Publications by authors named "Christopher P Nelson"

136 Publications

The genomics of heart failure: design and rationale of the HERMES consortium.

ESC Heart Fail 2021 Sep 3. Epub 2021 Sep 3.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Aims: The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.

Methods And Results: The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 under an additive genetic model.

Conclusions: HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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http://dx.doi.org/10.1002/ehf2.13517DOI Listing
September 2021

Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank.

EBioMedicine 2021 Aug 23;70:103485. Epub 2021 Jul 23.

Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom. Electronic address:

Background Older age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain whether leucocyte telomere length (LTL), previously proposed as a marker of biological age, is also associated with COVID-19 outcomes. Methods We associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006-2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 130 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships. Findings Of 6775 participants in UKB who tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1·17 (95% CI 1·05-1·30; P = 0·004) per 1-SD shorter usual LTL, after adjustment for age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant. Interpretation Shorter LTL is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including age. Further data are needed to determine whether this association reflects causality. Funding UK Medical Research Council, Biotechnology and Biological Sciences Research Council and British Heart Foundation.
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http://dx.doi.org/10.1016/j.ebiom.2021.103485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299112PMC
August 2021

Cis-epistasis at the LPA locus and risk of cardiovascular diseases.

Cardiovasc Res 2021 Apr 20. Epub 2021 Apr 20.

Estonian Genome Center, Institute of Genomics, University of Tartu, 51010, Tartu, Estonia.

Aims: Coronary artery disease (CAD) has a strong genetic predisposition. However, despite substantial discoveries made by genome-wide association studies (GWAS), a large proportion of heritability awaits identification. Non-additive genetic-effects might be responsible for part of the unaccounted genetic variance. Here we attempted a proof-of-concept study to identify non-additive genetic effects, namely epistatic interactions, associated with CAD.

Methods And Results: We tested for epistatic interactions in ten CAD case-control studies and UK Biobank with focus on 8,068 SNPs at 56 loci with known associations with CAD risk. We identified a SNP pair located in cis at the LPA locus, rs1800769 and rs9458001, to be jointly associated with risk for CAD (odds ratio [OR]=1.37, p = 1.07 × 10-11), peripheral arterial disease (OR = 1.22, p = 2.32 × 10-4), aortic stenosis (OR = 1.47, p = 6.95 × 10-7), hepatic lipoprotein(a) (Lp(a)) transcript levels (beta = 0.39, p = 1.41 × 10-8), and Lp(a) serum levels (beta = 0.58, p = 8.7 × 10-32), while individual SNPs displayed no association. Further exploration of the LPA locus revealed a strong dependency of these associations on a rare variant, rs140570886, that was previously associated with Lp(a) levels. We confirmed increased CAD risk for heterozygous (relative OR = 1.46, p = 9.97 × 10-32) and individuals homozygous for the minor allele (relative OR = 1.77, p = 0.09) of rs140570886. Using forward model selection, we also show that epistatic interactions between rs140570886, rs9458001, and rs1800769 modulate the effects of the rs140570886 risk allele.

Conclusions: These results demonstrate the feasibility of a large-scale knowledge-based epistasis scan and provide rare evidence of an epistatic interaction in a complex human disease. We were directed to a variant (rs140570886) influencing risk through additive genetic as well as epistatic effects. In summary, this study provides deeper insights into the genetic architecture of a locus important for cardiovascular diseases.

Translational Perspective: Genetic variants identified by GWAS studies explain about a quarter of the heritability of coronary artery disease by additive genetic effects. Our study demonstrates that non-additive effects contribute to the genetic architecture of the disease as well and identifies complex interaction patterns at the LPA locus, which affect LPA expression, Lp(a) plasma levels and risk of atherosclerosis. This proof-of-concept study encourages systematic searches for epistatic interactions in further studies to shed new light on the aetiology of the disease.
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http://dx.doi.org/10.1093/cvr/cvab136DOI Listing
April 2021

Telomere length is independently associated with all-cause mortality in chronic heart failure.

Heart 2021 Mar 31. Epub 2021 Mar 31.

