Publications by authors named "Natalie Van Zuydam"

34 Publications

Correction of a urea cycle defect after ex vivo gene editing of human hepatocytes.

Mol Ther 2021 May 21;29(5):1903-1917. Epub 2021 Jan 21.

Department of Laboratory Medicine, Karolinska Institutet, 141 52 Huddinge, Sweden. Electronic address:

Ornithine transcarbamylase deficiency (OTCD) is a monogenic disease of ammonia metabolism in hepatocytes. Severe disease is frequently treated by orthotopic liver transplantation. An attractive approach is the correction of a patient's own cells to regenerate the liver with gene-repaired hepatocytes. This study investigates the efficacy and safety of ex vivo correction of primary human hepatocytes. Hepatocytes isolated from an OTCD patient were genetically corrected ex vivo, through the deletion of a mutant intronic splicing site achieving editing efficiencies >60% and the restoration of the urea cycle in vitro. The corrected hepatocytes were transplanted into the liver of FRGN mice and repopulated to high levels (>80%). Animals transplanted and liver repopulated with genetically edited patient hepatocytes displayed normal ammonia, enhanced clearance of an ammonia challenge and OTC enzyme activity, as well as lower urinary orotic acid when compared to mice repopulated with unedited patient hepatocytes. Gene expression was shown to be similar between mice transplanted with unedited or edited patient hepatocytes. Finally, a genome-wide screening by performing CIRCLE-seq and deep sequencing of >70 potential off-targets revealed no unspecific editing. Overall analysis of disease phenotype, gene expression, and possible off-target editing indicated that the gene editing of a severe genetic liver disease was safe and effective.
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http://dx.doi.org/10.1016/j.ymthe.2021.01.024DOI Listing
May 2021

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus.

Circ Genom Precis Med 2020 12 13;13(6):e002769. Epub 2020 Aug 13.

The Usher Institute of Population Health Sciences & Informatics (A.D.M.), University of Edinburgh, Edinburgh, U.K.

Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D).

Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D).

Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background.

Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
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http://dx.doi.org/10.1161/CIRCGEN.119.002769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748049PMC
December 2020

In Vitro and In Vivo Evaluation of 3D Printed Capsules with Pressure Triggered Release Mechanism for Oral Peptide Delivery.

J Pharm Sci 2021 01 17;110(1):228-238. Epub 2020 Nov 17.

The Swedish Drug Delivery Center, Department of Pharmacy, Uppsala University, BMC P.O. Box 580, SE-751 23 Uppsala, Sweden. Electronic address:

In this study a 3D printed capsule designed to break from the physiological pressures in the antropyloric region was evaluated for its ability to deliver the synthetic octapeptide octreotide in beagle dogs when co-formulated with the permeation enhancer sodium caprate. The pressure sensitive capsules were compared to traditional enteric coated hard gelatin capsules and enteric coated tablets. Paracetamol, which is completely absorbed in dogs, was included in the formulations and used as an absorption marker to give information about the in vivo performance of the dosage forms. The pressure sensitive capsules released drug in 50% of the dogs. In the cases where drug was released, there was no difference in octreotide bioavailability or C compared to the enteric coated dosage forms. When comparing all dosage forms, a correlation was seen between paracetamol C and octreotide bioavailability, suggesting that a high drug release rate may be beneficial for peptide absorption when delivered together with sodium caprate.
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http://dx.doi.org/10.1016/j.xphs.2020.10.066DOI Listing
January 2021

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

Targeted Sequencing Study to Uncover Shared Genetic Susceptibility Between Peripheral Artery Disease and Coronary Heart Disease-Brief Report.

Arterioscler Thromb Vasc Biol 2019 06;39(6):1227-1233

From the Department of Cardiovascular Medicine (M.S.S., X.F., E.E.A., I.J.K.), Mayo Clinic, Rochester, MN.

