| 1. |
- Folkersen, Lasse, et al.
(author)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Journal article (peer-reviewed)abstract
- 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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| 2. |
- Lind, Lars, et al.
(author)
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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
- 2020
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In: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 295, s. 25-30
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Journal article (peer-reviewed)abstract
- 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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| 3. |
- Borné, Yan, et al.
(author)
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Biomarkers of blood cadmium and incidence of cardiovascular events in non-smokers: results from a population-based proteomics study
- 2019
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In: Clinical Proteomics. - : Springer Science and Business Media LLC. - 1542-6416 .- 1559-0275. ; 16:21
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Journal article (peer-reviewed)abstract
- BackgroundCadmium is a toxic metal with multiple adverse health effects, including risk of cardiovascular disease (CVD). The mechanistic link between cadmium and CVD is unclear. Our aim was to examine the associations between blood cadmium (B-Cd) and 88 potential protein biomarkers of CVD.MethodsB-Cd and 88 plasma proteins were measured in a community-based prospective cohort, the Malmo Diet and Cancer study. The primary analysis was performed in never smokers (n=1725). Multiple linear regression was used with adjustments for age and sex, and correction for multiple comparisons using the false discovery rate method. Proteins significantly associated with B-Cd were replicated in long-term former smokers (n=782). Significant proteins were then studied in relation to incidence of CVD (i.e., coronary events or ischemic stroke) in never smokers.ResultsFifteen proteins were associated with B-Cd in never smokers. Eight of them were replicated in long-term former smokers. Kidney injury molecule-1, fibroblast growth factor-23 (FGF23), tumor necrosis factor receptor-2, matrix metalloproteinase-12, cathepsin L1, urokinase plasminogen activator receptor, C-C motif chemokine-3 (CCL3), and chemokine (C-X3-C motif) ligand-1 were associated with B-Cd both in never smokers and long-term former smokers. Except for CCL3 and FGF23, these proteins were also significantly associated with incidence of CVD.ConclusionsB-Cd in non-smokers was associated with eight potential plasma biomarkers of CVD and kidney injury. The results suggest pathways for the associations between B-Cd and CVD and kidney injury.
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| 4. |
- Gränsbo, Klas, et al.
(author)
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Cardiovascular and Cancer Mortality in Very Elderly Post-Myocardial Infarction Patients Receiving Statin Treatment
- 2010
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 55:13, s. 1362-1369
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Journal article (peer-reviewed)abstract
- Objectives The purpose of this study was to determine whether statin treatment is effective and safe in very elderly (80 years and older) acute myocardial infarction (AMI) patients. Background Elderly individuals constitute an increasing percentage of patients admitted to hospitals for AMI. Despite that these patients have a higher mortality risk, the application of evidence-based medicine remains much lower than for younger patients. Methods We included all patients 80 years and older who were admitted with the diagnosis of AMI in the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions between 1999 and 2003 (n = 21,410). Of these, complete covariate and follow-up data were available for 14,907 patients (study population A). To limit the bias related comorbidity on statin therapy, we also performed analyses excluding patients who died within 14 days of the acute event (study population B) and all patients who died within 365 days (study population C). A propensity score was used to adjust for initial differences between treatment groups. Results All-cause mortality was significantly lower in patients receiving statin treatment at discharge in study population A (relative risk: 0.55, 95% confidence interval: 0.51 to 0.59), in study population B (relative risk: 0.65; 95% confidence interval: 0.60 to 0.71), and in study population C (relative risk: 0.66; 95% confidence interval: 0.59 to 0.76). Similar observations were made for cardiovascular mortality as well as for AMI mortality. There was no increase in cancer mortality in statin-treated patients. Conclusions Statin treatment is associated with lower cardiovascular mortality in very elderly post-infarction patients without increasing the risk of the development of cancer.
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| 5. |
- Sveen, Kari Anne, et al.
