Publications by authors named "Ruth McPherson"

205 Publications

Colchicine for Prevention of Atherothrombotic Events in Patients With Coronary Artery Disease: Review and Practical Approach for Clinicians.

Can J Cardiol 2021 Aug 18. Epub 2021 Aug 18.

Montréal Heart Institute, Université de Montréal, Montréal, Québec, Canada.

A better understanding of the central role of inflammation in the development of coronary artery disease (CAD) has been the impetus for the evaluation of therapeutic strategies targeting the interleukin-1ß/interleukin-6 cytokine signaling pathway, involved in both chronic atherogenesis and in triggering of atherosclerotic plaque rupture. As an inexpensive pharmacologic agent with relatively few adverse effects that tend to be mild and tolerable, the role of colchicine in secondary prevention of atherothrombotic events has been the focus of multiple recent large-scale randomized controlled trials involving patients with stable CAD (Low-Dose Colchicine [LoDoCo] and LoDoCo2 trials), a recent myocardial infarction (Colchicine Cardiovascular Outcome Trial [COLCOT], Colchicine in Patients With Acute Coronary Syndrome [COPS], and Colchicine and Spironolactone in Patients With Myocardial Infarction/Synergy Stent Registry [CLEAR SYNERGY] trials), and undergoing percutaneous coronary interventions (Colchicine in Percutaneous Coronary Intervention [COLCHICINE-PCI] trial). Based on this evidence, low-dose colchicine (0.5 mg once daily) should be considered in patients with recent myocardial infarctions-within 30 days and, ideally, within 3 days-or with stable CAD to improve cardiovascular outcomes. Colchicine should not be used in patients with severe renal or hepatic disease because of the risk of severe toxicity. No serious adverse effect was associated with the combined use of colchicine and high-intensity statin therapy in large trials. The impact of colchicine in high-risk populations of patients with peripheral arterial disease and in those with diabetes for the primary prevention of CAD remains to be established.
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http://dx.doi.org/10.1016/j.cjca.2021.08.009DOI Listing
August 2021

Interindividual variability in weight loss in the treatment of obesity.

Am J Clin Nutr 2021 08;114(2):824-825

Ottawa Hospital Weight Management Clinic, Division of Endocrinology, Ottawa Hospital, Ottawa, Ontario, Canada (RD).

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http://dx.doi.org/10.1093/ajcn/nqab213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326033PMC
August 2021

Epigenome-Wide Study Identified Methylation Sites Associated with the Risk of Obesity.

Nutrients 2021 Jun 9;13(6). Epub 2021 Jun 9.

Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, 40 Ruskin St-H4208, Ottawa, ON K1Y 4W7, Canada.

Here, we performed a genome-wide search for methylation sites that contribute to the risk of obesity. We integrated methylation quantitative trait locus (mQTL) data with BMI GWAS information through a SNP-based multiomics approach to identify genomic regions where mQTLs for a methylation site co-localize with obesity risk SNPs. We then tested whether the identified site contributed to BMI through Mendelian randomization. We identified multiple methylation sites causally contributing to the risk of obesity. We validated these findings through a replication stage. By integrating expression quantitative trait locus (eQTL) data, we noted that lower methylation at cg21178254 site upstream of contributes to obesity by increasing the expression of this gene. Higher methylation at cg02814054 increases the risk of obesity by lowering the expression of , whereas lower methylation at cg06028605 contributes to obesity by decreasing the expression of . Finally, we noted that rare variants within 2p23.3 impact obesity by making the cg01884057 site more susceptible to methylation, which consequently lowers the expression of , and . In this study, we identify methylation sites associated with the risk of obesity and reveal the mechanism whereby a number of these sites exert their effects. This study provides a framework to perform an omics-wide association study for a phenotype and to understand the mechanism whereby a rare variant causes a disease.
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http://dx.doi.org/10.3390/nu13061984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229089PMC
June 2021

A Common Polymorphism in the Locus Links miR1908 to Low-Density Lipoprotein Cholesterol Through BMP1.

Arterioscler Thromb Vasc Biol 2021 08 17;41(8):2252-2262. Epub 2021 Jun 17.

