intensive) and 9.1 ± 1.6% (conventional). Through EDIC, participants in the intensive group had significantly lower heart rate in comparison with the conventional group. While significant group differences in heart rate were fully attenuated by DCCT/EDIC mean HbA, higher heart rate predicted CVD and major adverse cardiovascular events independent of other risk factors.

Conclusions: After 22 years of follow-up, former intensive versus conventional therapy remained significantly associated with lower heart rate, consistent with the long-term beneficial effects of intensive therapy on CVD. DCCT treatment group effects on heart rate were explained by differences in DCCT/EDIC mean HbA.
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http://dx.doi.org/10.2337/dc20-2387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132325PMC
May 2021

Patients with Protein-Truncating Mutations and Mild ADPKD.

Clin J Am Soc Nephrol 2021 03 18;16(3):374-383. Epub 2021 Feb 18.

Division of Nephrology, University Health Network and University of Toronto, Toronto, Ontario, Canada

Background And Objectives: Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating mutations may also have mild kidney disease, a finding not previously well recognized.

Design, Setting, Participants, & Measurements: From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had and sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR.

Results: Among 174 study patients with typical imaging patterns and protein-truncating mutations, 32 (18%) were found to have mild disease on the basis of imaging results (., Mayo Clinic Imaging class 1A-1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with mutations and Mayo Clinic Imaging class 1A-1B. Most of these mildly affected patients with protein-truncating mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability.

Conclusions: Despite having the most severe mutation class, 18% of patients with protein-truncating mutations had mild disease on the basis of clinical and imaging assessment.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3.
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http://dx.doi.org/10.2215/CJN.11100720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011025PMC
March 2021

Genome-wide association study of pediatric obsessive-compulsive traits: shared genetic risk between traits and disorder.

Transl Psychiatry 2021 02 2;11(1):91. Epub 2021 Feb 2.

Genetics and Genome Biology Hospital for Sick Children, Toronto, Canada.

Using a novel trait-based measure, we examined genetic variants associated with obsessive-compulsive (OC) traits and tested whether OC traits and obsessive-compulsive disorder (OCD) shared genetic risk. We conducted a genome-wide association analysis (GWAS) of OC traits using the Toronto Obsessive-Compulsive Scale (TOCS) in 5018 unrelated Caucasian children and adolescents from the community (Spit for Science sample). We tested the hypothesis that genetic variants associated with OC traits from the community would be associated with clinical OCD using a meta-analysis of all currently available OCD cases. Shared genetic risk was examined between OC traits and OCD in the respective samples using polygenic risk score and genetic correlation analyses. A locus tagged by rs7856850 in an intron of PTPRD (protein tyrosine phosphatase δ) was significantly associated with OC traits at the genome-wide significance level (p = 2.48 × 10). rs7856850 was also associated with OCD in a meta-analysis of OCD case/control genome-wide datasets (p = 0.0069). The direction of effect was the same as in the community sample. Polygenic risk scores from OC traits were significantly associated with OCD in case/control datasets and vice versa (p's < 0.01). OC traits were highly, but not significantly, genetically correlated with OCD (r = 0.71, p = 0.062). We report the first validated genome-wide significant variant for OC traits in PTPRD, downstream of the most significant locus in a previous OCD GWAS. OC traits measured in the community sample shared genetic risk with OCD case/control status. Our results demonstrate the feasibility and power of using trait-based approaches in community samples for genetic discovery.
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http://dx.doi.org/10.1038/s41398-020-01121-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870035PMC
February 2021

Residual β cell function in long-term type 1 diabetes associates with reduced incidence of hypoglycemia.

J Clin Invest 2021 Feb;131(3)

University of Washington, Seattle, Washington, USA.