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Objective: Patients with heart failure have shorter mean leucocyte telomere length (LTL), a marker of biological age, compared with healthy subjects, but it is unclear whether this is of prognostic significance. We therefore sought to determine whether LTL is associated with outcomes in patients with heart failure.

Methods: We measured LTL in patients with heart failure from the BIOSTAT-CHF Index (n=2260) and BIOSTAT-CHF Tayside (n=1413) cohorts. Cox proportional hazards analyses were performed individually in each cohort and the estimates combined using meta-analysis. Our co-primary endpoints were all-cause mortality and heart failure hospitalisation.

Results: In age-adjusted and sex-adjusted analyses, shorter LTL was associated with higher all-cause mortality in both cohorts individually and when combined (meta-analysis HR (per SD decrease in LTL)=1.16 (95% CI 1.08 to 1.24); p=2.66×10), an effect equivalent to that of being four years older. The association remained significant after adjustment for the BIOSTAT-CHF clinical risk score to account for known prognostic factors (HR=1.12 (95% CI 1.05 to 1.20); p=1.04×10). Shorter LTL was associated with both cardiovascular (HR=1.09 (95% CI 1.00 to 1.19); p=0.047) and non-cardiovascular deaths (HR=1.18 (95% CI 1.05 to 1.32); p=4.80×10). There was no association between LTL and heart failure hospitalisation (HR=0.99 (95% CI 0.92 to 1.07); p=0.855).

Conclusion: In patients with heart failure, shorter mean LTL is independently associated with all-cause mortality.
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http://dx.doi.org/10.1136/heartjnl-2020-318654DOI Listing
March 2021

Polygenic risk scores in cardiovascular risk prediction: A cohort study and modelling analyses.

PLoS Med 2021 01 14;18(1):e1003498. Epub 2021 Jan 14.

Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

Background: Polygenic risk scores (PRSs) can stratify populations into cardiovascular disease (CVD) risk groups. We aimed to quantify the potential advantage of adding information on PRSs to conventional risk factors in the primary prevention of CVD.

Methods And Findings: Using data from UK Biobank on 306,654 individuals without a history of CVD and not on lipid-lowering treatments (mean age [SD]: 56.0 [8.0] years; females: 57%; median follow-up: 8.1 years), we calculated measures of risk discrimination and reclassification upon addition of PRSs to risk factors in a conventional risk prediction model (i.e., age, sex, systolic blood pressure, smoking status, history of diabetes, and total and high-density lipoprotein cholesterol). We then modelled the implications of initiating guideline-recommended statin therapy in a primary care setting using incidence rates from 2.1 million individuals from the Clinical Practice Research Datalink. The C-index, a measure of risk discrimination, was 0.710 (95% CI 0.703-0.717) for a CVD prediction model containing conventional risk predictors alone. Addition of information on PRSs increased the C-index by 0.012 (95% CI 0.009-0.015), and resulted in continuous net reclassification improvements of about 10% and 12% in cases and non-cases, respectively. If a PRS were assessed in the entire UK primary care population aged 40-75 years, assuming that statin therapy would be initiated in accordance with the UK National Institute for Health and Care Excellence guidelines (i.e., for persons with a predicted risk of ≥10% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), then it could help prevent 1 additional CVD event for approximately every 5,750 individuals screened. By contrast, targeted assessment only among people at intermediate (i.e., 5% to <10%) 10-year CVD risk could help prevent 1 additional CVD event for approximately every 340 individuals screened. Such a targeted strategy could help prevent 7% more CVD events than conventional risk prediction alone. Potential gains afforded by assessment of PRSs on top of conventional risk factors would be about 1.5-fold greater than those provided by assessment of C-reactive protein, a plasma biomarker included in some risk prediction guidelines. Potential limitations of this study include its restriction to European ancestry participants and a lack of health economic evaluation.

Conclusions: Our results suggest that addition of PRSs to conventional risk factors can modestly enhance prediction of first-onset CVD and could translate into population health benefits if used at scale.
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http://dx.doi.org/10.1371/journal.pmed.1003498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808664PMC
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

Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis.

Diabetes Care 2021 02 4;44(2):556-562. Epub 2020 Dec 4.

George Institute for Global Health, University of Oxford, Oxford, U.K.