Objective- It is unclear to what extent genetic susceptibility variants are shared between peripheral artery disease (PAD) and coronary heart disease (CHD), both manifestations of atherosclerotic vascular disease. We investigated whether common and low-frequency/rare variants in loci associated with CHD are also associated with PAD. Approach and Results- Targeted sequencing of 41 genomic regions associated with CHD in genome-wide association studies was performed in 1749 PAD cases (65±11 years, 61% men) and 1855 controls (60±11 years, 56% men) of European ancestry. PAD cases had a resting/postexercise ankle-brachial index ≤0.9, or history of lower extremity revascularization; controls had no history of PAD. We tested the association of common (defined as minor allele frequency ≥5%) variants with PAD assuming an additive genetic model with adjustment for age and sex. To identify low-frequency/rare variants (minor allele frequency <5%) associated with PAD, we conducted gene-level analyses using sequence kernel association test and permutation test. After Bonferroni correction, we found common variants in SH2B3, ABO, and ZEB2 to be associated with PAD ( P<4.5×10). At the gene level, the strongest associations were for LPL and SH2B3. Conclusions- Targeted sequencing of 41 genomic regions associated with CHD revealed several common variants/genes to be associated with PAD, highlighting the basis of shared genetic susceptibility between CHD and PAD.
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http://dx.doi.org/10.1161/ATVBAHA.118.312128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531315PMC
June 2019

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
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http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

Causal relationships among the gut microbiome, short-chain fatty acids and metabolic diseases.

Nat Genet 2019 04 18;51(4):600-605. Epub 2019 Feb 18.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity. However, the causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality, we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.
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http://dx.doi.org/10.1038/s41588-019-0350-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441384PMC
April 2019

A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.

PLoS One 2018 19;13(12):e0208654. Epub 2018 Dec 19.

Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208654PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300288PMC
May 2019

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria.

Diabetologia 2019 02 13;62(2):292-305. Epub 2018 Dec 13.

Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Aims/hypothesis: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.

Methods: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.

Results: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (p = 7.0 × 10, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (p < 2.7 × 10).

Conclusions/interpretation: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.
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http://dx.doi.org/10.1007/s00125-018-4783-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323095PMC
February 2019

Shared Genetic Contribution of Type 2 Diabetes and Cardiovascular Disease: Implications for Prognosis and Treatment.

Curr Diab Rep 2018 06 25;18(8):59. Epub 2018 Jun 25.

Wellcome Centre Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, Oxfordshire, OX3 7BN, UK.

Purpose Of Review: The increased cardiovascular disease (CVD) risk in subjects with type 2 diabetes (T2D) is well established. This review collates the available evidence and assesses the shared genetic background between T2D and CVD: the causal contribution of common risk factors to T2D and CVD and how genetics can be used to improve drug development and clinical outcomes.

Recent Findings: Large-scale genome-wide association studies (GWAS) of T2D and CVD support a shared genetic background but minimal individual locus overlap. Mendelian randomisation (MR) analyses show that T2D is causal for CVD, but GWAS of CVD, T2D and their common risk factors provided limited evidence for individual locus overlap. Distinct but functionally related pathways were enriched for CVD and T2D genetic associations reflecting the lack of locus overlap and providing some explanation for the variable associations of common risk factors with CVD and T2D from MR analyses.
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http://dx.doi.org/10.1007/s11892-018-1021-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015804PMC
June 2018

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes.

Diabetes 2018 07 27;67(7):1414-1427. Epub 2018 Apr 27.

Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near (rs9942471, = 4.5 × 10) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at and , both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
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http://dx.doi.org/10.2337/db17-0914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014557PMC
July 2018

Exome-wide association study of plasma lipids in >300,000 individuals.

Nat Genet 2017 Dec 30;49(12):1758-1766. Epub 2017 Oct 30.

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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http://dx.doi.org/10.1038/ng.3977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709146PMC
December 2017

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

Diabetes 2017 11 31;66(11):2888-2902. Epub 2017 May 31.

MRC Epidemiology Unit, University of Cambridge, Cambridge, U.K.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci ( < 5 × 10), including variants near the , , and genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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http://dx.doi.org/10.2337/db16-1253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652602PMC
November 2017

Loss of Cardioprotective Effects at the Locus as a Result of Gene-Smoking Interactions.