(author)
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High levels of autoantibodies against apoB100 p210 are associated with lower incidence of atrial fibrillation in women
- 2022
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In: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 291:2, s. 207-217
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Journal article (peer-reviewed)abstract
- Background and objectives Atrial fibrillation (AF) is associated with inflammation systemically and in the atrial tissue. Oxidized low-density lipoprotein (LDL) is increased in patients with AF and is suggested to be one of the molecules that drives inflammation. Autoantibodies against oxidized LDL and apolipoprotein B100, the protein component of LDL, are linked to atherosclerotic disease. However, whether these autoantibodies are associated with occurrence of AF is not known. We investigated autoantibodies against oxidized apolipoprotein B100 peptides and incidence of AF in a large population-based cohort. Methods IgM and IgG against native and aldehyde-modified apoB100 peptides 210 (p210) and 45 were analyzed by enzyme-linked immunosorbent assay (ELISA) in 5169 individuals from the Malmo Diet and Cancer cohort. Results Seven hundred sixty-nine incident AF cases were recorded during a follow-up of 21.3 years. Individuals with high levels of IgM against native p210 at baseline had a lower risk to develop AF; however, the association did not remain after adjustment for age and sex. Women had higher levels of IgM against native p210 than men (0.70 +/- 0.22 AU vs. 0.63 +/- 0.21 AU, p < 0.001). The association of IgM against native p210 and AF was significantly different between sexes (p for interaction = 0.024), where females with high IgM against p210 had a lower risk for incidence of AF (hazard ratio [95% confidence interval] 4th versus 1st quartile: 0.67 [0.49-0.91]; p = 0.01) after adjusting for risk factors and comorbidities. Conclusion These findings support an association of humoral autoimmunity with AF.
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| 6. |
- Velasquez, Ilais Moreno, et al.
(author)
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Duffy antigen receptor genetic variant and the association with Interleukin 8 levels
- 2015
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In: Cytokine. - : Elsevier BV. - 1043-4666 .- 1096-0023. ; 72:2, s. 178-184
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Journal article (peer-reviewed)abstract
- The aim of this study is to identify loci associated with circulating levels of Interleukin 8 (IL8). We investigated the associations of 121,445 single nucleotide polymorphisms (SNPs) from the Illumina 200K CardioMetabochip with IL8 levels in 1077 controls from the Stockholm Heart Epidemiology Program (SHEEP) study, using linear regression under an additive model of inheritance. Five SNPs (rs12075A/G, rs13179413C/T, rs6907989T/A, rs9352745A/C, rs1779553T/C) reached the predefined threshold of genome-wide significance (p < 1.0 x 10(-5)) and were tested for in silico replication in three independent populations, derived from the PIVUS, MDC-CC and SCARF studies. IL8 was measured in serum (SHEEP, PIVUS) and plasma (MDC-CC, SCARF). The strongest association was found with the SNP rs12075 A/G, Asp42Gly (p = 1.6 x 10(-6)), mapping to the Duffy antigen receptor for chemokines (DARC) gene on chromosome 1. The minor allele G was associated with 15.6% and 10.4% reduction in serum IL8 per copy of the allele in SHEEP and PIVUS studies respectively. No association was observed between rs12075 and plasma IL8. Conclusion: rs12075 was associated with serum levels but not with plasma levels of IL8. It is likely that serum IL8 represents the combination of levels of circulating plasma IL8 and additional chemokine liberated from the erythrocyte DARC reservoir due to clotting. These findings highlight the importance of understanding ILS as a biomarker in cardiometabolic diseases.
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| 7. |
- Brunkwall, Louise, et al.
(author)
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The Malmö Offspring Study (MOS) : design, methods and first results.
- 2021
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In: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284. ; 36, s. 103-116
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Journal article (peer-reviewed)abstract
- As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18-71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms.
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| 8. |
- Drake, Isabel, et al.
(author)
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Methodological considerations for identifying multiple plasma proteins associated with all-cause mortality in a population-based prospective cohort
- 2021
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Journal article (peer-reviewed)abstract
- Novel methods to characterize the plasma proteome has made it possible to examine a wide range of proteins in large longitudinal cohort studies, but the complexity of the human proteome makes it difficult to identify robust protein-disease associations. Nevertheless, identification of individuals at high risk of early mortality is a central issue in clinical decision making and novel biomarkers may be useful to improve risk stratification. With adjustment for established risk factors, we examined the associations between 138 plasma proteins measured using two proximity extension assays and long-term risk of all-cause mortality in 3,918 participants of the population-based Malmö Diet and Cancer Study. To examine the reproducibility of protein-mortality associations we used a two-step random-split approach to simulate a discovery and replication cohort and conducted analyses using four different methods: Cox regression, stepwise Cox regression, Lasso-Cox regression, and random survival forest (RSF). In the total study population, we identified eight proteins that associated with all-cause mortality after adjustment for established risk factors and with Bonferroni correction for multiple testing. In the two-step analyses, the number of proteins selected for model inclusion in both random samples ranged from 6 to 21 depending on the method used. However, only three proteins were consistently included in both samples across all four methods (growth/differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide, and epididymal secretory protein E4). Using the total study population, the C-statistic for a model including established risk factors was 0.7222 and increased to 0.7284 with inclusion of the most predictive protein (GDF-15; P < 0.0001). All multiple protein models showed additional improvement in the C-statistic compared to the single protein model (all P < 0.0001). We identified several plasma proteins associated with increased risk of all-cause mortality independently of established risk factors. Further investigation into the putatively causal role of these proteins for longevity is needed. In addition, the examined methods for identifying multiple proteins showed tendencies for overfitting by including several putatively false positive findings. Thus, the reproducibility of findings using such approaches may be limited.