Objective: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.

Research Design And Methods: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment.

Results: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08-1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17-1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs.

Conclusions: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.
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http://dx.doi.org/10.2337/dc20-1137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818328PMC
February 2021

Author Correction: Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival.

Commun Biol 2020 Nov 10;3(1):679. Epub 2020 Nov 10.

Department of Health Sciences, University of Leicester, Leicester, UK.

A Correction to this paper has been published: https://doi.org/10.1038/s42003-020-01447-6 .
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http://dx.doi.org/10.1038/s42003-020-01447-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656244PMC
November 2020

The importance of previous lifetime trauma in stroke-induced PTSD symptoms and mental health outcomes.

J Psychiatr Res 2021 04 27;136:589-594. Epub 2020 Oct 27.

Charité-Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik und Hochschulambulanz für Neurologie und Centrum für Schlaganfallforschung Berlin (CSB), Berlin, Germany. Electronic address:

The 'Stroke Complications after Traumatic Experiences and Stress' (SATURN) study was designed to investigate the effects of a prior traumatic event on PTSD symptoms triggered by a subsequent stroke. First-ever ischemic stroke patients were surveyed 9-13 months after hospitalization at the Charité University Medical Center. Stroke-induced PTSD symptoms were measured using the Impact of Event Scale-revised (IES-R). Prior traumatization together with past PTSD symptoms was assessed retrospectively with the Brief Trauma Questionnaire (BTQ) and the 7-item Short Screening Scale for PTSD. Depressive symptoms were assessed with the Beck Depression Inventory (BDI-II). The Short Form (SF)-36 was used to evaluate physical and mental health outcomes. We received 258 responses from 636 eligible patients (~41%). Based on respondents' scores on the IES-R, the prevalence of probable PTSD due to the stroke event was 11% in our sample. Female sex and younger age were associated with more severe PTSD symptoms. Psychological endpoints did not differ between patients who denied prior trauma exposure and those who reported earlier trauma exposure but denied subsequent PTSD symptoms. However, a history of trauma exposure in tandem with endorsing subsequent PTSD symptoms was linked with significantly increased post-stroke PTSD and depressive symptoms together with decreased psychological well-being. Self-reported physical health did not differ across groups. Younger age, being a woman, and having developed PTSD symptoms in the aftermath of a prior trauma were associated with adverse psychological outcomes after stroke.
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http://dx.doi.org/10.1016/j.jpsychires.2020.10.033DOI Listing
April 2021

Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival.

Commun Biol 2020 10 30;3(1):634. Epub 2020 Oct 30.

Department of Health Sciences, University of Leicester, Leicester, UK.

Walking is a simple form of exercise, widely promoted for its health benefits. Self-reported walking pace has been associated with a range of cardiorespiratory and cancer outcomes, and is a strong predictor of mortality. Here we perform a genome-wide association study of self-reported walking pace in 450,967 European ancestry UK Biobank participants. We identify 70 independent associated loci (P < 5 × 10), 11 of which are novel. We estimate the SNP-based heritability as 13.2% (s.e. = 0.21%), reducing to 8.9% (s.e. = 0.17%) with adjustment for body mass index. Significant genetic correlations are observed with cardiometabolic, respiratory and psychiatric traits, educational attainment and all-cause mortality. Mendelian randomization analyses suggest a potential causal link of increasing walking pace with a lower cardiometabolic risk profile. Given its low heritability and simple measurement, these findings suggest that self-reported walking pace is a pragmatic target for interventions aiming for general benefits on health.
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http://dx.doi.org/10.1038/s42003-020-01357-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599247PMC
October 2020

Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells.