BACKGROUNDWe investigated residual β cell function in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study participants with an average 35-year duration of type 1 diabetes mellitus (T1DM).METHODSSerum C-peptide was measured during a 4-hour mixed-meal tolerance test. Associations with metabolic outcomes and complications were explored among nonresponders (all C-peptide values after meal <0.003 nmol/L) and 3 categories of responders, classified by peak C-peptide concentration (nmol/L) as high (>0.2), intermediate (>0.03 to ≤0.2), and low (≥ 0.003 to ≤0.03).RESULTSOf the 944 participants, 117 (12.4%) were classified as responders. Residual C-peptide concentrations were associated with higher DCCT baseline concentrations of stimulated C-peptide (P value for trend = 0.0001). Residual C-peptide secretion was not associated with current or mean HbA1c, HLA high-risk haplotypes for T1DM, or the current presence of T1DM autoantibodies. The proportion of subjects with a history of severe hypoglycemia was lower with high (27%) and intermediate (48%) residual C-peptide concentrations than with low (74%) and no (70%) residual C-peptide concentrations (P value for trend = 0.0001). Responders and nonresponders demonstrated similar rates of advanced microvascular complications.CONCLUSIONβ Cell function can persist in long-duration T1DM. With a peak C-peptide concentration of >0.03 nmol/L, we observed clinically meaningful reductions in the prevalence of severe hypoglycemia.TRIAL REGISTRATIONClinicalTrials.gov NCT00360815 and NCT00360893.FUNDINGDivision of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (DP3-DK104438, U01 DK094176, and U01 DK094157).
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http://dx.doi.org/10.1172/JCI143011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843223PMC
February 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Skin autofluorescence predicts new cardiovascular disease and mortality in people with type 2 diabetes.

BMC Endocr Disord 2021 Jan 12;21(1):14. Epub 2021 Jan 12.

Department of Endocrinology, University of Groningen, University Medical Center Groningen, P.O. Box 30001, HPC AA31, Groningen, RB, 9700, The Netherlands.

Background: Skin autofluorescence (SAF) is a non-invasive marker of tissue accumulation of advanced glycation endproducts (AGE). Recently, we demonstrated in the general population that elevated SAF levels predict the development of type 2 diabetes (T2D), cardiovascular disease (CVD) and mortality. We evaluated whether elevated SAF may predict the development of CVD and mortality in individuals with T2D.

Methods: We included 2349 people with T2D, available baseline SAF measurements (measured with the AGE reader) and follow-up data from the Lifelines Cohort Study. Of them, 2071 had no clinical CVD at baseline. 60% were already diagnosed with diabetes (median duration 5, IQR 2-9 years), while 40% were detected during the baseline examination by elevated fasting blood glucose ≥7.0 mmol/l) and/or HbA1c ≥6.5% (48 mmol/mol).

Results: Mean (±SD) age was 57 ± 12 yrs., BMI 30.2 ± 5.4 kg/m. 11% of participants with known T2D were treated with diet, the others used oral glucose-lowering medication, with or without insulin; 6% was using insulin alone. Participants with known T2D had higher SAF than those with newly-detected T2D (SAF Z-score 0.56 ± 0.99 vs 0.34 ± 0.89 AU, p < 0.001), which reflects a longer duration of hyperglycaemia in the former group. Participants with existing CVD and T2D had the highest SAF Z-score: 0.78 ± 1.25 AU. During a median follow-up of 3.7 yrs., 195 (7.6%) developed an atherosclerotic CVD event, while 137 (5.4%) died. SAF was strongly associated with the combined outcome of a new CVD event or mortality (OR 2.59, 95% CI 2.10-3.20, p < 0.001), as well as incidence of CVD (OR 2.05, 95% CI 1.61-2.61, p < 0.001) and death (OR 2.98, 2.25-3.94, p < 0.001) as a single outcome. In multivariable analysis for the combined endpoint, SAF retained its significance when sex, systolic blood pressure, HbA1c, total cholesterol, eGFR, as well as antihypertensive and statin medication were included. In a similar multivariable model, SAF was independently associated with mortality as a single outcome, but not with incident CVD.

