Publications by authors named "Erik Ingelsson"

381 Publications

Clinical Conditions and Their Impact on Utility of Genetic Scores for Prediction of Acute Coronary Syndrome.

Circ Genom Precis Med 2021 Jul 7. Epub 2021 Jul 7.

Broad Institute of MIT & Harvard, Cambridge & Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA & Finnish Institute for Molecular Medicine, HiLIFE, University of Helsinki, Helsinki, Finland.

- Acute coronary syndrome (ACS) is a clinically significant presentation of coronary heart disease (CHD). Genetic information has been proposed to improve prediction beyond well-established clinical risk factors. While polygenic scores (PS) can capture an individual's genetic risk for ACS, its prediction performance may vary in the context of diverse correlated clinical conditions. Here, we aimed to test whether clinical conditions impact the association between PS and ACS. - We explored the association between 405 clinical conditions diagnosed before baseline and 9,080 incident cases of ACS in 387,832 individuals from the UK Biobank. Results were replicated in 6,430 incident cases of ACS in 177,876 individuals from FinnGen. - We identified 80 conventional (e.g., stable angina pectoris (SAP), type 2 diabetes mellitus) and unconventional (e.g., diaphragmatic hernia, inguinal hernia) associations with ACS. The association between PS and ACS was consistent in individuals with and without most clinical conditions. However, a diagnosis of SAP yielded a differential association between PS and ACS. PS was associated with a significantly reduced (interaction p-value=2.87×10-8) risk for ACS in individuals with SAP (HR=1.163 [95% CI: 1.082-1.251]) compared to individuals without SAP (HR=1.531 [95% CI: 1.497-1.565]). These findings were replicated in FinnGen (interaction p-value=1.38×10-6). - In summary, while most clinical conditions did not impact utility of PS for prediction of ACS, we found that PS was substantially less predictive of ACS in individuals with prevalent stable CHD. PS may be more appropriate for prediction of ACS in asymptomatic individuals than symptomatic individuals with clinical suspicion for CHD.
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http://dx.doi.org/10.1161/CIRCGEN.120.003283DOI Listing
July 2021

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.

Nat Commun 2021 06 28;12(1):3987. Epub 2021 Jun 28.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
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http://dx.doi.org/10.1038/s41467-021-23899-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238961PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
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http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Fatty Liver Index and Development of Cardiovascular Disease: Findings from the UK Biobank.

Dig Dis Sci 2021 Jun 29;66(6):2092-2100. Epub 2021 Mar 29.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA, 94304, USA.

Background: Nonalcoholic fatty liver disease is common and is associated with rising morbidity and mortality in the UK. Cardiovascular disease is the main cause of death in people with nonalcoholic fatty liver disease.

Aims: To determine the association between baseline cardiovascular risk factors with fatty liver index, and to investigate the association between fatty liver index and the incidence of cardiovascular disease in the UK.

Methods: This study is a population-based retrospective cohort study using the UK Biobank database.

Results: The mean fatty liver index in the study cohort was 44.9, and 33.7% met the criteria for nonalcoholic fatty liver disease. Fatty liver index was significantly associated with a wide range of cardiovascular risk factors at baseline. During a mean follow-up of 7.86 years, the combined incidence of cardiovascular disease was 6.92 per 1000-person years at risk. We found significant association between fatty liver index and incident cardiovascular disease in the fully adjusted model. We found significant association between fatty liver index and incident cardiovascular disease in subgroups stratified by BMI as well as subgroups with fatty liver index < 30, < 60, and ≥ 60.

Conclusions: Fatty liver index not only predicts NAFLD diagnosis, but also indicates baseline and future development of cardiovascular disease on long-term follow-up across weight categories and fatty liver index spectrum. These findings can inform clinicians and other stakeholders on cardiovascular disease management and preventive efforts. Patients with high fatty liver index should be counseled on the increased future risk of developing cardiovascular disease.
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http://dx.doi.org/10.1007/s10620-021-06954-yDOI Listing
June 2021

Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases: A Mendelian Randomization Study.

JAMA Netw Open 2021 01 4;4(1):e2034461. Epub 2021 Jan 4.

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania.

Importance: Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood.

Objective: To determine the association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke.