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| 9. |
- Fernandez, Celine, et al.
(author)
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Circulating protein biomarkers predict incident hypertensive heart failure independently of N-terminal pro-B-type natriuretic peptide levels
- 2020
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In: ESC Heart Failure. - : Wiley. - 2055-5822. ; 7:4, s. 1891-1899
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Journal article (peer-reviewed)abstract
- Aims: Hypertension is the leading cause for the development of heart failure (HF). Here, we aimed to identify cardiomyocyte stretch-induced circulating biomarkers for predicting hypertension-associated HF. Methods and results: Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4742 individuals from the Malmö Diet and Cancer study. Protein levels were compared with stretch-activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVMs) in response to 1–48 h of mechanical stretch. We also studied the association between protein levels and hypertension and HF incidence using respectively binary logistic and Cox regressions. Levels of 35 proteins were differentially expressed after Bonferroni correction in incident HF vs. control (P < 3.4E−4). Growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), IL-1 receptor type 1, and urokinase plasminogen activator surface receptor had corresponding mRNA levels up-regulated by stretch in NRVMs at all time points (P < 0.05). These four proteins were individually associated with increased risk of HF after age and sex adjustment [hazard ratio (HR) per standard deviation: 1.19 ≤ HR ≤ 1.49, P ≤ 4.90E−3]. GDF-15 and IL-6 were associated with HF independently of each other (1.22 ≤ HR ≤ 1.33, P ≤ 0.001). In subjects with hypertension, these associations remained significant after further adjustment for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (1.23 ≤ HR ≤ 1.45, P ≤ 0.001). A higher fasting value of a GDF-15, IL-6 score aggregate was associated with increased risk of hypertensive HF after adjustment for all traditional risk factors for HF and NT-proBNP (HR = 1.31, P = 2.19E−4). Conclusions: Cardiomyocyte mRNA levels of GDF-15 and IL-6 are consistently up-regulated by stretch, and their circulating protein levels predict HF in hypertensive subjects independently of NT-proBNP during long-term follow-up. Our results encourage further studies on lower blood pressure goals in hypertensive subjects with high GDF-15 and IL-6, and interventions targeted at stretch-induced cardiomyocyte expressed biomarkers.
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| 10. |
- Svensson, Thomas, et al.
(author)
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Very short sleep duration reveals a proteomic fingerprint that is selectively associated with incident diabetes mellitus but not with incident coronary heart disease : a cohort study
- 2024
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In: BMC Medicine. - 1741-7015. ; 22:1
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Journal article (peer-reviewed)abstract
- Background: The molecular pathways linking short and long sleep duration with incident diabetes mellitus (iDM) and incident coronary heart disease (iCHD) are not known. We aimed to identify circulating protein patterns associated with sleep duration and test their impact on incident cardiometabolic disease. Methods: We assessed sleep duration and measured 78 plasma proteins among 3336 participants aged 46–68 years, free from DM and CHD at baseline, and identified cases of iDM and iCHD using national registers. Incident events occurring in the first 3 years of follow-up were excluded from analyses. Tenfold cross-fit partialing-out lasso logistic regression adjusted for age and sex was used to identify proteins that significantly predicted sleep duration quintiles when compared with the referent quintile 3 (Q3). Predictive proteins were weighted and combined into proteomic scores (PS) for sleep duration Q1, Q2, Q4, and Q5. Combinations of PS were included in a linear regression model to identify the best predictors of habitual sleep duration. Cox proportional hazards regression models with sleep duration quintiles and sleep-predictive PS as the main exposures were related to iDM and iCHD after adjustment for known covariates. Results: Sixteen unique proteomic markers, predominantly reflecting inflammation and apoptosis, predicted sleep duration quintiles. The combination of PSQ1 and PSQ5 best predicted sleep duration. Mean follow-up times for iDM (n = 522) and iCHD (n = 411) were 21.8 and 22.4 years, respectively. Compared with sleep duration Q3, all sleep duration quintiles were positively and significantly associated with iDM. Only sleep duration Q1 was positively and significantly associated with iCHD. Inclusion of PSQ1 and PSQ5 abrogated the association between sleep duration Q1 and iDM. Moreover, PSQ1 was significantly associated with iDM (HR = 1.27, 95% CI: 1.06–1.53). PSQ1 and PSQ5 were not associated with iCHD and did not markedly attenuate the association between sleep duration Q1 with iCHD. Conclusions: We here identify plasma proteomic fingerprints of sleep duration and suggest that PSQ1 could explain the association between very short sleep duration and incident DM.
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