Conclusions: Measuring SAF can assist in prediction of incident cardiovascular disease and mortality in individuals with T2D. SAF showed a stronger association with future CVD events and mortality than cholesterol or blood pressure levels.
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http://dx.doi.org/10.1186/s12902-020-00676-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802158PMC
January 2021

Statistical power in COVID-19 case-control host genomic study design.

Genome Med 2020 12 28;12(1):115. Epub 2020 Dec 28.

Dalla Lana School of Public Health, University of Toronto, Room 500, 155 College St, Toronto, ON, M5T3M7, Canada.

The identification of genetic variation that directly impacts infection susceptibility to SARS-CoV-2 and disease severity of COVID-19 is an important step towards risk stratification, personalized treatment plans, therapeutic, and vaccine development and deployment. Given the importance of study design in infectious disease genetic epidemiology, we use simulation and draw on current estimates of exposure, infectivity, and test accuracy of COVID-19 to demonstrate the feasibility of detecting host genetic factors associated with susceptibility and severity in published COVID-19 study designs. We demonstrate that limited phenotypic data and exposure/infection information in the early stages of the pandemic significantly impact the ability to detect most genetic variants with moderate effect sizes, especially when studying susceptibility to SARS-CoV-2 infection. Our insights can aid in the interpretation of genetic findings emerging in the literature and guide the design of future host genetic studies.
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http://dx.doi.org/10.1186/s13073-020-00818-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768597PMC
December 2020

Genetically determined lean mass and dietary response.

Diabetes Obes Metab 2021 03 20;23(3):661-663. Epub 2020 Dec 20.

Banting & Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada.

Weight loss attenuates many obesity-related co-morbidities, but is difficult to sustain with dietary change. Dietary adherence, not macronutrient composition, is a better predictor of weight loss. Weight loss-induced endocrine changes promote food intake and increase energy efficiency, contributing to the difficulty with dietary adherence and weight regain. Macronutrient preference is partly genetically determined, suggesting that personalized dietary interventions might be more successful. In this issue, Li et al. report that a genetic risk score comprising the cumulative weighted effects of variants previously associated with increased lean mass is associated with increased satiety and weight loss 6 months after initiating a low- but not a high-fat diet. The effects were attenuated by 2 years. These findings suggest that genetic variants may influence response to specific diet. Further studies are necessary to assess whether genetically determined lean mass is causally associated with dietary response. Significant progress has recently been made in identifying additional genetic determinants of lean mass, which will enable such investigations and potentially inform future nutritional studies.
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http://dx.doi.org/10.1111/dom.14275DOI Listing
March 2021

Linkage analysis identifies an isolated strabismus locus at 14q12 overlapping with FOXG1 syndrome region.

J Med Genet 2020 Nov 30. Epub 2020 Nov 30.

Centre for Molecular Medicine and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada

Strabismus is a common condition, affecting 1%-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis. Among these, nine are affected and four are unaffected. A single linkage signal has been identified at an 8.5 Mb region of chromosome 14q12 with a multipoint LOD (logarithm of the odds) score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next-generation sequencing and in-depth bioinformatic analyses, a 4 bp non-coding deletion was prioritised as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of , which encodes a transcription factor of the Forkhead family. Suggestive of an autoregulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. Future study of this specific deletion may shed light on the regulation of expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.
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http://dx.doi.org/10.1136/jmedgenet-2020-107226DOI Listing
November 2020

Associations of NOD2 polymorphisms with Erysipelotrichaceae in stool of in healthy first degree relatives of Crohn's disease subjects.

BMC Med Genet 2020 10 15;21(1):204. Epub 2020 Oct 15.

Department of Medicine, University of Toronto, Toronto, ON, Canada.