Design, Setting, And Participants: Mendelian randomization study using summary statistics from genome-wide associations of smoking (UK Biobank; up to 462 690 individuals), CAD (Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; up to 60 801 cases, 123 504 controls), PAD (VA Million Veteran Program; up to 24 009 cases, 150 983 controls), and large-artery stroke (MEGASTROKE; up to 4373 cases, 406 111 controls). This study was conducted using summary statistic data from large, previously described cohorts. Review of those publications does not reveal the total recruitment dates for those cohorts. Data analyses were conducted from August 2019 to June 2020.

Exposures: Genetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index).

Main Outcomes And Measures: Risk (odds ratios [ORs]) of CAD, PAD, and large-artery stroke.

Results: Genetic liability to smoking was associated with increased risk of PAD (OR, 2.13; 95% CI, 1.78-2.56; P = 3.6 × 10-16), CAD (OR, 1.48; 95% CI, 1.25-1.75; P = 4.4 × 10-6), and stroke (OR, 1.40; 95% CI, 1.02-1.92; P = .04). Genetic liability to smoking was associated with greater risk of PAD than risk of large-artery stroke (ratio of ORs, 1.52; 95% CI, 1.05-2.19; P = .02) or CAD (ratio of ORs, 1.44; 95% CI, 1.12-1.84; P = .004). The association between genetic liability to smoking and atherosclerotic cardiovascular diseases remained independent from the effects of smoking on traditional cardiovascular risk factors.

Conclusions And Relevance: In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.34461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816104PMC
January 2021

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.

Nat Commun 2021 01 5;12(1):24. Epub 2021 Jan 5.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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http://dx.doi.org/10.1038/s41467-020-19366-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785747PMC
January 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

Plasma proteomics and lung function in four community-based cohorts.

Respir Med 2021 01 5;176:106282. Epub 2020 Dec 5.

Division of Family Medicine and Primary Care, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institute, Huddinge, Sweden; Region Dalarna, Falun, Sweden; School of Health and Social Sciences, Dalarna University, Falun, Sweden. Electronic address:

Background: Underlying mechanism leading to impaired lung function are incompletely understood.

Objectives: To investigate whether protein profiling can provide novel insights into mechanisms leading to impaired lung function.

Methods: We used four community-based studies (n = 2552) to investigate associations between 79 cardiovascular/inflammatory proteins and forced expiratory volume in 1 s percent predicted (FEV%) assessed by spirometry. We divided the cohorts into discovery and replication samples and used risk factor-adjusted linear regression corrected for multiple comparison (false discovery rate of 5%). We performed Mendelian randomization analyses using genetic and spirometry data from the UK Biobank (n = 421,986) to assess causality.

Measurements And Main Results: In cross-sectional analysis, 22 proteins were associated with lower FEV% in both the discovery and replication sample, regardless of stratification by smoking status. The combined proteomic data cumulatively explained 5% of the variation in FEV%. In longitudinal analyses (n = 681), higher plasma levels of growth differentiation factor 15 (GDF-15) and interleukin 6 (IL-6) predicted a more rapid 5-year decline in lung function (change in FEV% per standard deviation of protein level -1.4, (95% CI, -2.5 to -0.3) for GDF-15, and -0.8, (95% CI, -1.5 to -0.2) for IL-6. Mendelian randomization analysis in UK-biobank provided support for a causal effect of increased GDF-15 levels and reduced FEV%.

Conclusions: Our combined approach identified GDF-15 as a potential causal factor in the development of impaired lung function in the general population. These findings encourage additional studies evaluating the role of GDF-15 as a causal factor for impaired lung function.
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http://dx.doi.org/10.1016/j.rmed.2020.106282DOI Listing
January 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

A phenome-wide association study of 26 mendelian genes reveals phenotypic expressivity of common and rare variants within the general population.

PLoS Genet 2020 11 23;16(11):e1008802. Epub 2020 Nov 23.

Stanford Cardiovascular Institute, Stanford University, Stanford, Stanford, California, United States of America.