Atherogenomics Laboratory (K.B., M.N., P.L., A.-T.D., S.S., R.M.), University of Ottawa Heart Institute, Canada.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.316473DOI Listing
August 2021

2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults.

Can J Cardiol 2021 Aug 26;37(8):1129-1150. Epub 2021 Mar 26.

McGill University Health Centre, Montréal, Québec, Canada.

The 2021 guidelines primary panel selected clinically relevant questions and produced updated recommendations, on the basis of important new findings that have emerged since the 2016 guidelines. In patients with clinical atherosclerosis, abdominal aortic aneurysm, most patients with diabetes or chronic kidney disease, and those with low-density lipoprotein cholesterol ≥ 5 mmol/L, statin therapy continues to be recommended. We have introduced the concept of lipid/lipoprotein treatment thresholds for intensifying lipid-lowering therapy with nonstatin agents, and have identified the secondary prevention patients who have been shown to derive the largest benefit from intensification of therapy with these agents. For all other patients, we emphasize risk assessment linked to lipid/lipoprotein evaluation to optimize clinical decision-making. Lipoprotein(a) measurement is now recommended once in a patient's lifetime, as part of initial lipid screening to assess cardiovascular risk. For any patient with triglycerides ˃ 1.5 mmol/L, either non-high-density lipoprotein cholesterol or apolipoprotein B are the preferred lipid parameter for screening, rather than low-density lipoprotein cholesterol. We provide updated recommendations regarding the role of coronary artery calcium scoring as a clinical decision tool to aid the decision to initiate statin therapy. There are new recommendations on the preventative care of women with hypertensive disorders of pregnancy. Health behaviour modification, including regular exercise and a heart-healthy diet, remain the cornerstone of cardiovascular disease prevention. These guidelines are intended to provide a platform for meaningful conversation and shared-decision making between patient and care provider, so that individual decisions can be made for risk screening, assessment, and treatment.
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http://dx.doi.org/10.1016/j.cjca.2021.03.016DOI Listing
August 2021

Convergence of biomarkers and risk factor trait loci of coronary artery disease at 3p21.31 and HLA region.

NPJ Genom Med 2021 Feb 11;6(1):12. Epub 2021 Feb 11.

Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada.

Here we seek to identify molecular biomarkers that mediate the effect of risk factors on coronary artery disease (CAD). We perform a SNP-based multiomics data analysis to find biomarkers (probes) causally associated with the risk of CAD within known genomic loci for its risk factors. We identify 78 biomarkers, the majority (64%) of which are methylation probes. We detect the convergence of several CNS and lifestyle trait loci and their biomarkers at the 3p21.31 and human leukocyte antigen (HLA) regions. The 3p21.31 locus was the most populated region in the convergence of biomarkers and risk factors. In this region, we noted as the BSN gene becomes methylated the level of stomatin (STOM) in blood increases and this contributes to higher risk of CAD. In the HLA locus, we identify several methylation biomarkers associated with various CAD risk factors. SNPs in the CFB gene display a trans-regulatory impact on the GRIA4 protein level. A methylation site upstream of the APOE gene is associated with a higher protein level of S100A13 which in turn leads to higher LDL-C and greater CAD risk. We find UHRF1BP1 and ILRUN mediate the effect of obesity on CAD whereas methylation sites within NOS3 and CKM mediate the effect of their associated-risk factors on CAD. This study provides further insight into the biology of CAD and identifies a list of biomarkers that mediate the impact of risk factors on CAD. A SNP-based initiative can unite data from various fields of omics into a single network of knowledge.
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http://dx.doi.org/10.1038/s41525-021-00174-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878768PMC
February 2021

Factors affecting weight loss variability in obesity.

Metabolism 2020 12 7;113:154388. Epub 2020 Oct 7.

Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, Ottawa Institute of Systems Biology, University of Ottawa, 451 Smyth Rd., Ottawa, ON K1H 8M5, Canada. Electronic address:

Current obesity treatment strategies include diet, exercise, bariatric surgery, and a limited but growing repertoire of medications. Individual weight loss in response to each of these strategies is highly variable. Here we review research into factors potentially contributing to inter-individual variability in response to treatments for obesity, with a focus on studies in humans. Well-recognized factors associated with weight loss capacity include diet adherence, physical activity, sex, age, and specific medications. However, following control for each of these, differences in weight loss appear to persist in response to behavioral, pharmacological and surgical interventions. Adaptation to energy deficit involves complex feedback mechanisms, and inter-individual differences likely to arise from a host of poorly defined genetic factors, as well as differential responses in neurohormonal mechanisms (including gastrointestinal peptides), metabolic efficiency and capacity of tissues, non-exercise activity thermogenesis, thermogenic response to food, and in gut microbiome. A better understanding of the factors involved in inter-individual variability in response to therapies will guide more personalized approaches to the treatment of obesity.
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http://dx.doi.org/10.1016/j.metabol.2020.154388DOI Listing
December 2020

RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice.

Nat Metab 2020 10 28;2(10):1113-1125. Epub 2020 Sep 28.

Cardiometabolic microRNA Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. We show that one of these single nucleotide polymorphisms is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T cell accumulation in adipose tissue. These findings demonstrate that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.
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http://dx.doi.org/10.1038/s42255-020-00279-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362891PMC
October 2020

Multiomics Screening Identifies Molecular Biomarkers Causally Associated With the Risk of Coronary Artery Disease.

Circ Genom Precis Med 2020 12 24;13(6):e002876. Epub 2020 Sep 24.

Ruddy Canadian Cardiovascular Genetics Centre (M.N., R.M.), University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Background: In this study, we aimed to investigate functional mechanisms underlying coronary artery disease (CAD) loci and find molecular biomarkers for CAD.

Methods: We devised a multiomics data analysis approach based on Mendelian randomization and utilized it to search for molecular biomarkers causally associated with the risk of CAD within genomic regions known to be associated with CAD.

Results: Through our CAD-centered multiomics data analysis approach, we identified 33 molecular biomarkers (probes) that were causally associated with the risk of CAD. The majority of these (N=19) were methylation probes; moreover, methylation was often behind the causal effect of expression/protein probes. We identified a number of novel loci that have a causal impact on CAD including , , , and . Furthermore, by integrating the risk factors of CAD in our analysis, we were able to investigate the clinical pathways whereby several of our probes exert their effect. We found that the SELE protein level in the blood is under the trans-regulatory impact of methylation sites within the gene and that SELE exerts its effect on CAD through immune, glycemic, and lipid metabolism, making it a candidate of interest for therapeutic interventions. We found the methylation site, cg05126514 within the gene exert its effect on CAD through central nervous system-lifestyle risk factors. Finally, genes with a transcriptional regulatory role (, , and ) exert their effect on CAD through height.

Conclusions: We demonstrate that multiomics data analysis is a powerful approach to unravel the functional mechanisms underlying CAD loci and to identify novel molecular biomarkers. Our results indicate epigenetic modifications are important in the pathogenesis of CAD and identifying and targeting these sites is of potential therapeutic interest to address the detrimental effects of both environmental and genetic factors.
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http://dx.doi.org/10.1161/CIRCGEN.119.002876DOI Listing
December 2020

Heterozygous Gene Deficiency and Risk of Coronary Artery Disease.

Circ Genom Precis Med 2020 10 30;13(5):417-423. Epub 2020 Aug 30.

Center for Genomic Medicine (C.A.E., P.N., N.G., S.G., A.V.K., S.K.), Massachusetts General Hospital, Boston.

Background: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

Methods: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in or .

Results: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; =1.1×10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

Conclusions: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.
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http://dx.doi.org/10.1161/CIRCGEN.119.002871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983048PMC
October 2020

Association of Factor V Leiden With Subsequent Atherothrombotic Events: A GENIUS-CHD Study of Individual Participant Data.

Circulation 2020 08 13;142(6):546-555. Epub 2020 Jul 13.

Department of Cardiology, Division Heart and Lungs (V.T., A.F.S., J.v.S., A.O.K., F.W.A.), UMC Utrecht, Utrecht University, the Netherlands.

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD.

Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality.

Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; =28%; -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity.

Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493828PMC
August 2020

Is a Long Non-coding RNA Locus That Regulates Expression.