Nature 2020 10 14;586(7831):769-775. Epub 2020 Oct 14.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Myeloproliferative neoplasms (MPNs) are blood cancers that are characterized by the excessive production of mature myeloid cells and arise from the acquisition of somatic driver mutations in haematopoietic stem cells (HSCs). Epidemiological studies indicate a substantial heritable component of MPNs that is among the highest known for cancers. However, only a limited number of genetic risk loci have been identified, and the underlying biological mechanisms that lead to the acquisition of MPNs remain unclear. Here, by conducting a large-scale genome-wide association study (3,797 cases and 1,152,977 controls), we identify 17 MPN risk loci (P < 5.0 × 10), 7 of which have not been previously reported. We find that there is a shared genetic architecture between MPN risk and several haematopoietic traits from distinct lineages; that there is an enrichment for MPN risk variants within accessible chromatin of HSCs; and that increased MPN risk is associated with longer telomere length in leukocytes and other clonal haematopoietic states-collectively suggesting that MPN risk is associated with the function and self-renewal of HSCs. We use gene mapping to identify modulators of HSC biology linked to MPN risk, and show through targeted variant-to-function assays that CHEK2 and GFI1B have roles in altering the function of HSCs to confer disease risk. Overall, our results reveal a previously unappreciated mechanism for inherited MPN risk through the modulation of HSC function.
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http://dx.doi.org/10.1038/s41586-020-2786-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606745PMC
October 2020

Genetic Associations With Plasma Angiotensin Converting Enzyme 2 Concentration: Potential Relevance to COVID-19 Risk.

Circulation 2020 09 7;142(11):1117-1119. Epub 2020 Jul 7.

Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, United Kingdom (C.P.N., V.C., T.R.W., S.Y., L.L.N., N.J.S.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049007DOI Listing
September 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

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

Exome Sequencing Analysis Identifies Rare Variants in and That Are Associated With Shorter Telomere Length.

Front Genet 2020 30;11:337. Epub 2020 Apr 30.

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

Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (-value < 1.42 × 10, minor allele frequency of 0.2-0.5%) in the ERF study. Eight of these variants (in , , , , , and ) were located on chromosome 11q22.3 that contains , a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in (- = 1.48 × 10), which has previously been associated with age. Additionally, a novel rare variant in the known locus showed suggestive evidence for association (-value = 1.18 × 10) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.
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http://dx.doi.org/10.3389/fgene.2020.00337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204400PMC
April 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 Jun 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

Genetic determinants of telomere length and cancer risk.

Curr Opin Genet Dev 2020 02 11;60:63-68. Epub 2020 Mar 11.

Department of Cardiovascular Sciences, University of Leicester, UK; NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK. Electronic address:

The relationship of telomere length with cancer risk has been the source of much debate within epidemiological studies, which have produced inconsistent finding both between and within different cancer types. Over recent years, genome-wide association studies of increasing size have identified variants that determine human telomere length. These variants have subsequently been utilised as instrumental variables in Mendelian randomisation based studies, allowing the investigation of potential causal relationships between telomere length and cancer. Here we discuss recent advances in both genomic discovery, studies that give increasing evidence towards a causal role for telomere length in cancer risk and considerations for future studies.
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http://dx.doi.org/10.1016/j.gde.2020.02.007DOI Listing
February 2020

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Am J Hum Genet 2020 03 27;106(3):389-404. Epub 2020 Feb 27.

Department of Cardiovascular Sciences, University of Leicester, LE3 9QP, United Kingdom; NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, LE3 9QP, United Kingdom.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
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http://dx.doi.org/10.1016/j.ajhg.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058826PMC
March 2020

Genetic risk and atrial fibrillation in patients with heart failure.

Eur J Heart Fail 2020 03 9;22(3):519-527. Epub 2020 Jan 9.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Aims: To study the association between an atrial fibrillation (AF) genetic risk score with prevalent AF and all-cause mortality in patients with heart failure.

Methods And Results: An AF genetic risk score was calculated in 3759 European ancestry individuals (1783 with sinus rhythm, 1976 with AF) from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) by summing 97 single nucleotide polymorphism (SNP) alleles (ranging from 0-2) weighted by the natural logarithm of the relative SNP risk from the latest AF genome-wide association study. Further, we assessed AF risk variance explained by additive SNP variation, and performance of clinical or genetic risk factors, and the combination in classifying AF prevalence. AF was classified as AF or atrial flutter (AFL) at baseline electrocardiogram and/or a history of AF or AFL. The genetic risk score was associated with AF after multivariable adjustment. Odds ratio for AF prevalence per 1-unit increase genetic risk score was 2.12 (95% confidence interval 1.84-2.45, P = 2.15 × 10 ) in the total cohort, 2.08 (1.72-2.50, P = 1.30 × 10 ) in heart failure with reduced ejection fraction (HFrEF) and 2.02 (1.37-2.99, P = 4.37 × 10 ) in heart failure with preserved ejection fraction (HFpEF). AF-associated loci explained 22.9% of overall AF SNP heritability. Addition of the genetic risk score to clinical risk factors increased the C-index by 2.2% to 0.721.