Circulation 2017 Jun 1;135(24):2336-2353. Epub 2017 May 1.

From Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia (D.S., W.Z.); Center for Non-Communicable Diseases, Karachi, Pakistan (D.S., A.R., P.M.F., PROMIS); Department of Public Health and Primary Care, University of Cambridge, United Kingdom (R.Y., W.K.H., EPIC-CVD); Department of Cardiovascular Sciences, University of Leicester, United Kingdom (C.P.N., N.J.S.); Cardiology Division, Department of Medicine, Vanderbilt University, Nashville, TN (J.F.F., K.O.); Division of Cardiovascular Medicine, Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom (A.G., M.F.); The Charles Bronfman Institute of Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY (R.D.); Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (R.D.); Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Canada (A.F.R.S., R.M.); Institute for Genetic Medicine and Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (J.H., H.A.); Department of Epidemiology and Biostatistics, Imperial College London, United Kingdom (W.Z., J.C.C., J.K.); Department of Cardiology, Ealing Hospital NHS Trust, Middlesex, United Kingdom (W.Z., J.C.C.); Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (R.J.S.); Helsinki University Central Hospital HUCH Heart and Lung Center, Helsinki, Uusimaa, Finland (J.S.); Cardiology Division, Department of Medicine and the Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY (R.C.B., M.P.R.); William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (S.K., E.M., P.D.); Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands (S.S., A.D.); Department of Dietetics-Nutrition, Harokopio University, Athens, Greece (E.M., G.D.); National Institute for Health and Welfare, Helsinki, Finland (K.K., A.J., V.S., K.K., M.P.); MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, United Kingdom (J.H.Z., R.S.); INSERM, UMRS1138, Centre de Recherche des Cordeliers, Paris, France (D.G., N.W.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.H.S.); Icelandic Heart Association, Kopavogur, Iceland (A.V.S., V.G.); Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, United Kingdom (N.v.Z., C.N.A.P.); Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC (A.J.C., D.W.B.); Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Germany (C.W., J.E.); DZHK (German Research Center for Cardiovascular Research) partner site Hamburg-Lübeck-Kiel, Germany (C.W., J.E.); Deutsches Herzzentrum München, Technische Universität München, Germany (T.K., L.Z., H.S.); Klinikum rechts der Isar, München, Germany (T.K.); DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Germany (L.Z., H.S.); Department of Genetics, Washington University School of Medicine, St. Louis, MO (M.A.P., M.F.F.); Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (A.G.); Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA (A.G.); Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Sweden (L.L.); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (N.L.P.); Department of Biostatistics Boston University School of Public Health Framingham Heart Study, MA (C.C.W.); Faculty of Medicine, University of Iceland, Reykjavik (A.V.S., V.G.); University of Helsinki, Institute for Molecular Medicine, Finland (FIMM) (A.J., M.P.); Department of Medicine, Mannheim Medical Faculty, Heidelberg University, Germany (M.E.K.); Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, United Kingdom (A.S.H.); Synlab Academy, Synlab Services GmbH, Mannheim, Germany and Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria (W.M.); National Heart, Lung, and Blood Institute and the Framingham Heart Study, National Institutes of Health, Bethesda, MD (C.O'D.); Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Sweden (E.I.); Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (E.I.); Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (U.D.F.); Lebanese American University, School of Medicine, Beirut (P.Z.); Department of Health Sciences, University of Leicester, United Kingdom (J.R.T.); Imperial College Healthcare NHS Trust, London, United Kingdom (J.C.C., J.K.); Cardiovascular Science, National Heart and Lung Institute, Imperial College London, United Kingdom (J.K.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia (P.D.); deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland (G.T., K.S.); University of Iceland, School of Medicine, Reykjavik, Iceland (G.T., K.S.); Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge (S.K.); Cardiovascular Research Center, Massachusetts General Hospital, Boston (S.K.); Center for Human Genetic Research, Massachusetts General Hospital, Boston (S.K.); Department of Medicine, Harvard Medical School, Boston, MA (S.K.); Department of Genetics, University of Pennsylvania, Philadelphia (D.J.R.); and Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.T.N., D.J.R.).