Front Genet 2020 17;11:631. Epub 2020 Jun 17.

Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada.

Genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) most of them located in non-protein coding regions of the genome. One such locus is the CAD Associated Region between and (CARMA), a ∼18 kb haplotype that was recently shown to regulate vicinal protein coding genes. Here, we further investigate the region by examining a long non-coding RNA gene locus (RP11-326A19.4/AC013565) abutting the CARMA region. Expression-genotype correlation analyses of public databases indicate that levels are influenced by CAD associated variants suggesting that it might have cardioprotective functions. We found to be stably expressed at relatively low levels and enriched in the cytosol. function was investigated by several gene targeting approaches in HEK293T: inactive CRISPR fusion proteins, antisense, overexpression and inactivation by CRISPR-mediated knock-out. Modest increases in (3-4×) obtained via CRISPRa using distinct single-guided RNAs did not result in consistent transcriptome effects. By contrast, deletion or reduced expression via CRISPRi increased levels, suggesting that is contributing to reduce expression under basal conditions. While future investigations are required to clarify the mechanism(s) by which acts on , integrative bioinformatic analyses of the transcriptome of deleted cells suggest that this locus may also be involved in leucine metabolism, splicing, transcriptional regulation and Shwachman-Bodian-Diamond syndrome protein function.
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http://dx.doi.org/10.3389/fgene.2020.00631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311772PMC
June 2020

Molecular mechanism linking a novel PCSK9 copy number variant to severe hypercholesterolemia.

Atherosclerosis 2020 07 28;304:39-43. Epub 2020 May 28.

Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada. Electronic address:

Background And Aims: A 42 year-old male with premature atherosclerosis, severe dyslipidemia and resistance to treatment with high dose statin and a recommended dose of a PCSK9 inhibitor, was found to have a duplication of the PCSK9 gene. However, the clinical phenotype, which included a more than 15-fold elevation in circulating PCSK9, was unexpected given that he had one additional gene copy.

Methods: Here we have carried out whole genome sequencing and transcriptional reporter assays to investigate the molecular mechanism leading to this unusual FH phenotype.

Results: The PCSK9 duplication was found to contain the full coding sequence but with an 829 bp shorter 3'-untranslated region (UTR) sequence. All possible rearrangements include a head-to-head fusion between a completely duplicated PCSK9 and a chromosomal region, normally situated ~80 kb away, that includes HNF4 and USF1 binding sites that could promote transcription of the PCSK9 gene. Transcriptional reporter assays demonstrated that a construct harboring the HNF4 binding site significantly increased the promoter activity by 2.5-fold with a smaller effect noted for a USF1 construct.

Conclusions: Here we describe, in a patient with resistant hypercholesterolemia, a novel PCSK9 gene rearrangement that enables upregulation of PCSK9 expression by allowing proximity to an active enhancer binding to HNF4A.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.05.013DOI Listing
July 2020

rs679482 Associates With Weight Loss Success in Response to an Intensively Supervised Outpatient Program.

Diabetes 2020 09 11;69(9):2017-2026. Epub 2020 Jun 11.

Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada

Weight loss in response to energy restriction is highly variable, and identification of genetic contributors can provide insights into underlying biology. Leveraging 1000 Genomes imputed genotypes, we carried out genome-wide association study (GWAS) analysis in 551 unrelated obese subjects of European ancestry who participated in an intensively supervised weight loss program with replication of promising signals in an independent sample of 1,331 obese subjects who completed the program at a later date. By single nucleotide polymorphism-based and sib-pair analysis, we show that that weight loss is a heritable trait, with estimated heritability ( = 0.49) within the range reported for obesity. We find rs679482, intronic to (sarcoglycan γ), highly expressed in skeletal muscle, to concordantly associate with weight loss in discovery and replication samples reaching GWAS significance in the combined meta-analysis (β = -0.35, = 1.7 × 10). Located in a region of open chromatin, rs679482 is predicted to bind DMRT2, and allele-specific transcription factor binding analysis indicates preferential binding of DMRT2 to rs679482-A. Concordantly, rs679482-A impairs native repressor activity and increases basal and DMRT2-mediated enhancer activity. These findings confirm that weight loss is a heritable trait and provide evidence by which a novel variant in SGCG, rs679482, leads to impaired diet response.
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http://dx.doi.org/10.2337/db20-0219DOI Listing
September 2020

A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.