The clinical evaluation of a genetic syndrome relies upon recognition of a characteristic pattern of signs or symptoms to guide targeted genetic testing for confirmation of the diagnosis. However, individuals displaying a single phenotype of a complex syndrome may not meet criteria for clinical diagnosis or genetic testing. Here, we present a phenome-wide association study (PheWAS) approach to systematically explore the phenotypic expressivity of common and rare alleles in genes associated with four well-described syndromic diseases (Alagille (AS), Marfan (MS), DiGeorge (DS), and Noonan (NS) syndromes) in the general population. Using human phenotype ontology (HPO) terms, we systematically mapped 60 phenotypes related to AS, MS, DS and NS in 337,198 unrelated white British from the UK Biobank (UKBB) based on their hospital admission records, self-administrated questionnaires, and physiological measurements. We performed logistic regression adjusting for age, sex, and the first 5 genetic principal components, for each phenotype and each variant in the target genes (JAG1, NOTCH2 FBN1, PTPN1 and RAS-opathy genes, and genes in the 22q11.2 locus) and performed a gene burden test. Overall, we observed multiple phenotype-genotype correlations, such as the association between variation in JAG1, FBN1, PTPN11 and SOS2 with diastolic and systolic blood pressure; and pleiotropy among multiple variants in syndromic genes. For example, rs11066309 in PTPN11 was significantly associated with a lower body mass index, an increased risk of hypothyroidism and a smaller size for gestational age, all in concordance with NS-related phenotypes. Similarly, rs589668 in FBN1 was associated with an increase in body height and blood pressure, and a reduced body fat percentage as observed in Marfan syndrome. Our findings suggest that the spectrum of associations of common and rare variants in genes involved in syndromic diseases can be extended to individual phenotypes within the general population.
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http://dx.doi.org/10.1371/journal.pgen.1008802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735621PMC
November 2020

Commonly used clinical chemistry tests as mortality predictors: Results from two large cohort studies.

PLoS One 2020 5;15(11):e0241558. Epub 2020 Nov 5.

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.

Background: The normal ranges for clinical chemistry tests are usually defined by cut-offs given by the distribution in healthy individuals. This approach does however not indicate if individuals outside the normal range are more prone to disease.

Methods: We studied the associations and risk prediction of 11 plasma and serum biomarkers with all-cause mortality in two population-based cohorts: a Swedish cohort (X69) initiated in 1969, and the UK Biobank (UKB) initiated in 2006-2010, with up to 48- and 9-years follow-up, respectively.

Results: In X69 and in UKB, 18,529 and 425,264 individuals were investigated, respectively. During the follow-up time, 14,475 deaths occurred in X69 and 17,116 in UKB. All evaluated tests were associated with mortality in X69 (P<0.0001, except bilirubin P<0.005). For calcium, blood urea nitrogen, bilirubin, hematocrit, uric acid, and iron, U-shaped associations were seen (P<0.0001). For leukocyte count, gamma-glutamyl transferase, alkaline phosphatases and lactate dehydrogenase, linear positive associations were seen, while for albumin the association was negative. Similar associations were seen in UKB. Addition of all biomarkers to a model with classical risk factors improved mortality prediction (delta C-statistics: +0.009 in X69 and +0.023 in UKB, P<0.00001 in both cohorts).

Conclusions: Commonly used clinical chemistry tests were associated with all-cause mortality both in the medium- and long-term perspective, and improved mortality prediction beyond classical risk factors. Since both linear and U-shaped relationships were found, we propose to define the normal range of a clinical chemistry test based on its association with mortality, rather than from the distribution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241558PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644047PMC
December 2020

Comprehensive Investigation of Circulating Biomarkers and Their Causal Role in Atherosclerosis-Related Risk Factors and Clinical Events.

Circ Genom Precis Med 2020 12 30;13(6):e002996. Epub 2020 Oct 30.

Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (D.Z., T.L.A., E.I.).

Background: Circulating biomarkers have been previously associated with atherosclerosis-related risk factors, but the nature of these associations is incompletely understood.

Methods: We performed multivariable-adjusted regressions and 2-sample Mendelian randomization analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451 933 participants of the UK Biobank.

Results: After multiple-testing correction (alpha=1.3×10), we found a total of 15, 9, 21, 22, 26, 24, and 26 biomarkers strongly associated with coronary artery disease, ischemic stroke, atrial fibrillation, type 2 diabetes, systolic blood pressure, body mass index, and waist-to-hip ratio; respectively. The Mendelian randomization analyses confirmed strong evidence of previously suggested causal associations for several glucose- and lipid-related biomarkers with type 2 diabetes and coronary artery disease. Particularly interesting findings included a protective role of IGF-1 (insulin-like growth factor 1) in systolic blood pressure, and the strong causal association of lipoprotein(a) in coronary artery disease development (β, -0.13; per SD change in exposure and outcome and odds ratio, 1.28; =2.6×10 and =7.4×10, respectively). In addition, our results indicated a causal role of increased ALT (alanine aminotransferase) in the development of type 2 diabetes and hypertension (odds ratio, 1.59 and β, 0.06, per SD change in exposure and outcome; =4.8×10 and =6.0×10). Our results suggest that it is unlikely that CRP (C-reactive protein) and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease.