Conclusions: The AF genetic risk score was associated with increased AF prevalence in HFrEF and HFpEF. Genetic variation accounted for 22.9% of overall AF SNP heritability. Addition of genetic risk to clinical risk improved model performance in classifying AF prevalence.
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http://dx.doi.org/10.1002/ejhf.1735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319410PMC
March 2020

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure.

Nat Commun 2020 01 9;11(1):163. Epub 2020 Jan 9.

Department of Biostatistics, University of Liverpool, Liverpool, UK.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-019-13690-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952380PMC
January 2020

Addenbrooke's Cognitive Examination III (ACE-III) and mini-ACE for the detection of dementia and mild cognitive impairment.

Cochrane Database Syst Rev 2019 12 17;12:CD013282. Epub 2019 Dec 17.

University of Leicester, Department of Cardiovascular Sciences, Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK, LE2 7LX.

Background: The number of new cases of dementia is projected to rise significantly over the next decade. Thus, there is a pressing need for accurate tools to detect cognitive impairment in routine clinical practice. The Addenbrooke's Cognitive Examination III (ACE-III), and the mini-ACE are brief, bedside cognitive screens that have previously reported good sensitivity and specificity. The quality and quantity of this evidence has not, however, been robustly investigated.

Objectives: To assess the diagnostic test accuracy of the ACE-III and mini-ACE for the detection of dementia, dementia sub-types, and mild cognitive impairment (MCI) at published thresholds in primary, secondary, and community care settings in patients presenting with, or at high risk of, cognitive decline.

Search Methods: We performed the search for this review on 13 February 2019. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science Core Collection (ISI Web of Knowledge), PsycINFO (OvidSP), and LILACS (BIREME). We applied no language or date restrictions to the electronic searches; and to maximise sensitivity we did not use methodological filters. The search yielded 5655 records, of which 2937 remained after we removed duplicates. We identified a further four articles through PubMed 'related articles'. We found no additional records through reference list citation searching, or grey literature.

Selection Criteria: Cross-sectional studies investigating the accuracy of the ACE-III or mini-ACE in patients presenting with, or at high risk of, cognitive decline were suitable for inclusion. We excluded case-control, delayed verification and longitudinal studies, and studies which investigated a secondary cause of dementia. We did not restrict studies by language; and we included those with pre-specified thresholds (88 and 82 for the ACE-III, and 21 or 25 for the mini-ACE).

Data Collection And Analysis: We extracted information on study and participant characteristics and used information on dementia and MCI prevalence, sensitivity, specificity, and sample size to generate 2×2 tables in Review Manager 5. We assessed methodological quality of included studies using the QUADAS-2 tool; and we assessed the quality of study reporting with the STARDdem tool. Due to significant heterogeneity in the included studies and an insufficient number of studies, we did not perform meta-analyses.

Main Results: This review identified seven studies (1711 participants in total) of cross-sectional design, four examining the accuracy of the ACE-III, and three of the mini-ACE. Overall, the majority of studies were at low or unclear risk of bias and applicability on quality assessment. Studies were at high risk of bias for the index test (n = 4) and reference standard (n = 2). Study reporting was variable across the included studies. No studies investigated dementia sub-types. The ACE-III had variable sensitivity across thresholds and patient populations (range for dementia at 82 and 88: 82% to 97%, n = 2; range for MCI at 88: 75% to 77%, n = 2), but with more variability in specificity (range for dementia: 4% to 77%, n = 2; range for MCI: 89% to 92%, n = 2). Similarly, sensitivity of the mini-ACE was variable (range for dementia at 21 and 25: 70% to 99%, n = 3; range for MCI at 21 and 25: 64% to 95%, n = 3) but with more variability specificity (range for dementia: 32% to 100%, n = 3; range for MCI: 46% to 79%, n = 3). We identified no studies in primary care populations: four studies were conducted in outpatient clinics, one study in an in-patient setting, and in two studies the settings were unclear.