Background: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk.

Methods: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a value of <1.0×10 (Bonferroni correction for 50 tests).

Results: We identified novel gene-smoking interaction for a variant upstream of the gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (=1.3×10) in comparison with 5% in ever-smokers (=2.5×10), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction value=8.7×10). The protective T allele at rs7178051 was also associated with reduced expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular expression may contribute to the loss of CHD protection in smokers.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612779PMC
June 2017

Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease.

J Am Coll Cardiol 2017 Feb;69(7):823-836

Department of Biostatistics, Academic Medical Center, Amsterdam, the Netherlands.

Background: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.

Objectives: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.

Methods: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.

Results: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10 with a range of other diseases/traits.

Conclusions: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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http://dx.doi.org/10.1016/j.jacc.2016.11.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314135PMC
February 2017

Genome-wide associations for birth weight and correlations with adult disease.

Nature 2016 10 28;538(7624):248-252. Epub 2016 Sep 28.

Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, the Netherlands.

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (R = -0.22, P = 5.5 × 10), T2D (R = -0.27, P = 1.1 × 10) and coronary artery disease (R = -0.30, P = 6.5 × 10). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
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http://dx.doi.org/10.1038/nature19806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5164934PMC
October 2016

The Genetic Landscape of Renal Complications in Type 1 Diabetes.

J Am Soc Nephrol 2017 02 19;28(2):557-574. Epub 2016 Sep 19.

The Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10) and the risk of type 2 diabetes (P=6.1×10) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10), and pentose and glucuronate interconversions (P=3.0×10) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.
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http://dx.doi.org/10.1681/ASN.2016020231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5280020PMC
February 2017

Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity.

Am J Hum Genet 2016 Sep;99(3):636-646

Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.

We analyzed genome-wide association studies (GWASs), including data from 71,638 individuals from four ancestries, for estimated glomerular filtration rate (eGFR), a measure of kidney function used to define chronic kidney disease (CKD). We identified 20 loci attaining genome-wide-significant evidence of association (p < 5 × 10(-8)) with kidney function and highlighted that allelic effects on eGFR at lead SNPs are homogeneous across ancestries. We leveraged differences in the pattern of linkage disequilibrium between diverse populations to fine-map the 20 loci through construction of "credible sets" of variants driving eGFR association signals. Credible variants at the 20 eGFR loci were enriched for DNase I hypersensitivity sites (DHSs) in human kidney cells. DHS credible variants were expression quantitative trait loci for NFATC1 and RGS14 (at the SLC34A1 locus) in multiple tissues. Loss-of-function mutations in ancestral orthologs of both genes in Drosophila melanogaster were associated with altered sensitivity to salt stress. Renal mRNA expression of Nfatc1 and Rgs14 in a salt-sensitive mouse model was also reduced after exposure to a high-salt diet or induced CKD. Our study (1) demonstrates the utility of trans-ethnic fine mapping through integration of GWASs involving diverse populations with genomic annotation from relevant tissues to define molecular mechanisms by which association signals exert their effect and (2) suggests that salt sensitivity might be an important marker for biological processes that affect kidney function and CKD in humans.
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http://dx.doi.org/10.1016/j.ajhg.2016.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011075PMC
September 2016

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease.

N Engl J Med 2016 03 2;374(12):1134-44. Epub 2016 Mar 2.

Background: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets.

Methods: Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes.

Results: We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)).

Conclusions: We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1507652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850838PMC
March 2016

A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease.

Nat Genet 2015 Oct 7;47(10):1121-1130. Epub 2015 Sep 7.

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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http://dx.doi.org/10.1038/ng.3396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589895PMC
October 2015

Sex-Specific Effects of Adiponectin on Carotid Intima-Media Thickness and Incident Cardiovascular Disease.

J Am Heart Assoc 2015 Aug 14;4(8):e001853. Epub 2015 Aug 14.

Clinical Research Center, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden (C.F., B.H., O.M.).

Background: Plasma adiponectin levels have previously been inversely associated with carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis. In this study, we used a sex-stratified Mendelian randomization approach to investigate whether adiponectin has a causal protective influence on IMT.