Background: Genetic analyses have identified many variants associated with the risk of inflammatory bowel disease (IBD) development. Among these variants, the ones located within the NOD2 gene have the highest odds ratio of all IBD genetic risk variants. Also, patients with Crohn's disease (CD) have been shown to have an altered gut microbiome, which might be a reflection of inflammation itself or an effect of other parameters that contribute to the risk of the disease. Since NOD2 is an intracellular pattern recognition receptor that senses bacterial peptidoglycan in the cytosol and stimulates the host immune response (Al Nabhani et al., PLoS Pathog 13:e1006177, 2017), it is hypothesized that NOD2 variants represent perfect candidates for influencing host-microbiome interactions. We hypothesized that NOD2 risk variants affect the microbiome composition of healthy first degree relative (FDR) of CD patients and thus potentially contribute to an altered microbiome state before disease onset.

Methods: Based on this, we studied a large cohort of 1546 healthy FDR of CD patients and performed a focused analysis of the association of three major CD SNPs in the coding region of the NOD2 gene, which are known to confer a 15-40-fold increased risk of developing CD in homozygous or compound heterozygous individuals.

Results: Our results show that carriers of the C allele at rs2066845 was significantly associated with an increase in relative abundance in the fecal bacterial family Erysipelotrichaceae.

Conclusions: This result suggests that NOD2 polymorphisms contribute to fecal microbiome composition in asymptomatic individuals. Whether this modulation of the microbiome influences the future development of CD remains to be assessed.
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http://dx.doi.org/10.1186/s12881-020-01115-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566148PMC
October 2020

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia.

J Clin Endocrinol Metab 2020 12;105(12)

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.

Context: Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations.

Objective: To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals.

Design And Participants: We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants.

Results: Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level.

Conclusion: We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.
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http://dx.doi.org/10.1210/clinem/dgaa658DOI Listing
December 2020

Increased Intestinal Permeability Is Associated With Later Development of Crohn's Disease.

Gastroenterology 2020 12 10;159(6):2092-2100.e5. Epub 2020 Aug 10.

Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background & Aims: Increased intestinal permeability has been associated with Crohn's disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD.

Methods: We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6-35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR.

Results: An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64-5.63; P = 3.97 × 10). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051-2.50; P = .029).

Conclusions: Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.
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http://dx.doi.org/10.1053/j.gastro.2020.08.005DOI Listing
December 2020

DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes.

Nat Metab 2020 08 20;2(8):744-762. Epub 2020 Jul 20.

Department of Diabetes Complications and Metabolism, Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, USA.

Metabolic memory, the persistent benefits of early glycaemic control on preventing and/or delaying the development of diabetic complications, has been observed in the Diabetes Control and Complications Trial (DCCT) and in the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study, but the underlying mechanisms remain unclear. Here, we show the involvement of epigenetic DNA methylation (DNAme) in metabolic memory by examining its associations with preceding glycaemic history, and with subsequent development of complications over an 18-yr period in the blood DNA of 499 randomly selected DCCT participants with type 1 diabetes who are also followed up in EDIC. We demonstrate the associations between DNAme near the closeout of DCCT and mean HbA1c during DCCT (mean-DCCT HbA1c) at 186 cytosine-guanine dinucleotides (CpGs) (FDR < 15%, including 43 at FDR < 5%), many of which were located in genes related to complications. Exploration studies into biological function reveal that these CpGs are enriched in binding sites for the C/EBP transcription factor, as well as enhancer/transcription regions in blood cells and haematopoietic stem cells, and open chromatin states in myeloid cells. Mediation analyses show that, remarkably, several CpGs in combination explain 68-97% of the association of mean-DCCT HbA1c with the risk of complications during EDIC. In summary, DNAme at key CpGs appears to mediate the association between hyperglycaemia and complications in metabolic memory, through modifying enhancer activity at myeloid and other cells.
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http://dx.doi.org/10.1038/s42255-020-0231-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590966PMC
August 2020

Bleeding risks for uncharacterized platelet function disorders.

Res Pract Thromb Haemost 2020 Jul 30;4(5):799-806. Epub 2020 May 30.

Department of Pathology and Molecular Medicine McMaster University Hamilton ON Canada.

Background: The bleeding risks for nonsyndromic platelet function disorders (PFDs) that impair aggregation responses and/or cause dense granule deficiency (DGD) are uncertain.

