Dermot Francis Reilly

Janssen Research & Development, LLC | JANSSEN · Cardiovascular & Metabolism

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 3...

Two common missense variants inAPOL1(G1 and G2) have been definitively linked to CKD in black Americans. However, not all individuals with the renal-risk genotype develop CKD, and little is known about howAPOL1variants drive disease. Given the association of APOL1 with HDL particles, which are cleared by the kidney, differences in the level or qual...

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 n...

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery)...

Objective Impaired expansion of peripheral fat contributes to the pathogenesis of insulin resistance and Type 2 Diabetes (T2D). We aimed to identify novel disease–gene interactions during adipocyte differentiation. Methods Genes in disease-associated loci for T2D, adiposity and insulin resistance were ranked according to expression in human adipoc...

Phenome-wide association studies (PheWAS) have been proposed as a possible aid in drug development through elucidating mechanisms of action, identifying alternative indications, or predicting adverse drug events (ADEs). Here, we select 25 single nucleotide polymorphisms (SNPs) linked through genome-wide association studies (GWAS) to 19 candidate dr...

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP var...

Aims/hypothesis Ceramides are sphingolipids that contribute to insulin resistance in preclinical studies. We hypothesised that plasma ceramides would be associated with body fat distribution, insulin resistance and incident type 2 diabetes in a multi-ethnic cohort. Methods A total of 1557 participants in the Dallas Heart Study without type 2 diabe...

Body fat distribution is a heritable risk factor for a range of adverse health consequences, including hyperlipidemia and type 2 diabetes. To identify protein-coding variants associated with body fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, we analyzed 228,985 predicted coding and splice site variants available on...

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University...

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triglyceride (TG) synthesis and has been shown to play a role in regulating hepatic very-low-density lipoprotein (VLDL) production in rodents. To explore the potential of DGAT2 as a therapeutic target for the treatment of dyslipidemia, we tested the effects of small-molecule inhib...

In the published version of this paper, the name of author Emanuele Di Angelantonio was misspelled. This error has now been corrected in the HTML and PDF versions of the article.

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (mino...

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MA...

eTable 1. Allele Frequencies of 5 CETP Genetic Variants eTable 2. Pairwise Linkage Disequilibrium Among 5 CETP Genetic Variants eTable 3. Derivation of a CETP Genetic Score Weighted by Independent Effects on HDL Cholesterol eTable 4. Selected Baseline Characteristics Among Major Vascular Disease Cases and Common Vascular Disease Controls eTable 5...

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (mino...

We report four novel loci associated with blood pressure regulation, and one independent variant at an established blood pressure locus. This analysis highlights several candidate genes with variation that alters protein function or gene expression for potential follow-up.

Importance Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). Objective To use genetic variants in the CETP gene to assess potential risks and benefits of lifel...

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 t...

Knowledge of biological relatedness between samples is important for many genetic studies. In large-scale human genetic association studies, the estimated kinship is used to remove cryptic relatedness, control for family structure, and estimate trait heritability. However, estimation of kinship is challenging for sparse sequencing data, such as tho...

Expectations and variances of the SEEKIN estimators. (PDF)

Performance of relationship classification based on homogeneous kinship estimators in ~0.15X sequencing data of 254 Chinese. (DOCX)

Performance of homogeneous kinship estimators in ~0.75X sequencing data of 254 Chinese. (DOCX)

Performance of homogeneous kinship estimators in ~0.75X sequencing data of 254 Chinese. In each panel, we compared sequence-based estimates (ϕseq, y-axis) with the array-based estimates from PC-Relate (ϕarray, x-axis). Colored circles represent kinship coefficients between two individuals and different types of relatedness were determined in Fig 2....

Performance of homogeneous kinship estimators in ~0.15X sequencing data of 254 Chinese using SNPs with r2>0.3. In each panel, we compared sequence-based estimates (ϕseq, y-axis) with the array-based estimates from PC-Relate (ϕarray, x-axis). Colored circles represent kinship coefficients between two individuals and different types of relatedness we...

Performance of relationship classification based on heterogeneous kinship estimators in ~0.15X sequencing data of 762 Chinese and Malays. (DOCX)

Performance of relationship classification based on heterogeneous kinship estimators in ~0.75X sequencing data of 762 Chinese and Malays. (DOCX)

Illustration of the “single producer/consumer” design in the SEEKIN software. A single-threading “producer” job scans the input files, extracts required information for each SNP, and packs into a data block for every L SNPs. These data blocks are stored in the buffer, labeled as the blocking queue. Concurrently, a “consumer” job takes the data bloc...

Calibration of posterior genotype probabilities from BEAGLE for different sequencing datasets. For each dataset, we binned the genotype probabilities into 100 bins spaced by 0.01 from 0 to 1 (x-axis). For each bin, we calculated the proportion of correct genotypes by comparing to the array genotypes (y-axis). The number of genotypes in each bin is...

Performance of heterogeneous kinship estimators in ~0.75X sequencing data of 762 Chinese and Malays using SNPs with r2>0.3. In each panel, we compared sequence-based estimates (ϕseq, y-axis) with the array-based estimates from PC-Relate (ϕarray, x-axis). Colored circles represent kinship coefficients between two individuals and different types of r...

Performance of relationship classification based on homogeneous kinship estimators in ~0.75X sequencing data of 254 Chinese. (DOCX)

Performance of heterogeneous kinship estimators in ~0.75X sequencing data of 762 Chinese and Malays. In each panel, we compared sequence-based estimates (ϕseq, y-axis) with the array-based estimates from PC-Relate (ϕarray, x-axis). Colored circles represent kinship coefficients between two individuals and different types of relatedness were determi...

