Showing papers by "Mark Trinder published in 2020"
TL;DR: This cohort study uses the UK Biobank cohort data to compare the association of monogenic vs polygenic hypercholesterolemia with the risk of atherosclerotic cardiovascular disease among individuals with comparable levels of low-density lipoprotein cholesterol.
Abstract: Importance Monogenic familial hypercholesterolemia (FH) is associated with lifelong elevations in low-density lipoprotein cholesterol (LDL-C) levels and increased risk of atherosclerotic cardiovascular disease (CVD). However, many individuals with hypercholesterolemia have a polygenic rather than a monogenic cause for their condition. It is unclear if a genetic variant for hypercholesterolemia alters the risk of CVD. Objectives To assess whether a genetic variant for hypercholesterolemia alters the risk of atherosclerotic CVD and to evaluate how this risk compares with that of nongenetic hypercholesterolemia. Design, Setting, and Participants In this genetic-association, case-control, cohort study, individuals aged 40 to 69 years were recruited by the UK Biobank from across the United Kingdom between March 13, 2006, and October 1, 2010, and followed up until March 31, 2017. Genotyping array and exome sequencing data from the UK Biobank cohort were used to identify individuals with monogenic (LDLR,APOB, andPCSK9) or polygenic hypercholesterolemia (LDL-C polygenic score >95th percentile based on 223 single-nucleotide variants in the entire cohort). The data were analyzed from July 1, 2019, to December 30, 2019. Main Outcomes and Measures The study investigated the association of genotype with the risk of coronary and carotid revascularization, myocardial infarction, ischemic stroke, and all-cause mortality among the overall study population and among participants with monogenic FH (n = 277), polygenic hypercholesterolemia (n = 2379), or hypercholesterolemia with undetermined cause (n = 2232) at comparable levels of LDL-C measured at study enrollment. Results For the 48 741 individuals with genotyping array and exome sequencing data, the mean (SD) age was 56.6 (8.0) years, and 54.5% were female (n = 26 541 of 48 741). A monogenic FH variant for hypercholesterolemia was found in 277 individuals (0.57%, 1 in 176 individuals). Participants with monogenic FH were significantly more likely than those without monogenic FH to experience an atherosclerotic CVD event at 55 years or younger (17 of 277 [6.1%] vs 988 of 48 464 [2.0%];P Conclusions and Relevance The findings of this study suggest that among individuals with hypercholesterolemia, genetic determinants of LDL-C levels may impose additional risk of CVD. Thus, understanding the possible genetic cause of hypercholesterolemia may provide important prognostic information to treat patients.
130 citations
TL;DR: This research presents a novel probabilistic approach that allows us to assess the importance of knowing the carrier and removal status of canine coronavirus, as a source of infection for other animals.
Abstract: Objective: HDL (high-density lipoprotein) cholesterol (HDL-C) and LDL (low-density lipoprotein) cholesterol (LDL-C) are inversely associated with infectious hospitalizations. Whether these represen...
72 citations
TL;DR: It is reported that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.
Abstract: Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases = 270/Ncontrols = 5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication = 2.19 × 10−12, OR = 1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P < 5 × 10−8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P = 0.021, OR = 1.82 [95% CI: 1.09–3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P = 1.28 × 10−17, HR = 0.91 [95% CI :0.89–0.93], for MI) and Million Veteran Program (P = 9.33 × 10−36, OR = 0.95 [95% CI: 0.94–0.96], for CAD; P = 3.35 × 10−6, OR = 0.96 [95% CI: 0.95–0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology. Spontaneous coronary artery dissection (SCAD) is a cause of myocardial infarction Here, the authors present a genome-wide association study of SCAD, finding an association at 1q21.2 which potentially affects expression of ADAMTSL4.
47 citations
TL;DR: Elevated lipoprotein(a) is associated with increased low-density lipop protein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH, and it is demonstrated that an individual with genetic FH will be clinically recognized.
44 citations
13 Aug 2020
TL;DR: Polygenic contributions to LDL-C explain some of the heterogeneity in clinical presentation and ASCVD risk for individuals with FH.
Abstract: Background: Familial hypercholesterolemia (FH) is a common autosomal codominant genetic disorder, which causes elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of p...
32 citations
TL;DR: The data suggest that CAD genomic scores influence cardiovascular risk among individuals with elevated lipoprotein(a) and may aid in identifying candidates for preventive therapies.
Abstract: Aims Elevated levels of lipoprotein(a) are one of the strongest inherited risk factors for coronary artery disease (CAD). However, there is variability in cardiovascular risk among individuals with elevated lipoprotein(a). The sources of this variability are incompletely understood. We assessed the effects of a genomic risk score (GRS) for CAD on risk of myocardial infarction among individuals with elevated lipoprotein(a). Methods We calculated CAD GRSs for 408,896 individuals of British white ancestry from the UK Biobank using 6.27 million common genetic variants. Lipoprotein(a) levels were measured in 310,020 individuals. The prevalence and risk of myocardial infarction versus CAD GRS percentiles were compared for individuals with and without elevated lipoprotein(a) defined as ≥120 or 168 nmol/L (≈50 or 70 mg/dL, respectively). Results Individuals with elevated lipoprotein(a) displayed significantly greater CAD GRSs than individuals without elevated lipoprotein(a), which was largely dependent on the influence of genetic variants within or near the LPA gene. Continuous levels of CAD GRS percentile were significantly associated with risk of myocardial infarction for individuals with elevated lipoprotein(a). Notably, the risk of myocardial infarction for males with elevated lipoprotein(a) levels, but a CAD GRS percentile in the lower quintile ( Conclusion These data suggest that CAD genomic scores influence cardiovascular risk among individuals with elevated lipoprotein(a) and may aid in identifying candidates for preventive therapies.
2 citations
01 Jan 2020
TL;DR: This work briefly reviews genomics discovery methods, recent advances that highlight novel approaches, and specific biomarkers closer to clinical utility that are in use clinically in critical care.
Abstract: Many areas of medicine have genomic biomarkers for diagnosis, assessment of prognosis, and prediction of response to treatment (diagnostic, prognostic, and predictive biomarkers, respectively). The story is different in critical care. In sepsis, acute respiratory distress syndrome (ARDS), and acute kidney injury (AKI), the potential uses of biomarkers include diagnosis, differentiating viral from bacterial infection, differentiating an inflammatory from an infectious process, prognostication, predicting relapse, and predicting response to treatment. Despite intense research and publication of more than 200 distinct biological molecules that fulfill some of these criteria, there are no genomic biomarkers in use clinically in critical care. Studies must show discovery and validation in large, adequately powered cohorts. Population genomics studies in critical illness are plagued by lack of validation. Most studies of genomics of critical illness are population studies. The characteristics of strong population genomics studies include appropriate controls, adequate sample size and power, correction for multiple comparisons (numerous in population genomics studies), control for ethnicity, confirmation of genomic function, and evidence of high clinical utility, i.e. clinicians would use a kit to detect the variant and payers would pay because the genomic test adds useful information that complements other assessments. We briefly review genomics discovery methods, recent advances that highlight novel approaches, and specific biomarkers closer to clinical utility.