Objectives: Our goal was to quantify bleeding risks for a cohort of consecutive cases with uncharacterized PFD.

Methods: Sequential cases with uncharacterized PFDs that had reduced maximal aggregation (MA) with multiple agonists and/or nonsyndromic DGD were invited to participate along with additional family members to reduce bias. Index cases were further evaluated by exome sequencing, with analysis of -dependent genes for cases with sequence variants. Bleeding assessment tools were used to estimate bleeding scores, with bleeding risks estimated as odds ratios (ORs) relative to general population controls. Relationships between symptoms and laboratory findings were also explored.

Results: Participants with uncharacterized PFD (n = 37; 23 index cases) had impaired aggregation function (70%), nonsyndromic DGD (19%) or both (11%), unlike unaffected relatives. Probable pathogenic variants were found in 2 (9%) index cases/families, whereas others had PFD of unknown cause. Participants with PFD had increased bleeding scores compared to unaffected family members and general population controls, and increased risks for mucocutaneous (OR, 4-207) and challenge-related bleeding (OR, 12-43), and for receiving transfusions for bleeding (OR, 100). Reduced MA with collagen was associated with wound healing problems and bruising, and more severe DGD was associated with surgical bleeding ( < .04).

Conclusions: PFDs that impair MA and/or cause nonsyndromic DGD have significantly increased bleeding risks, and some symptoms are more common in those with more severe DGD or impaired collagen aggregation.
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http://dx.doi.org/10.1002/rth2.12374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354414PMC
July 2020

Enhancer-gene rewiring in the pathogenesis of Quebec platelet disorder.

Blood 2020 12;136(23):2679-2690

Program in Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78-kb tandem duplication of PLAU. How this duplication causes megakaryocyte-specific PLAU overexpression is unknown. To investigate the mechanism that causes QPD, we used epigenomic profiling, comparative genomics, and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes from participants with QPD and unaffected controls. QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD). Our results support a unique disease mechanism whereby the reorganization of sub-TAD genome architecture results in a dramatic, cell-type-specific blood disorder phenotype.
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http://dx.doi.org/10.1182/blood.2020005394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735161PMC
December 2020

TaxoNN: ensemble of neural networks on stratified microbiome data for disease prediction.

Bioinformatics 2020 11;36(17):4544-4550

Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada M5T 3M7.

Motivation: Research supports the potential use of microbiome as a predictor of some diseases. Motivated by the findings that microbiome data is complex in nature, and there is an inherent correlation due to hierarchical taxonomy of microbial Operational Taxonomic Units (OTUs), we propose a novel machine learning method incorporating a stratified approach to group OTUs into phylum clusters. Convolutional Neural Networks (CNNs) were used to train within each of the clusters individually. Further, through an ensemble learning approach, features obtained from each cluster were then concatenated to improve prediction accuracy. Our two-step approach comprising stratification prior to combining multiple CNNs, aided in capturing the relationships between OTUs sharing a phylum efficiently, as compared to using a single CNN ignoring OTU correlations.

Results: We used simulated datasets containing 168 OTUs in 200 cases and 200 controls for model testing. Thirty-two OTUs, potentially associated with risk of disease were randomly selected and interactions between three OTUs were used to introduce non-linearity. We also implemented this novel method in two human microbiome studies: (i) Cirrhosis with 118 cases, 114 controls; (ii) type 2 diabetes (T2D) with 170 cases, 174 controls; to demonstrate the model's effectiveness. Extensive experimentation and comparison against conventional machine learning techniques yielded encouraging results. We obtained mean AUC values of 0.88, 0.92, 0.75, showing a consistent increment (5%, 3%, 7%) in simulations, Cirrhosis and T2D data, respectively, against the next best performing method, Random Forest.

Availability And Implementation: https://github.com/divya031090/TaxoNN_OTU.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750934PMC
November 2020

Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees.

Am J Med Genet B Neuropsychiatr Genet 2020 07 6;183(5):268-276. Epub 2020 May 6.