PLoS Genet 2020 04 13;16(4):e1008629. Epub 2020 Apr 13.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.
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http://dx.doi.org/10.1371/journal.pgen.1008629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200007PMC
April 2020

Off-target effects of CRISPRa on interleukin-6 expression.

PLoS One 2019 28;14(10):e0224113. Epub 2019 Oct 28.

Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Inactive fusion variants of the CRISPR-Cas9 system are increasingly being used as standard methodology to study transcription regulation. Their ability to readily manipulate the native genomic loci is particularly advantageous. In this work, we serendipitously uncover the key cytokine IL6 as an off-target of the activating derivative of CRISPR (CRISPRa) while studying RP11-326A19.4, a novel long-non coding RNA (lncRNA). Increasing RP11-326A19.4 expression in HEK293T cells via CRISPRa-mediated activation of its promoter region induced genome-wide transcriptional changes, including upregulation of IL6, an important cytokine. IL6 was increased in response to distinct sgRNA targeting the RP11-326A19.4 promoter region, suggesting specificity. Loss of the cognate sgRNA recognition sites failed to abolish CRISPRa mediated activation of IL6 however, pointing to off-target effects. Bioinformatic approaches did not reveal predicted off-target binding sites. Off-target activation of IL6 was sustained and involved low level activation of known IL6 regulators. Increased IL6 remained sensitive to further activation by TNFα, consistent with the existence of independent mechanisms. This study provides experimental evidence that CRISPRa has discrete, unpredictable off-targeting limitations that must be considered when using this emerging technology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224113PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816553PMC
March 2020

2018 George Lyman Duff Memorial Lecture: Genetics and Genomics of Coronary Artery Disease: A Decade of Progress.

Authors:
Ruth McPherson

Arterioscler Thromb Vasc Biol 2019 10 29;39(10):1925-1937. Epub 2019 Aug 29.

From the Division of Cardiology, Atherogenomics Laboratory, Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, ON, Canada.

Recent studies have led to a broader understanding of the genetic architecture of coronary artery disease and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on coronary artery disease risk. The tools applied include genome-wide association studies encompassing over 200 000 individuals complemented by bioinformatic approaches including imputation from whole-genome data sets, expression quantitative trait loci analyses, and interrogation of ENCODE (Encyclopedia of DNA Elements), Roadmap Epigenetic Project, and other data sets. Over 160 genome-wide significant loci associated with coronary artery disease risk have been identified using the genome-wide association studies approach, 90% of which are situated in intergenic regions. Here, I will describe, in part, our research over the last decade performed in collaboration with a series of bright trainees and an extensive number of groups and individuals around the world as it applies to our understanding of the genetic basis of this complex disease. These studies include computational approaches to better understand missing heritability and identify causal pathways, experimental approaches, and progress in understanding at the molecular level the function of the multiple risk loci identified and potential applications of these genomic data in clinical medicine and drug discovery.
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http://dx.doi.org/10.1161/ATVBAHA.119.311392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766359PMC
October 2019

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation.

Cardiovasc Diabetol 2019 06 4;18(1):71. Epub 2019 Jun 4.

Unidad de Prevención Cardiometabólica Cardiocob. Servicio de Cardiología Hospital el Pino Santiago de Chile, Sociedad Inter Americana de Cardiología SIAC Chairman Cardiovascular Prevention Comite, Santiago de Chile, Chile.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.
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http://dx.doi.org/10.1186/s12933-019-0864-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549355PMC
June 2019

Rare Protein-Truncating Variants in APOB, Lower Low-Density Lipoprotein Cholesterol, and Protection Against Coronary Heart Disease.

Circ Genom Precis Med 2019 05;12(5):e002376

Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (A.V.K., M.C., S.K.).