Methods And Results: Baseline plasma adiponectin concentration was tested for association with baseline IMT, IMT progression over 30 months, and occurrence of cardiovascular events within 3 years in 3430 participants (women, n=1777; men, n=1653) with high cardiovascular risk but no prevalent disease. Plasma adiponectin levels were inversely associated with baseline mean bifurcation IMT after adjustment for established risk factors (β=-0.018, P<0.001) in men but not in women (β=-0.006, P=0.185; P for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid IMT in men (β=-0.0022, P=0.047), whereas no association was seen in women (0.0007, P=0.475; P for interaction=0.018). Moreover, we observed that adiponectin levels were inversely associated with coronary events in women (hazard ratio 0.57, 95% CI 0.37 to 0.87) but not in men (hazard ratio 0.82, 95% CI 0.54 to 1.25). A gene score of adiponectin-raising alleles in 6 loci, reported recently in a large multi-ethnic meta-analysis, was inversely associated with baseline mean bifurcation IMT in men (β=-0.0008, P=0.004) but not in women (β=-0.0003, P=0.522; P for interaction=0.007).

Conclusions: This report provides some evidence for adiponectin protecting against atherosclerosis, with effects being confined to men; however, compared with established cardiovascular risk factors, the effect of plasma adiponectin was modest. Further investigation involving mechanistic studies is warranted.
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http://dx.doi.org/10.1161/JAHA.115.001853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599454PMC
August 2015

The genetics of diabetic complications.

Nat Rev Nephrol 2015 May 31;11(5):277-87. Epub 2015 Mar 31.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.

The rising global prevalence of diabetes mellitus is accompanied by an increasing burden of morbidity and mortality that is attributable to the complications of chronic hyperglycaemia. These complications include blindness, renal failure and cardiovascular disease. Current therapeutic options for chronic hyperglycaemia reduce, but do not eradicate, the risk of these complications. Success in defining new preventative and therapeutic strategies hinges on an improved understanding of the molecular processes involved in the development of these complications. This Review explores the role of human genetics in delivering such insights, and describes progress in characterizing the sequence variants that influence individual predisposition to diabetic kidney disease, retinopathy, neuropathy and accelerated cardiovascular disease. Numerous risk variants for microvascular complications of diabetes have been reported, but very few have shown robust replication. Furthermore, only limited evidence exists of a difference in the repertoire of risk variants influencing macrovascular disease between those with and those without diabetes. Here, we outline the challenges associated with the genetic analysis of diabetic complications and highlight ongoing efforts to deliver biological insights that can drive translational benefits.
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http://dx.doi.org/10.1038/nrneph.2015.37DOI Listing
May 2015

Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes.

Diabetologia 2015 Jun 5;58(6):1363-71. Epub 2015 Mar 5.

Diabetes Epidemiology Unit, University of Dundee, Mackenzie Building, Kirsty Semple Way, Dundee, DD2 4BF, UK,

Aims/hypothesis: We selected the most informative protein biomarkers for the prediction of incident cardiovascular disease (CVD) in people with type 2 diabetes.

Methods: In this nested case-control study we measured 42 candidate CVD biomarkers in 1,123 incident CVD cases and 1,187 controls with type 2 diabetes selected from five European centres. Combinations of biomarkers were selected using cross-validated logistic regression models. Model prediction was assessed using the area under the receiver operating characteristic curve (AUROC).

Results: Sixteen biomarkers showed univariate associations with incident CVD. The most predictive subset selected by forward selection methods contained six biomarkers: N-terminal pro-B-type natriuretic peptide (OR 1.69 per 1 SD, 95% CI 1.47, 1.95), high-sensitivity troponin T (OR 1.29, 95% CI 1.11, 1.51), IL-6 (OR 1.13, 95% CI 1.02, 1.25), IL-15 (OR 1.15, 95% CI 1.01, 1.31), apolipoprotein C-III (OR 0.79, 95% CI 0.70, 0.88) and soluble receptor for AGE (OR 0.84, 95% CI 0.76, 0.94). The prediction of CVD beyond clinical covariates improved from an AUROC of 0.66 to 0.72 (AUROC for Framingham Risk Score covariates 0.59). In addition to the biomarkers, the most important clinical covariates for improving prediction beyond the Framingham covariates were estimated GFR, insulin therapy and HbA1c.