Conclusions: We confirmed and extended known associations and reported several novel causal associations providing important insights about the cause of these diseases, which can help accelerate new prevention strategies.
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http://dx.doi.org/10.1161/CIRCGEN.120.002996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202726PMC
December 2020

Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.

Nat Metab 2020 10 16;2(10):1135-1148. Epub 2020 Oct 16.

SCALLOP consortium.

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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http://dx.doi.org/10.1038/s42255-020-00287-2DOI Listing
October 2020

Non-targeted urine metabolomics and associations with prevalent and incident type 2 diabetes.

Sci Rep 2020 10 5;10(1):16474. Epub 2020 Oct 5.

Department of Neurobiology, Care Sciences and Society (NVS), Family Medicine and Primary Care Unit, Karolinska Institutet, Huddinge, Sweden.

Better risk prediction and new molecular targets are key priorities in type 2 diabetes (T2D) research. Little is known about the role of the urine metabolome in predicting the risk of T2D. We aimed to use non-targeted urine metabolomics to discover biomarkers and improve risk prediction for T2D. Urine samples from two community cohorts of 1,424 adults were analyzed by ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). In a discovery/replication design, three out of 62 annotated metabolites were associated with prevalent T2D, notably lower urine levels of 3-hydroxyundecanoyl-carnitine. In participants without diabetes at baseline, LASSO regression in the training set selected six metabolites that improved prediction of T2D beyond established risk factors risk over up to 12 years' follow-up in the test sample, from C-statistic 0.866 to 0.892. Our results in one of the largest non-targeted urinary metabolomics study to date demonstrate the role of the urine metabolome in identifying at-risk persons for T2D and suggest urine 3-hydroxyundecanoyl-carnitine as a biomarker candidate.
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http://dx.doi.org/10.1038/s41598-020-72456-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536211PMC
October 2020

Adults With Mild-to-Moderate Congenital Heart Disease Demonstrate Measurable Neurocognitive Deficits.

J Am Heart Assoc 2020 10 28;9(19):e015379. Epub 2020 Sep 28.

Stanford Cardiovascular Institute Stanford University School of Medicine Palo Alto CA.

Background Neurocognitive impairment is a common complication of congenital heart disease (CHD) as well as acquired cardiovascular disease. Data are limited on neurocognitive function in adults with CHD (ACHD). Methods and Results A total of 1020 individuals with mild-to-moderate ACHD and 497 987 individuals without ACHD from the volunteer-based UK Biobank study underwent neurocognitive tests for fluid intelligence, reaction time, numeric memory, symbol-digit substitution, and trail making at enrollment and follow-up. Performance scores were compared before and after exclusion of preexisting stroke or coronary artery disease as measures of cerebro- and cardiovascular disease. Individuals with ACHD had significantly poorer performance on alpha-numeric trail making, a measure of visual attention and cognitive flexibility, spending 6.4 seconds longer on alpha-numeric trail making (95% CI, 3.0-9.9 seconds, =0.002) and 2.5 seconds longer on numeric trail making (95% CI, 0.5-4.6 seconds, =0.034), a measure of visual attention and processing speed. The ACHD cohort had modestly lower performance on symbol-digit substitution, a measure of processing speed, with 0.9 fewer correct substitutions (95% CI, - 1.5 to - 0.2 substitutions, =0.021). After excluding preexisting stroke or coronary artery disease, individuals with ACHD continued to show poorer performance in all 6 domains (=NS). Conclusions Individuals with mild-to-moderate ACHD had poorer neurocognitive performance, most significantly in tests of cognitive flexibility, analogous to deficits in children with CHD. These differences appear to be driven by increased burden of cerebro- and cardiovascular disease among individuals with ACHD.
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http://dx.doi.org/10.1161/JAHA.119.015379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792385PMC
October 2020

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes 2020 12 11;69(12):2806-2818. Epub 2020 Sep 11.