Authors' Conclusions: There is insufficient information in terms of both quality and quantity to recommend the use of either the ACE-III or mini-ACE for the screening of dementia or MCI in patients presenting with, or at high risk of, cognitive decline. No studies were conducted in a primary care setting so the accuracy of the ACE-III and mini-ACE in this setting are not known. Lower thresholds (82 for the ACE-III, and 21 for the mini-ACE) provide better specificity with acceptable sensitivity and may provide better clinical utility. The ACE-III and mini-ACE should only be used to support the diagnosis as an adjunct to a full clinical assessment. Further research is needed to determine the utility of the ACE-III and mini-ACE for the detection of dementia, dementia sub-types, and MCI. Specifically, the optimal thresholds for detection need to be determined in a variety of settings (primary care, secondary care (inpatient and outpatient), and community services), prevalences, and languages.
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http://dx.doi.org/10.1002/14651858.CD013282.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916534PMC
December 2019

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.

JCI Insight 2019 12 5;4(23). Epub 2019 Dec 5.

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments.
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http://dx.doi.org/10.1172/jci.insight.131156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962032PMC
December 2019

New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders.

Nat Hum Behav 2019 09 29;3(9):950-961. Epub 2019 Jul 29.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.
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http://dx.doi.org/10.1038/s41562-019-0653-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711277PMC
September 2019

Geographical location affects the levels and association of trimethylamine N-oxide with heart failure mortality in BIOSTAT-CHF: a post-hoc analysis.

Eur J Heart Fail 2019 10 28;21(10):1291-1294. Epub 2019 Jul 28.

Department of Cardiovascular Sciences, University of Leicester, NIHR Leicester Biomedical Research Centre, Leicester, UK.

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http://dx.doi.org/10.1002/ejhf.1550DOI Listing
October 2019

A flexible and parallelizable approach to genome-wide polygenic risk scores.

Genet Epidemiol 2019 10 22;43(7):730-741. Epub 2019 Jul 22.

Department of Health Sciences, Centre for Medicine, University of Leicester, Leicester, UK.

The heritability of most complex traits is driven by variants throughout the genome. Consequently, polygenic risk scores, which combine information on multiple variants genome-wide, have demonstrated improved accuracy in genetic risk prediction. We present a new two-step approach to constructing genome-wide polygenic risk scores from meta-GWAS summary statistics. Local linkage disequilibrium (LD) is adjusted for in Step 1, followed by, uniquely, long-range LD in Step 2. Our algorithm is highly parallelizable since block-wise analyses in Step 1 can be distributed across a high-performance computing cluster, and flexible, since sparsity and heritability are estimated within each block. Inference is obtained through a formal Bayesian variable selection framework, meaning final risk predictions are averaged over competing models. We compared our method to two alternative approaches: LDPred and lassosum using all seven traits in the Welcome Trust Case Control Consortium as well as meta-GWAS summaries for type 1 diabetes (T1D), coronary artery disease, and schizophrenia. Performance was generally similar across methods, although our framework provided more accurate predictions for T1D, for which there are multiple heterogeneous signals in regions of both short- and long-range LD. With sufficient compute resources, our method also allows the fastest runtimes.
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http://dx.doi.org/10.1002/gepi.22245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764842PMC
October 2019

Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals.

J Am Coll Cardiol 2019 06;73(24):3118-3131

Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.

Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.

Methods: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.

Results: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.

Conclusions: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.
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http://dx.doi.org/10.1016/j.jacc.2019.03.519DOI Listing
June 2019

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Hum Mol Genet 2019 08;28(15):2615-2633

Icelandic Heart Association, Kopavogur, Iceland.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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http://dx.doi.org/10.1093/hmg/ddz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644157PMC
August 2019

Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.

Nat Genet 2019 04 29;51(4):636-648. Epub 2019 Mar 29.

Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
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http://dx.doi.org/10.1038/s41588-019-0378-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467258PMC
April 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
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