Background Familial hypobetalipoproteinemia is a genetic disorder caused by rare protein-truncating variants (PTV) in the gene encoding APOB (apolipoprotein B), the major protein component of LDL (low-density lipoprotein) and triglyceride-rich lipoprotein particles. Whether heterozygous APOB deficiency is associated with decreased risk for coronary heart disease (CHD) is uncertain. We combined family-based and large scale gene-sequencing to characterize the association of rare PTVs in APOB with circulating LDL-C (LDL cholesterol), triglycerides, and risk for CHD. Methods We sequenced the APOB gene in 29 Japanese hypobetalipoproteinemia families, as well as 57 973 individuals derived from 12 CHD case-control studies-18 442 with early-onset CHD and 39 531 controls. We defined PTVs as variants that lead to a premature stop, disrupt canonical splice-sites, or lead to insertions/deletions that shift reading frame. We tested the association of rare APOB PTV carrier status with blood lipid levels and CHD. Results Among 29 familial hypobetalipoproteinemia families, 8 families harbored APOB PTVs. Carrying 1 APOB PTV was associated with 55 mg/dL lower LDL-C ( P=3×10) and 53% lower triglyceride level ( P=2×10). Among 12 case-control studies, an APOB PTV was present in 0.038% of CHD cases as compared to 0.092% of controls. APOB PTV carrier status was associated with a 43 mg/dL lower LDL-C ( P=2×10), a 30% decrease in triglycerides ( P=5×10), and a 72% lower risk for CHD (odds ratio, 0.28; 95% CI, 0.12-0.64; P=0.002). Conclusions Rare PTV mutations in APOB which are associated with lower LDL-C and reduced triglycerides also confer protection against CHD.
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http://dx.doi.org/10.1161/CIRCGEN.118.002376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044908PMC
May 2019

Association of Chromosome 9p21 With Subsequent Coronary Heart Disease Events.

Circ Genom Precis Med 2019 04 21;12(4):e002471. Epub 2019 Mar 21.

Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (M.H.).

Background: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk.

Methods: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD.

Results: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09).

Conclusions: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.
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http://dx.doi.org/10.1161/CIRCGEN.119.002471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625876PMC
April 2019

Subsequent Event Risk in Individuals With Established Coronary Heart Disease.

Circ Genom Precis Med 2019 04 21;12(4):e002470. Epub 2019 Mar 21.

Department of Pharmacotherapy and Translational Research, Centre for Pharmacogenomics (Y.G., R.M.C.-D., J.A.J.), University of Florida, Gainesville.

Background: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD.

Methods: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events.

Results: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints.

Conclusions: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.
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http://dx.doi.org/10.1161/CIRCGEN.119.002470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629546PMC
April 2019

Regulation of MFGE8 by the intergenic coronary artery disease locus on 15q26.1.

Atherosclerosis 2019 05 22;284:11-17. Epub 2019 Feb 22.

Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada; Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada. Electronic address:

Background And Aims: A recently identified locus for coronary artery disease (CAD) tagged by rs8042271 is in a region of tight linkage disequilibrium (LD) between 2 genes (MFGE8, ABHD2) previously linked to atherosclerosis. Here we have explored the regulatory framework of this region to identify its functional relationship to CAD.

Methods: The CAD Associated Region between MFGE8 and ABHD2 (CARMA) was investigated by bioinformatic approaches and transcriptional reporter assays to prioritize target genes and identify putative causal variants. Findings were integrated with publicly available gene expression datasets. MFGE8 silencing was performed in cell models relevant to CAD.

Results: The regulatory potential of CARMA is disseminated sparsely over the entire region. CARMA contains multiple eQTL that regulate MFGE8 in coronary artery and coronary artery smooth muscle cell (CoSMC). SNPs that predict the expression of MFGE8 in artery are concordantly associated with higher risk of CAD (pval = 0.0014). Targeting CARMA by CRISPR/Cas9 in a cellular model increased MFGE8 expression. MFGE8 silencing was found to reduce CoSMC and monocyte (THP-1) but not endothelial cell proliferation.