Department of Biostatistics, Boston University School of Public Health, Boston, MA.

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , , , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry ( = 2 × 10, = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.
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http://dx.doi.org/10.2337/db20-0070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679778PMC
December 2020

Development and validation of risk prediction models for multiple cardiovascular diseases and Type 2 diabetes.

PLoS One 2020 29;15(7):e0235758. Epub 2020 Jul 29.

Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.

Accurate risk assessment of an individuals' propensity to develop cardiovascular diseases (CVDs) is crucial for the prevention of these conditions. Numerous published risk prediction models used for CVD risk assessment are based on conventional risk factors and include only a limited number of biomarkers. The addition of novel biomarkers can boost the discriminative ability of risk prediction models for CVDs with different pathogenesis. The present study reports the development of risk prediction models for a range of heterogeneous CVDs, including coronary artery disease (CAD), stroke, deep vein thrombosis (DVT), and abdominal aortic aneurysm (AAA), as well as for Type 2 diabetes mellitus (DM2), a major CVD risk factor. In addition to conventional risk factors, the models incorporate various blood biomarkers and comorbidities to improve both individual and population stratification. An automatic variable selection approach was developed to generate the best set of explanatory variables for each model from the initial panel of risk factors. In total, up to 254,220 UK Biobank participants (ranging from 215,269 to 254,220 for different CVDs and DM2) were included in the analyses. The derived prediction models utilizing Cox proportional hazards regression achieved consistent discrimination performance (C-index) for all diseases: CAD, 0.794 (95% CI, 0.787-0.801); DM2, 0.909 (95% CI, 0.903-0.916); stroke, 0.778 (95% CI, 0.756-0.801); DVT, 0.743 (95% CI, 0.737-0.749); and AAA, 0.893 (95% CI, 0.874-0.912). When validated on various subpopulations, they demonstrated higher discrimination in healthier and middle-age individuals. In general, calibration of a five-year risk of developing the CVDs and DM2 demonstrated incremental overestimation of disease-related conditions amongst the highest decile of risk probabilities. In summary, the risk prediction models described were validated with high discrimination and good calibration for several CVDs and DM2. These models incorporate multiple shared predictor variables and may be integrated into a single platform to enhance clinical stratification to impact health outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235758PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390268PMC
September 2020

Translating GWAS-identified loci for cardiac rhythm and rate using an in vivo image- and CRISPR/Cas9-based approach.

Sci Rep 2020 07 16;10(1):11831. Epub 2020 Jul 16.

The Beijer Laboratory and Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

A meta-analysis of genome-wide association studies (GWAS) identified eight loci that are associated with heart rate variability (HRV), but candidate genes in these loci remain uncharacterized. We developed an image- and CRISPR/Cas9-based pipeline to systematically characterize candidate genes for HRV in live zebrafish embryos. Nine zebrafish orthologues of six human candidate genes were targeted simultaneously in eggs from fish that transgenically express GFP on smooth muscle cells (Tg[acta2:GFP]), to visualize the beating heart. An automated analysis of repeated 30 s recordings of beating atria in 381 live, intact zebrafish embryos at 2 and 5 days post-fertilization highlighted genes that influence HRV (hcn4 and si:dkey-65j6.2 [KIAA1755]); heart rate (rgs6 and hcn4); and the risk of sinoatrial pauses and arrests (hcn4). Exposure to 10 or 25 µM ivabradine-an open channel blocker of HCNs-for 24 h resulted in a dose-dependent higher HRV and lower heart rate at 5 days post-fertilization. Hence, our screen confirmed the role of established genes for heart rate and rhythm (RGS6 and HCN4); showed that ivabradine reduces heart rate and increases HRV in zebrafish embryos, as it does in humans; and highlighted a novel gene that plays a role in HRV (KIAA1755).
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http://dx.doi.org/10.1038/s41598-020-68567-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367351PMC
July 2020

Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade.

Proc Natl Acad Sci U S A 2020 07 15;117(27):15818-15826. Epub 2020 Jun 15.

Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305;

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.
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http://dx.doi.org/10.1073/pnas.2006348117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354942PMC
July 2020

Global Plasma Metabolomics to Identify Potential Biomarkers of Blood Pressure Progression.

Arterioscler Thromb Vasc Biol 2020 08 28;40(8):e227-e237. Epub 2020 May 28.