Centre for Addiction and Mental Health, The Hospital for Sick Children & University of Toronto, Toronto, Ontario, Canada.

Autism spectrum disorder (ASD) is a relatively common childhood onset neurodevelopmental disorder with a complex genetic etiology. While progress has been made in identifying the de novo mutational landscape of ASD, the genetic factors that underpin the ASD's tendency to run in families are not well understood. In this study, nine extended pedigrees each with three or more individuals with ASD, and others with a lesser autism phenotype, were phenotyped and genotyped in an attempt to identify heritable copy number variants (CNVs). Although these families have previously generated linkage signals, no rare CNV segregated with these signals in any family. A small number of clinically relevant CNVs were identified. Only one CNV was identified that segregated with ASD phenotype; namely, a duplication overlapping DLGAP2 in three male offspring each with an ASD diagnosis. This gene encodes a synaptic scaffolding protein, part of a group of proteins known to be pathologically implicated in ASD. On the whole, however, the heritable nature of ASD in the families studied remains poorly understood.
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http://dx.doi.org/10.1002/ajmg.b.32785DOI Listing
July 2020

DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes.

Clin Epigenetics 2020 04 5;12(1):52. Epub 2020 Apr 5.

Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.

Background: Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath's four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated.

Results: Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18-20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E-3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = - 1.99, p = 0.045) and leisure time (β = - 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E-50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used.

Conclusions: Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.
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http://dx.doi.org/10.1186/s13148-020-00840-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132894PMC
April 2020

Prevalence and Clinical Features of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified by Whole-Exome Sequencing in 1000 Children at a Single Center.

Gastroenterology 2020 06 19;158(8):2208-2220. Epub 2020 Feb 19.

SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background & Aims: A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD.

Methods: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0-18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and histochemical analyses.

Results: We identified 40 rare variants associated with 21 monogenic genes among 31 of the 1005 children with IBD (including 5 variants in XIAP, 3 in DOCK8, and 2 each in FOXP3, GUCY2C, and LRBA). These variants occurred in 7.8% of children younger than 6 years and 2.3% of children aged 6-18 years. Of the 17 patients with monogenic Crohn's disease, 35% had abdominal pain, 24% had nonbloody loose stool, 18% had vomiting, 18% had weight loss, and 5% had intermittent bloody loose stool. The 14 patients with monogenic ulcerative colitis or IBD-unclassified received their diagnosis at a younger age, and their most predominant feature was bloody loose stool (78%). Features associated with monogenic IBD, compared to cases of IBD not associated with a single variant, were age of onset younger than 2 years (odds ratio [OR], 6.30; P = .020), family history of autoimmune disease (OR, 5.12; P = .002), extra-intestinal manifestations (OR, 15.36; P < .0001), and surgery (OR, 3.42; P = .042). Seventeen patients had variants in genes that could be corrected with allogeneic hematopoietic stem cell transplantation.

Conclusions: In whole-exome sequencing analyses of more than 1000 children with IBD at a single center, we found that 3% had rare variants in genes previously associated with pediatric IBD. These were associated with different IBD phenotypes, and 1% of the patients had variants that could be potentially corrected with allogeneic hematopoietic stem cell transplantation. Monogenic IBD is rare, but should be considered in analysis of all patients with pediatric onset of IBD.
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http://dx.doi.org/10.1053/j.gastro.2020.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283012PMC
June 2020

Rare Genetic Variants of Large Effect Influence Risk of Type 1 Diabetes.

Diabetes 2020 04 31;69(4):784-795. Epub 2020 Jan 31.

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with < 0.05 and < In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of with an effect size comparable with those of common variants in the and loci (combined [from the discovery and replication cohorts] estimate of odds ratio [OR] 1.97, 95% CI 1.58-2.47, = 2.9 × 10). Pharmacological inhibition of activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk.
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http://dx.doi.org/10.2337/db19-0831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085253PMC
April 2020

Bleeding assessment tools to predict von Willebrand disease: Utility of individual bleeding symptoms.

