ORCID Profile
0000-0003-4508-7990
Current Organisations
Danderyd Hospital
,
Karolinska Institutet
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-05-2019
DOI: 10.1161/CIRCULATIONAHA.118.038908
Abstract: Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. We performed harmonized, de novo, in idual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance–weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15 198 incident cardiovascular events occurred among 68 659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88–0.99), 0.78 (0.70–0.85), and 0.88 (0.79–0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94 0.88–1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92 0.86–0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.
Publisher: Cold Spring Harbor Laboratory
Date: 05-08-2021
DOI: 10.1101/2021.08.03.21261494
Abstract: We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis -instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1016/J.ATHEROSCLEROSIS.2020.01.011
Abstract: 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. 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. 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). 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.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2014
Publisher: Public Library of Science (PLoS)
Date: 06-06-2013
Publisher: Elsevier BV
Date: 03-2012
Publisher: Springer Science and Business Media LLC
Date: 26-04-2017
DOI: 10.1038/NCOMMS14977
Abstract: Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study s le. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-08-2015
Abstract: Plasma adiponectin levels have previously been inversely associated with carotid intima‐media thickness ( IMT ), a marker of subclinical atherosclerosis. In this study, we used a sex‐stratified Mendelian randomization approach to investigate whether adiponectin has a causal protective influence on IMT . Baseline plasma adiponectin concentration was tested for association with baseline IMT , IMT progression over 30 months, and occurrence of cardiovascular events within 3 years in 3430 participants (women, n=1777 men, n=1653) with high cardiovascular risk but no prevalent disease. Plasma adiponectin levels were inversely associated with baseline mean bifurcation IMT after adjustment for established risk factors (β=−0.018, P .001) in men but not in women (β=−0.006, P =0.185 P for interaction=0.061). Adiponectin levels were inversely associated with progression of mean common carotid IMT in men (β=−0.0022, P =0.047), whereas no association was seen in women (0.0007, P =0.475 P for interaction=0.018). Moreover, we observed that adiponectin levels were inversely associated with coronary events in women (hazard ratio 0.57, 95% CI 0.37 to 0.87) but not in men (hazard ratio 0.82, 95% CI 0.54 to 1.25). A gene score of adiponectin‐raising alleles in 6 loci, reported recently in a large multi‐ethnic meta‐analysis, was inversely associated with baseline mean bifurcation IMT in men (β=−0.0008, P =0.004) but not in women (β=−0.0003, P =0.522 P for interaction=0.007). This report provides some evidence for adiponectin protecting against atherosclerosis, with effects being confined to men however, compared with established cardiovascular risk factors, the effect of plasma adiponectin was modest. Further investigation involving mechanistic studies is warranted.
Publisher: Public Library of Science (PLoS)
Date: 29-06-2016
Publisher: Springer Science and Business Media LLC
Date: 12-08-2012
DOI: 10.1038/NG.2385
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-03-2016
Abstract: Coronary heart disease is a tale of two forms of plasma cholesterol. In contrast to the well-established effects of “bad” cholesterol (LDL-C), the role of “good” cholesterol (HDL-C) is mysterious. Elevated HDL-C correlates with a lower risk of heart disease, yet drugs that raise HDL-C levels do not reduce risk. Zanoni et al. found that some people with exceptionally high levels of HDL-C carry a rare sequence variant in the gene encoding the major HDL-C receptor, scavenger receptor BI. This variant destroys the receptor's ability to take up HDL-C. Interestingly, people with this variant have a higher risk of heart disease despite having high levels of HDL-C. Science , this issue p. 1166
Publisher: Public Library of Science (PLoS)
Date: 10-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2020
Publisher: Springer Science and Business Media LLC
Date: 06-10-2013
DOI: 10.1038/NG.2795
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NG.3667
Publisher: Springer Science and Business Media LLC
Date: 09-02-2014
DOI: 10.1038/NG.2897
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14177
Publisher: Springer Science and Business Media LLC
Date: 06-10-2013
DOI: 10.1038/NG.2797
Publisher: Springer Science and Business Media LLC
Date: 11-02-2015
DOI: 10.1038/NATURE14132
No related grants have been discovered for Bruna Gigante.