From the Department of Medical Sciences, Uppsala University, Sweden (Y.-T.L., S.S., T.F., U.H., E.I., L.L., J.S.).

Objective: The pathophysiology of hypertension remains incompletely understood. We investigated associations of circulating metabolites with longitudinal blood pressure (BP) changes in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort and validated the findings in the Uppsala Longitudinal Study of Adult Men cohort. Approach and Results: Circulating metabolite levels were assessed with liquid- and gas-chromatography coupled to mass spectrometry among persons without BP-lowering medication at baseline. We studied associations of baseline levels of metabolites with changes in BP levels and the clinical BP stage between baseline and a follow-up examination 5 years later. In the discovery cohort, we investigated 504 individuals that contributed with 757 observations of paired BP measurements. The mean baseline systolic and diastolic BPs were 144 (19.7)/76 (9.7) mm Hg, and change in systolic and diastolic BPs were 3.7 (15.8)/-0.5 (8.6) mm Hg over 5 years. The metabolites associated with diastolic BP change were ceramide, triacylglycerol, total glycerolipids, oleic acid, and cholesterylester. No associations with longitudinal changes in systolic BP or BP stage were observed. Metabolites with similar structures to the 5 top findings in the discovery cohort were investigated in the validation cohort. Diacylglycerol (36:2) and monoacylglycerol (18:0), 2 glycerolipids, were associated with diastolic BP change in the validation cohort.

Conclusions: Circulating baseline levels of ceramide, triacylglycerol, total glycerolipids, and oleic acid were positively associated with longitudinal diastolic BP change, whereas cholesterylester levels were inversely associated with longitudinal diastolic BP change. Two glycerolipids were validated in an independent cohort. These metabolites may point towards pathophysiological pathways of hypertension.
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http://dx.doi.org/10.1161/ATVBAHA.120.314356DOI Listing
August 2020

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

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

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Proteomic profiles before and during weight loss: Results from randomized trial of dietary intervention.

Sci Rep 2020 05 13;10(1):7913. Epub 2020 May 13.

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Inflammatory and cardiovascular biomarkers have been associated with obesity, but little is known about how they change upon dietary intervention and concomitant weight loss. Further, protein biomarkers might be useful for predicting weight loss in overweight and obese individuals. We performed secondary analyses in the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) randomized intervention trial that included healthy 609 adults (18-50 years old) with BMI 28-40 kg/m, to evaluate associations between circulating protein biomarkers and BMI at baseline, during a weight loss diet intervention, and to assess predictive potential of baseline blood proteins on weight loss. We analyzed 263 plasma proteins at baseline and 6 months into the intervention using the Olink Proteomics CVD II, CVD III and Inflammation arrays. BMI was assessed at baseline, after 3 and 6 months of dietary intervention. At baseline, 102 of the examined inflammatory and cardiovascular biomarkers were associated with BMI (>90% with successful replication in 1,584 overweight/obese individuals from a community-based cohort study) and 130 tracked with weight loss shedding light into the pathophysiology of obesity. However, out of 263 proteins analyzed at baseline, only fibroblast growth factor 21 (FGF-21) predicted weight loss, and none helped individualize dietary assignment.
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http://dx.doi.org/10.1038/s41598-020-64636-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220904PMC
May 2020

Accuracy of Smartphone Camera Applications for Detecting Atrial Fibrillation: A Systematic Review and Meta-analysis.

JAMA Netw Open 2020 04 1;3(4):e202064. Epub 2020 Apr 1.

Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, California.

Importance: Atrial fibrillation (AF) affects more than 6 million people in the United States; however, much AF remains undiagnosed. Given that more than 265 million people in the United States own smartphones (>80% of the population), smartphone applications have been proposed for detecting AF, but the accuracy of these applications remains unclear.

Objective: To determine the accuracy of smartphone camera applications that diagnose AF.

Data Sources And Study Selection: MEDLINE and Embase were searched until January 2019 for studies that assessed the accuracy of any smartphone applications that use the smartphone's camera to measure the amplitude and frequency of the user's fingertip pulse to diagnose AF.

Data Extraction And Synthesis: Bivariate random-effects meta-analyses were constructed to synthesize data. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) of Diagnostic Test Accuracy Studies reporting guideline.