Res Pract Thromb Haemost 2020 Jan 30;4(1):92-99. Epub 2019 Oct 30.

Department of Medicine Queen's University Kingston ON Canada.

Background: Bleeding assessment is part of the diagnostic workup of von Willebrand disease (VWD). Bleeding assessment tools (BATs) have standardized obtaining this information but have been criticized because they are time consuming.

Objective: To use our legacy data to determine which questions from BATs are the strongest predictors of a VWD diagnosis.

Patients/methods: Bleeding score data from 3 different BATs were used. Patients aged <12 years were excluded. Questions on BATs relate to different bleeding symptoms, and each symptom is scored by severity. Scores for each symptom were sorted based on whether they indicated clinically significant bleeding, and nonsignificant scores were set as the reference category. Multivariable logistic regression was used to determine the symptoms that were the strongest predictors of a laboratory-confirmed VWD diagnosis.

Results: A total of 927 participants were included; 144 (16%) were patients with VWD, and 783 (84%) were healthy controls. The top 3 symptoms for which a clinically significant positive response increased the likelihood of VWD were hemarthrosis (odds ratio [OR], 19.2; 95% confidence interval [CI], 3.7-100.4), postsurgical bleeding (OR, 15.2; 95% CI, 5.9-38.9), and menorrhagia (OR, 10.3; 95% CI, 4.9-21.9). With each increase in number of bleeding symptom categories with clinically significant scores, subjects had a stepwise increase in odds of a VWD diagnosis.

Conclusions: Our results suggest that most of the bleeding symptoms on BATs are significant predictors of VWD, and there is value in assessing multiple bleeding symptoms when eliciting a bleeding history. Certain bleeding symptoms are more useful predictors than others. Future BAT revisions may consider adding a relative weighting to each symptom.
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http://dx.doi.org/10.1002/rth2.12256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971303PMC
January 2020

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

J Am Soc Nephrol 2019 10 19;30(10):2000-2016. Epub 2019 Sep 19.

Department of Biostatistics and.

Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.

Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.

Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( or renal biology ( and ).

Conclusions: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
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http://dx.doi.org/10.1681/ASN.2019030218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779358PMC
October 2019

Evaluation of the Genetic Association Between Adult Obesity and Neuropsychiatric Disease.

Diabetes 2019 12 10;68(12):2235-2246. Epub 2019 Sep 10.

Department of Medicine, Banting & Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada

Extreme obesity (EO) (BMI >50 kg/m) is frequently associated with neuropsychiatric disease (NPD). As both EO and NPD are heritable central nervous system disorders, we assessed the prevalence of protein-truncating variants (PTVs) and copy number variants (CNVs) in genes/regions previously implicated in NPD in adults with EO ( = 149) referred for weight loss/bariatric surgery. We also assessed the prevalence of CNVs in patients referred to University College London Hospital (UCLH) with EO ( = 218) and obesity (O) (BMI 35-50 kg/m; = 374) and a Swedish cohort of participants from the community with predominantly O ( = 161). The prevalence of variants was compared with control subjects in the Exome Aggregation Consortium/Genome Aggregation Database. In the discovery cohort (high NPD prevalence: 77%), the cumulative PTV/CNV allele frequency (AF) was 7.7% vs. 2.6% in control subjects (odds ratio [OR] 3.1 [95% CI 2-4.1]; < 0.0001). In the UCLH EO cohort (intermediate NPD prevalence: 47%), CNV AF (1.8% vs. 0.9% in control subjects; OR 1.95 [95% CI 0.96-3.93]; = 0.06) was lower than the discovery cohort. CNV AF was not increased in the UCLH O cohort (0.8%). No CNVs were identified in the Swedish cohort with no NPD. These findings suggest that PTV/CNVs, in genes/regions previously associated with NPD, may contribute to NPD in patients with EO.
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http://dx.doi.org/10.2337/db18-1254DOI Listing
December 2019
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