Performance of heterogeneous kinship estimators in ~0.75X sequencing data of 762 Chinese and Malays. (DOCX)

Background: Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Tria...

\textbf{Aims}$ Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A$_{2}$ (Lp-PLA$_{2}$), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA$_{2}$ enzyme activity is causally relevant to coronary heart disease. $\textbf{Methods }$ In 72,657 patients with coronary...

Background: Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Tri...

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 associa...

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1–4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, ST...

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 associat...

Aims: Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2 enzyme activity is causally relevant to coronary heart disease. Methods: In 72,657 patients with coronary heart disease and 110,218 contro...

Background: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD. Methods and results: -W...

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ~155,063 samples for ind...

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for ind...

Background & aims: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7,...

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for i...

-Despite recent discoveries of new genetic risk factors, the majority of risk for coronary artery disease (CAD) remains elusive. As the most proximal sensor of DNA variation, RNA abundance can help identify subpopulations of genetic variants active in and across tissues mediating CAD risk through gene expression. -By generating new genomic data on...

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants a...

With the advance of genome-wide association studies and newly identified SNP (single-nucleotide polymorphism) associations with complex disease, important discoveries have emerged focusing not only on individual genes but on disease-associated pathways and gene sets. The authors used prospective myocardial infarction case-control studies nested in...

Myocardial infarction, stroke, and sudden death undergo diurnal variation. Although genes relevant to hemostasis and vascular integrity undergo circadian oscillation, the role of the molecular clock in thrombotic events remains to be established. A diurnal variation in the time to thrombotic vascular occlusion (TTVO) subsequent to a photochemical i...

The incidence of heart attack and stroke undergo diurnal variation. Molecular clocks have been described in the heart and the vasculature; however it is largely unknown how the suprachiasmatic nucleus (SCN) entrains these peripheral oscillators. Norepinephrine and epinephrine, added to aortic smooth muscle cells (ASMCs) in vitro, altered Per1, E4bp...

Isoeicosanoids are free radical-catalyzed isomers of the enzymatic products of arachidonic acid. They are formed in situ in cell membranes, are cleaved, circulate, and are excreted in urine. Isomers of prostaglandin F2α, the F2-isoprostanes, have emerged as sensitive indices of lipid peroxidation in vivo. Analogous compounds formed from docosahexae...

Living organisms have adapted to the daily rotation of the earth and regular changes in the light environment. Life forms anticipate environmental transitions, adapt their own physiology, and perform activities at behaviorally advantageous times during the day. This is achieved by means of endogenous circadian clocks that can be synchronized to the...

The diurnal variation in the incidence of myocardial infarction and stroke may reflect an influence of the molecular clock and/or the time dependence of exposure to environmental stress. The circadian variation in blood pressure and heart rate is disrupted in mice, Bmal1(-/-), Clock(mut), and Npas2(mut), in which core clock genes are deleted or mut...

Circadian rhythmicity of many aspects of cardiovascular function-blood pressure, coagulation and contractile function-is well established, as is diurnal variation in important clinical events, such as myocardial infarction and stroke. Here, we undertake studies to globally assess circadian gene expression in murine aorta. Aortae from mice were harv...

A critical role for the conserved alpha-integrin cytoplasmic motif, KVGFFKR, is recognized in the regulation of activation of the platelet integrin alpha(IIb)beta(3). To understand the molecular mechanisms of this regulation, we sought to determine the nature of the protein interactions with this cytoplasmic motif. We used a tagged synthetic peptid...

The platelet integrin alphaIIbbeta3 alters conformation in response to platelet activation and ligand binding, although the molecular mechanisms involved are not known. We previously showed that a lipid modified peptide, corresponding to the membrane proximal 989KVGFFKR995 portion of the alphaIIb cytoplasmic tail, independently activates platelet a...

Platelets, while anucleate, contain RNA, some of which is translated into protein upon activation. Hypothesising that the platelet proteome is reflected in the transcriptome, we identified 82 proteins secreted from activated platelets and compared these, as well as published proteomic data, to the transcriptional profile. We also compared the trans...

The disciplines of scientific based medicine and evidence based medicine are in general complimentary: the basic science supporting the clinical data. Sometimes there is conflict,and the empirical evidence does not make scientific sense.The story behind the recent dramatic fall in incidence of the sudden infant death syndrome reflects this conflict...

All integrin alpha subunits contain a highly conserved KXGFFKR motif in their cytoplasmic domains that plays a crucial role in the regulation of integrin affinity for their ligands. We show that a lipid-modified peptide corresponding to the cytoplasmic region, 989-995, of the platelet integrin subunit glycoprotein GpIIb (alphaIIb), palmitoyl-KVGFFK...

Estrogens act by association with intracellular receptors which in turn bind to specific cis elements in inducible genes, thereby eliciting an appropriate transcriptional response. It is not clear how the level of the receptor for estrogen is controlled. This has important consequences as tumoors which are devoid of estrogen receptor (ER) present a...

Urokinase plasminogen activator (uPA) is a serine protease implicated in cancer spread and is thus a potential prognostic marker for human cancers. The aim of this investigation was therefore to compare uPA activity and uPA antigen as prognostic markers in breast cancer. Patients with tumours containing high levels of either uPA activity or antigen...

Cathepsin D (CD, EC 3.4.23.5) is a lysosomal protease induced by estrogen in certain estrogen receptor (ER)-positive breast cancer cell lines but produced constitutively by ER-negative cell lines. Our aims in this investigation were to study the distribution of CD in human breast cancers and to relate its concentrations to various biochemical, hist...