Main Outcomes And Measures: Sensitivity and specificity were measured with bivariate random-effects meta-analysis. To simulate the use of these applications as a screening tool, the positive predictive value (PPV) and negative predictive value (NPV) for different population groups (ie, age ≥65 years and age ≥65 years with hypertension) were modeled. Lastly, the association of methodological limitations with outcomes were analyzed with sensitivity analyses and metaregressions.

Results: A total of 10 primary diagnostic accuracy studies, with 3852 participants and 4 applications, were included. The oldest studies were published in 2016 (2 studies [20.0%]), while most studies (4 [40.0%]) were published in 2018. The applications analyzed the pulsewave signal for a mean (range) of 2 (1-5) minutes. The meta-analyzed sensitivity and specificity for all applications combined were 94.2% (95% CI, 92.2%-95.7%) and 95.8% (95% CI, 92.4%-97.7%), respectively. The PPV for smartphone camera applications detecting AF in an asymptomatic population aged 65 years and older was between 19.3% (95% CI, 19.2%-19.4%) and 37.5% (95% CI, 37.4%-37.6%), and the NPV was between 99.8% (95% CI, 99.83%-99.84%) and 99.9% (95% CI, 99.94%-99.95%). The PPV and NPV increased for individuals aged 65 years and older with hypertension (PPV, 20.5% [95% CI, 20.4%-20.6%] to 39.2% [95% CI, 39.1%-39.3%]; NPV, 99.8% [95% CI, 99.8%-99.8%] to 99.9% [95% CI, 99.9%-99.9%]). There were methodological limitations in a number of studies that did not appear to be associated with diagnostic performance, but this could not be definitively excluded given the sparsity of the data.

Conclusions And Relevance: In this study, all smartphone camera applications had relatively high sensitivity and specificity. The modeled NPV was high for all analyses, but the PPV was modest, suggesting that using these applications in an asymptomatic population may generate a higher number of false-positive than true-positive results. Future research should address the accuracy of these applications when screening other high-risk population groups, their ability to help monitor chronic AF, and, ultimately, their associations with patient-important outcomes.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.2064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125433PMC
April 2020

FAM13A affects body fat distribution and adipocyte function.

Nat Commun 2020 03 19;11(1):1465. Epub 2020 Mar 19.

Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Genetic variation in the FAM13A (Family with Sequence Similarity 13 Member A) locus has been associated with several glycemic and metabolic traits in genome-wide association studies (GWAS). Here, we demonstrate that in humans, FAM13A alleles are associated with increased FAM13A expression in subcutaneous adipose tissue (SAT) and an insulin resistance-related phenotype (e.g. higher waist-to-hip ratio and fasting insulin levels, but lower body fat). In human adipocyte models, knockdown of FAM13A in preadipocytes accelerates adipocyte differentiation. In mice, Fam13a knockout (KO) have a lower visceral to subcutaneous fat (VAT/SAT) ratio after high-fat diet challenge, in comparison to their wild-type counterparts. Subcutaneous adipocytes in KO mice show a size distribution shift toward an increased number of smaller adipocytes, along with an improved adipogenic potential. Our results indicate that GWAS-associated variants within the FAM13A locus alter adipose FAM13A expression, which in turn, regulates adipocyte differentiation and contribute to changes in body fat distribution.
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http://dx.doi.org/10.1038/s41467-020-15291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081215PMC
March 2020

Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses.

Hypertension 2020 03 3;75(3):714-722. Epub 2020 Feb 3.

From the Division of Cardiovascular Medicine, Department of Medicine (D.Z., T.L.A., E.I.), Stanford University School of Medicine, CA.

Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (β systolic BP ≥2.63; β diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; ≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, =0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032218PMC
March 2020

Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis.

Nat Nanotechnol 2020 02 27;15(2):154-161. Epub 2020 Jan 27.

Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, CA, USA.

Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of 'Trojan horse' nanoparticles to prevent atherosclerotic cardiovascular disease.
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http://dx.doi.org/10.1038/s41565-019-0619-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254969PMC
February 2020

The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb: A meta-analysis and a longitudinal evaluation.

Atherosclerosis 2020 02 18;295:25-30. Epub 2020 Jan 18.

Yan Borne Department of Clinical Sciences Malmö, Lund University, Sweden.

Background And Aims: Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease.

Methods: In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n > 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up.

Results: In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p < 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061).

Conclusions: Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.01.011DOI Listing
February 2020
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