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Sökning: WFRF:(Baras Aris)

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  • Akbari, Parsa, et al. (författare)
  • Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity
  • 2021
  • Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075. ; 373:6550
  • Tidskriftsartikel (refereegranskat)abstract
    • Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ∼4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.
  • Shah, Sonia, et al. (författare)
  • Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
  • 2020
  • Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723 .- 2041-1723. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
  • Bowman, Louise, et al. (författare)
  • Understanding the use of observational and randomized data in cardiovascular medicine
  • 2020
  • Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 41:27, s. 2571-2578
  • Tidskriftsartikel (refereegranskat)abstract
    • The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called 'real-world', and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular disease.
  • Damask, Amy, et al. (författare)
  • Patients with High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit from Alirocumab Treatment in the Odyssey Outcomes Trial
  • 2020
  • Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 141:8, s. 624-636
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Alirocumab, an antibody that blocks proprotein convertase subtilisin/kexin type 9 (PCSK9), was associated with reduced major adverse cardiovascular events (MACE) and death in the ODYSSEY OUTCOMES trial. In this study, higher baseline LDL cholesterol (LDL-C) levels predicted greater benefit from alirocumab treatment. Recent studies indicate high polygenic risk scores (PRS) for coronary artery disease (CAD) identify individuals at higher risk who derive increased benefit from statins. Herein we perform post hoc analyses to determine whether high PRS for CAD identifies higher-risk individuals, independently from baseline LDLC and other known risk factors, who might derive greater benefit from alirocumab treatment. Methods: ODYSSEY OUTCOMES was a randomized, double-blind, placebo-controlled trial comparing alirocumab or placebo in 18,924 patients with acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin treatment. The primary endpoint (MACE) comprised death from CAD, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. A genome-wide PRS for CAD comprising 6,579,025 genetic variants was evaluated in 11,953 patients with available DNA samples. Analysis of MACE risk was performed in placebo treated patients while treatment benefit analysis was performed in all patients. Results: The incidence of MACE in the placebo group was related to PRS for CAD: 17.0% for high PRS patients (>90th percentile) and 11.4% for lower PRS patients (≤90th percentile) (p<0.001); this PRS relationship was not explained by baseline LDL-C or other established risk factors. Both the absolute and relative reduction of MACE by alirocumab compared to placebo was greater in high versus low PRS patients. There was an absolute reduction by alirocumab in high versus low PRS groups of 6.0% and 1.5%, respectively, and relative risk reduction by alirocumab of 37% in the high PRS group (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.46-0.86; p = 0.004) versus 13% reduction in the low PRS group (HR 0.87; 95% CI 0.78-0.98; p=0.022; interaction p = 0.04). Conclusions: A high PRS for CAD is associated with elevated risk for recurrent MACE after ACS, and larger absolute and relative risk reduction with alirocumab treatment, providing an independent tool for risk stratification and precision medicine.
  • Dwivedi, Om Prakash, et al. (författare)
  • Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
  • 2019
  • Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036. ; , s. 1-22
  • Tidskriftsartikel (refereegranskat)abstract
    • A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.
  • Giontella, Alice, et al. (författare)
  • Causal effect of adiposity measures on blood pressure traits in 2 urban swedish cohorts : A mendelian randomization study
  • 2021
  • Ingår i: Journal of the American Heart Association. - : Wiley-Blackwell. - 2047-9980. ; 10:13
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Different adiposity traits may be causally related to hypertension in different ways. By using genetic variants as randomly allocated proxies for studying the effect of modifying adiposity traits, the Mendelian randomization approach can be used to investigate this. METHODS AND RESULTS: In this study, we used 4 different genetic risk scores (GRS; GRS-BMI 565, GRS-WHR 324, GRS-VAT 208, GRS-BF 81) including hundreds of single nucleotide polymorphisms associated with body mass index, waist-to-hip ratio, visceral adipose tissue, and body fat, respectively. These were applied as instrumental variables in Mendelian randomization analyses. Two Swedish urban-based cohort studies, the Malmö Diet and Cancer, and the Malmö Preventive Projects were used to obtain genetic association estimates with blood pressure (BP). In both the Malmö Preventive Projects and Malmö Diet and Cancer studies, except for that for body fat, all of the genetic risk scores were significantly associated with systolic BP and diastolic BP, but with different magnitudes. In particular, in both cohorts, each standard deviation increase in the genetic risk score made up by the 324 single nucleotide polymorphisms associated with waist-to-hip ratio was associated with doubling of the likelihood of hypertension prevalence at baseline. However, only the genetic risk score made up by the 565 SNPs associated with body mass index was significantly associated with hypertension incidence during 23.6±4.3 years of follow-up in the Malmö Preventive Project. CONCLUSIONS: We support a causal link between genetically mediated adiposity, especially waist-to-hip ratio and body mass index, and BP traits including hypertension prevalence and, for the first time to our knowledge, hypertension incidence. The differences in magnitude between these associations might suggest different mechanisms by which different adiposity affects BP/hypertension and consequently may indicate that tailored interventions are needed to reduce cardiovascular risk.