Conclusions/interpretation: We identified six protein biomarkers that in combination with clinical covariates improved the prediction of our model beyond the Framingham Score covariates. Biomarkers can contribute to improved prediction of CVD in diabetes but clinical data including measures of renal function and diabetes-specific factors not included in the Framingham Risk Score are also needed.
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http://dx.doi.org/10.1007/s00125-015-3535-6DOI Listing
June 2015

Both high and low HbA1c predict incident heart failure in type 2 diabetes mellitus.

Circ Heart Fail 2015 Mar 5;8(2):236-42. Epub 2015 Jan 5.

From the Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital, University of Dundee, Dundee, United Kingdom.

Background: Type 2 diabetes mellitus is an independent risk factor for heart failure development, but the relationship between incident heart failure and antecedent glycemia has not been evaluated.

Methods And Results: The Genetics of Diabetes Audit and Research in Tayside Study study holds data for 8683 individuals with type 2 diabetes mellitus. Dispensed prescribing, hospital admission data, and echocardiography reports were linked to extract incident heart failure cases from December 1998 to August 2011. All available HbA1c measures until heart failure development or end of study were used to model HbA1c time-dependently. Individuals were observed from study enrolment until heart failure development or end of study. Proportional hazard regression calculated heart failure development risk associated with specific HbA1c ranges accounting for comorbidities associated with heart failure, including blood pressure, body mass index, and coronary artery disease. Seven hundred and one individuals with type 2 diabetes mellitus (8%) developed heart failure during follow up (mean 5.5 years, ±2.8 years). Time-updated analysis with longitudinal HbA1c showed that both HbA1c <6% (hazard ratio =1.60; 95% confidence interval, 1.38-1.86; P value <0.0001) and HbA1c >10% (hazard ratio =1.80; 95% confidence interval, 1.60-2.16; P value <0.0001) were independently associated with the risk of heart failure.

Conclusions: Both high and low HbA1c predicted heart failure development in our cohort, forming a U-shaped relationship.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.113.000920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366571PMC
March 2015

Loss-of-function mutations in APOC3, triglycerides, and coronary disease.

N Engl J Med 2014 Jul 18;371(1):22-31. Epub 2014 Jun 18.

Background: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype.

Methods: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons.

Results: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)).

Conclusions: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).
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http://dx.doi.org/10.1056/NEJMoa1307095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180269PMC
July 2014

Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis.

Lancet Diabetes Endocrinol 2014 Jun 19;2(6):481-7. Epub 2014 Mar 19.

Medical Research Institute, University of Dundee, Dundee, UK. Electronic address:

Background: Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method.

Methods: In this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture.

Findings: 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect.

Interpretation: Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action.

Funding: Wellcome Trust.
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http://dx.doi.org/10.1016/S2213-8587(14)70050-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038749PMC
June 2014

Robust association of the LPA locus with low-density lipoprotein cholesterol lowering response to statin treatment in a meta-analysis of 30 467 individuals from both randomized control trials and observational studies and association with coronary artery disease outcome during statin treatment.

Pharmacogenet Genomics 2013 Oct;23(10):518-25

aMedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee bWellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK cDivision of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University dDepartment of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.

Objectives: The LPA single-nucleotide polymorphism rs10455872 has been associated with low-density lipoprotein cholesterol (LDLc) lowering response to statins in several randomized control trials (RCTs) and is a known coronary artery disease (CAD) marker. However, it is unclear what residual risk of CAD this marker may have during statin treatment.

Methods: Using electronic medical records linked to the GoDARTS genotyped population, we identified over 8000 patients on statins in Tayside, Scotland.