Conclusions: These findings support a mechanistic link between a GWAS identified CAD risk locus and atherosclerosis. The intergenic locus CARMA regulates MFGE8 in a haplotype dependent manner. Individuals genetically susceptible to increased MFGE8 expression exhibit greater CAD risk. Suppressing MFGE8 expression reduced SMC and THP-1 proliferation. These data support an atherogenic contribution of CARMA/MFGE8 that may be linked to cell proliferation and/or improved survival of CAD relevant cell types.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.02.012DOI Listing
May 2019

Genome-wide identification of circulating-miRNA expression quantitative trait loci reveals the role of several miRNAs in the regulation of cardiometabolic phenotypes.

Cardiovasc Res 2019 Sep;115(11):1629-1645

Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, 40 Ruskin St - H4208, Ottawa, Canada.

Aims: To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs) and to connect genetic risk to blood traits/biomarkers through the circulating miRNAs.

Methods And Results: Leveraging miRNA-Seq data and the 1000 Genomes imputed genotypes, we carried out genome-wide association analysis for SNPs that regulate the expression of circulating miRNAs in a sample of 710 unrelated subjects of European ancestry. Wherever possible, we used data from the Framingham and the Geuvadis studies to replicate our findings. We found at least one genome-wide significant (P < 5e-8) miRNA-eQTL (mirQTL) for 143 circulating miRNAs. Overall each mirQTL explained a small portion (<1%) of variation in miRNA levels; however, we identified a few mirQTLs that explained 4% to 20% of variation in miRNA levels in plasma. Unlike trans-mirQTLs (P = 0.7), cis-mirQTLs tend to be also associated with their counterpart mature miRNAs (P < 0.0001), this suggests trans-mirQTLs exert their effect through processes that affect the stability of mature miRNAs; whereas, cis-mirQTLs mainly regulate the expression of primary-miRNAs. Next, we used the identified mirQTLs to investigate the links between circulating miRNAs with blood traits/biomarkers through Mendelian randomization analysis. We found miR-1908-5p plays an important role in regulating low-density lipoprotein (LDL), total cholesterol (TC), fasting glucose, HbA1c, and several lipid-metabolites in blood, whereas, miR-10b-5p mediates the trans-regulatory effect of the ABO locus on several blood proteins, coronary artery disease, and TC. Moreover, we demonstrated that a higher plasma level of miR-199a is causally associated with lower levels of LDL and TC. Finally, we found miR-143-3p and miR-145-5p are functionally related and mediate the effect of ZFPM2 on a number of its protein targets in blood including VEGFA, SERPINE1, and PDGFs.

Conclusions: This study identifies SNPs that have a regulatory impact on circulating miRNAs, and underlines the role of several circulating miRNAs in mediating the effect of a number of GWAS loci on cardiometabolic phenotypes.
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http://dx.doi.org/10.1093/cvr/cvz030DOI Listing
September 2019

Obesity shows preserved plasma proteome in large independent clinical cohorts.

Sci Rep 2018 11 19;8(1):16981. Epub 2018 Nov 19.

Proteomics, Nestlé Institute of Health Sciences, Lausanne, Switzerland.

Holistic human proteome maps are expected to complement comprehensive profile assessment of health and disease phenotypes. However, methodologies to analyze proteomes in human tissue or body fluid samples at relevant scale and performance are still limited in clinical research. Their deployment and demonstration in large enough human populations are even sparser. In the present study, we have characterized and compared the plasma proteomes of two large independent cohorts of obese and overweight individuals using shotgun mass spectrometry (MS)-based proteomics. Herein, we showed, in both populations from different continents of about 500 individuals each, the concordance of plasma protein MS measurements in terms of variability, gender-specificity, and age-relationship. Additionally, we replicated several known and new associations between proteins, clinical and molecular variables, such as insulin and glucose concentrations. In conclusion, our MS-based analyses of plasma samples from independent human cohorts proved the practical feasibility and efficiency of a large and unified discovery/replication approach in proteomics, which was also recently coined "rectangular" design.
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http://dx.doi.org/10.1038/s41598-018-35321-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242904PMC
November 2018

DNA Sequence Variation in Encoding the Activin Receptor-Like Kinase 7 Influences Body Fat Distribution and Protects Against Type 2 Diabetes.

Diabetes 2019 01 2;68(1):226-234. Epub 2018 Nov 2.

Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

A genetic predisposition to higher waist-to-hip ratio adjusted for BMI (WHRadjBMI), a measure of body fat distribution, associates with increased risk for type 2 diabetes. We conducted an exome-wide association study of coding variation in UK Biobank (405,569 individuals) to identify variants that lower WHRadjBMI and protect against type 2 diabetes. We identified four variants in the gene (encoding the activin receptor-like kinase 7 receptor expressed on adipocytes and pancreatic β-cells), which independently associated with reduced WHRadjBMI: Asn150His (-0.09 SD, = 3.4 × 10), Ile195Thr (-0.15 SD, = 1.0 × 10), Ile482Val (-0.019 SD, = 1.6 × 10), and rs72927479 (-0.035 SD, = 2.6 × 10). Carriers of these variants exhibited reduced percent abdominal fat in DEXA imaging. Pooling across all four variants, a 0.2 SD decrease in WHRadjBMI through was associated with a 30% lower risk of type 2 diabetes (odds ratio [OR] 0.70, 95% CI 0.63, 0.77; = 5.6 × 10). In an analysis of exome sequences from 55,516 individuals, carriers of predicted damaging variants in were at 54% lower risk of type 2 diabetes (OR 0.46, 95% CI 0.27, 0.81; = 0.006). These findings indicate that variants predicted to lead to loss of gene function influence body fat distribution and protect from type 2 diabetes.
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http://dx.doi.org/10.2337/db18-0857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302541PMC
January 2019

Whole-Gene Duplication of PCSK9 as a Novel Genetic Mechanism for Severe Familial Hypercholesterolemia.

Can J Cardiol 2018 10 4;34(10):1316-1324. Epub 2018 Aug 4.

Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address:

Background: Familial hypercholesterolemia (FH) is a common genetic disorder of severely elevated low-density lipoprotein (LDL) cholesterol, characterized by premature atherosclerotic cardiovascular disease. Although copy number variations (CNVs) are a large-scale mutation-type capable of explaining FH cases, they have been, to date, assessed only in the LDLR gene. Here, we performed novel CNV screening in additional FH-associated genes using a next-generation sequencing-based approach.

Methods: In 704 patients with FH, we sequenced FH-associated genes APOB, PCSK9, LDLRAP1, APOE, STAP1, LIPA, and ABCG5/8 using our LipidSeq targeted next-generation sequencing panel. Bioinformatic tools were applied to LipidSeq data for CNV screening, and identified CNVs were validated using whole-exome sequencing and microarray-based copy number analyses.

Results: We identified a whole-gene duplication of PCSK9 in 2 unrelated Canadian FH index cases; this PCSK9 CNV was also found to cosegregate with affected status in family members. Features in affected individuals included severely elevated LDL cholesterol levels that were refractory to intensive statin therapy, pronounced clinical stigmata, premature cardiovascular events, and a plasma PCSK9 of approximately 5000 ng/mL in 1 index case. We found no CNVs in APOB, LDLRAP1, APOE, STAP1, LIPA, and ABCG5/8 in our cohort of 704 FH individuals.

Conclusions: Here, we report the first description of a CNV affecting the PCSK9 gene in FH. This finding is associated with a profound FH phenotype and the highest known plasma PCSK9 level reported in a human. This finding also has therapeutic relevance, as elevated PCSK9 levels may limit the efficacy of high-dose statin therapy and also PCSK9 inhibition.
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http://dx.doi.org/10.1016/j.cjca.2018.07.479DOI Listing
October 2018

The Cardiovascular Burden of Undiagnosed Familial Hypercholesterolemia: Need to Modify Guidelines to Encourage Earlier Diagnosis and Therapy.

Authors:
Ruth McPherson

Can J Cardiol 2018 09 11;34(9):1112-1113. Epub 2018 Jul 11.

Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.cjca.2018.06.019DOI Listing
September 2018

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Nat Commun 2018 04 24;9(1):1613. Epub 2018 Apr 24.

Department of Biomedical & Saint Luke's Mid America Heart Institute and the Health Informatics, Division of Endocrinology and Metabolism, University of Missouri-Kansas City, Kansas City, MO, 64110, USA.

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.
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http://dx.doi.org/10.1038/s41467-018-03911-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915445PMC
April 2018
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