  • Giontella, Alice, et al. (författare)
  • Clinical Evaluation of the Polygenetic Background of Blood Pressure in the Population-Based Setting
  • 2020
  • Ingår i: Hypertension. - : Lippincott Williams & Wilkins. - 0194-911X. ; , s. 169-177
  • Tidskriftsartikel (refereegranskat)abstract
    • The clinical value of the polygenetic component of blood pressure (BP) is commonly questioned. We evaluated a genetic risk score for BP (BP-GRS858), based on the most recently published genome-wide association studies variants that were significantly associated with either systolic BP or diastolic BP, for prediction of hypertension and cardiovascular end points. The genotyping was performed in 2 urban-based prospective cohorts: the Malmö Diet and Cancer (n=29 295) and the Malmö Preventive Project (n=9367) and a weighted BP-GRS858based on 858 SNPs was calculated. At baseline, we found a difference of 9.0 mm Hg (systolic BP) and 4.8 mm Hg (diastolic BP) between the top and the bottom quartile of BP-GRS858. In Malmö Preventive Project, the top versus bottom quartile of BP-GRS858was associated with a doubled risk of incident hypertension (odds ratio, 2.05 [95% CI, 1.75-2.39], P=1.4×10-21), a risk higher than that of body mass index, as evaluated in quartiles. In Malmö Diet and Cancer, significant association was found between the age and sex-adjusted BP-GRS858and the incidence of total cardiovascular events, stroke, coronary artery disease, heart failure, atrial fibrillation, and total mortality. Most of these associations remained significant after adjusting for traditional risk factors, including hypertension. BP-GRS858could contribute predictive information regarding future hypertension, with an effect size comparable to other well-known risk factors such as obesity, and predicts cardiovascular events. Given that the exposure to high polygenetic risk starts at birth, we suggest that the BP-GRS858might be useful to identify children or adolescents who would benefit from early hypertension screening and treatment.
  • Graham, Sarah E, et al. (författare)
  • The power of genetic diversity in genome-wide association studies of lipids.
  • 2021
  • Ingår i: Nature. - : Nature Publishing Group. - 1476-4687 .- 0028-0836. ; 600:7890, s. 675-679
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.
  • Gusarova, Viktoria, et al. (författare)
  • Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes
  • 2018
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9, s. 1-11
  • Tidskriftsartikel (refereegranskat)abstract
    • Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.
  • Hindy, George, et al. (författare)
  • Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease
  • 2020
  • Ingår i: Arteriosclerosis, Thrombosis, and Vascular Biology. - : Lippincott Williams & Wilkins. - 1524-4636. ; 40:11, s. 2738-2746
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPSCAD) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPSCAD in 28 556 middle-aged participants of the Malmö Diet and Cancer Study, of whom 4122 (14.4%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16% for those in the lowest GPSCAD decile to 48% in the highest. We evaluated the discriminative capacity of the GPSCAD-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPSCAD (+0.045, P<0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPSCAD and 10-year risk defined by the PCE (r=0.03), and addition of GPSCAD improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPSCAD, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank. CONCLUSIONS: GPSCAD-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPSCAD may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.
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