Results: We replicated the findings of the RCTs, with the G allele of rs10455872 being associated with a 0.10 mmol/l per allele poorer reduction in LDLc in response to statin treatment, and conducted a meta-analysis with previously published RCTs (P = 1.46 × 10, n = 30 467). We showed an association between rs10455872 and CAD in statin-treated individuals and have replicated this finding in the Utrecht Cardiovascular Pharmacogenetics study (combined odds ratio 1.41, 95% confidence interval 1.17-1.68, P = 4.5 × 10, n = 8822) suggesting that statin treatment does not abrogate this well-established genetic risk for CAD. Furthermore, in a Cox proportional hazards model with LDLc measured time dependently, we demonstrated that the relationship between CAD and rs10455872 was independent of LDLc during statin treatment.

Conclusion: Individuals with the G allele of rs10455872, which represents approximately one in seven patients, have a higher risk of CAD than the majority of the population even after treatment with statins; and therefore represent a vulnerable group requiring an alternative medication in addition to statin treatment.
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http://dx.doi.org/10.1097/FPC.0b013e3283642fd6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4110714PMC
October 2013

Genetic variants predicting left ventricular hypertrophy in a diabetic population: a Go-DARTS study including meta-analysis.

Cardiovasc Diabetol 2013 Jul 23;12:109. Epub 2013 Jul 23.

Division of Cardiovascular and Diabetes Medicine, University of Dundee, UK.

Background: Left ventricular hypertrophy has multiple aetiologies including diabetes and genetic factors. We aimed to identify genetic variants predicting left ventricular hypertrophy in diabetic individuals.

Methods: Demographic, echocardiographic, prescribing, morbidity, mortality and genotyping databases connected with the Genetics of Diabetes Audit and Research in Tayside, Scotland project were accurately linked using a patient-specific identifier. Left ventricular hypertrophy cases were identified using echocardiographic data.Genotyping data from 973 cases and 1443 non-left ventricular hypertrophy controls were analysed, investigating whether single nucleotide polymorphisms associated with left ventricular hypertrophy in previous Genome Wide Association Studies predicted left ventricular hypertrophy in our population of individuals with type 2 diabetes. Meta-analysis assessed overall significance of these single nucleotide polymorphisms, which were also used to create gene scores. Logistic regression assessed whether these scores predicted left ventricular hypertrophy.

Results: Two single nucleotide polymorphisms previously associated with left ventricular hypertrophy were significant: rs17132261: OR 2.03, 95% CI 1.10-3.73, p-value 0.02 and rs2292462: OR 0.82, 95% CI 0.73-0.93 and p-value 2.26x10-3. Meta-analysis confirmed rs17132261 and rs2292462 were associated with left ventricular hypertrophy (p=1.03x10-8 and p=5.86x10-10 respectively) and one single nucleotide polymorphisms in IGF1R (rs4966014) became genome wide significant upon meta-analysis although was not significant in our study. Gene scoring based on published single nucleotide polymorphisms also predicted left ventricular hypertrophy in our study.Rs17132261, within SLC25A46, encodes a mitochondrial phosphate transporter, implying abnormal myocardial energetics contribute to left ventricular hypertrophy development. Rs2292462 lies within the obesity-implicated neuromedin B gene. Rs4966014 lies within the IGF1R1 gene. IGF1 signalling is an established factor in cardiac hypertrophy.

Conclusions: We created a resource to study genetics of left ventricular hypertrophy in diabetes and validated our left ventricular hypertrophy phenotype in replicating single nucleotide polymorphisms identified by previous genome wide association studies investigating left ventricular hypertrophy.
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http://dx.doi.org/10.1186/1475-2840-12-109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729417PMC
July 2013

The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis.

PLoS Med 2013 25;10(6):e1001474. Epub 2013 Jun 25.

Molecular Epidemiology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.

Methods And Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n  =  198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p < 0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p < 0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p  =  0.001).

Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
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http://dx.doi.org/10.1371/journal.pmed.1001474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692470PMC
March 2014

Genetic loci for retinal arteriolar microcirculation.

PLoS One 2013 12;8(6):e65804. Epub 2013 Jun 12.

Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, United States of America.

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065804PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680438PMC
January 2014