| 31. |
- Lumbers, R. T., et al.
(författare)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Tidskriftsartikel (refereegranskat)abstract
- 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 x 10(-8) 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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| 32. |
- Manderstedt, Eric, et al.
(författare)
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Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle-aged and older adults: A population-based cohort study
- 2022
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Ingår i: Research and practice in thrombosis and haemostasis. - : Elsevier BV. - 2475-0379. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation. The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population-based cohort of middle-aged and older adults. Methods: The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991–1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequency less than 0.1%. Results: No common variant was associated with VTE. Nine rare variants (two loss-of-function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and ancestry showed a hazard ratio of 2.9 (95% CI, 1.2–7.1) for rare qualifying variants. Conclusion: Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene. © 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).
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| 33. |
- Manderstedt, Eric, et al.
(författare)
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Thrombotic risk determined by rare and common SERPINA1 variants in a population-based cohort study
- 2022
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 20:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case-control study. Objectives: This study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population-based cohort study. Patients/Methods: The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Individuals were followed from baseline until the first event of VTE, death, or 2018. Results: Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss-of-function variant. Kaplan-Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty-one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non-benign (PolyPhen-2) missense variants with minor allele frequency (MAF)
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| 34. |
- Mishra, Rajashree, et al.
(författare)
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Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC
- 2020
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 43:2, s. 418-425
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.
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| 35. |
- Ngo, D., et al.
(författare)
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Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk
- 2021
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Ingår i: Jci Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:5
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in proteomic technologies have made high-throughput profiling of low-abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across 2 large longitudinal cohorts (n = 2839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic, and clinical data from humans to nominate 1 specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Furthermore, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz, and NTR domain-containing protein 2 (WFIKKN2) was, in turn, associated with fasting glucose, hemoglobin A1c, and HOMA-IR measurements in humans. In addition to identifying potentially novel disease markers and pathways in T2DM, we provide publicly available data to be leveraged for insights about gene function and disease pathogenesis in the context of human metabolism.
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| 36. |
- Praveen, K., et al.
(författare)
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ANGPTL7, a therapeutic target for increased intraocular pressure and glaucoma
- 2022
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma. © 2022. The Author(s).
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| 37. |
- Sahlin, DANIEL, et al.
(författare)
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Self-care Management Intervention in Heart Failure (SMART-HF) : A Multicenter Randomized Controlled Trial
- 2022
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Ingår i: Journal of Cardiac Failure. - : Elsevier BV. - 1071-9164. ; 28:1, s. 3-12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Self-care behavior is important in avoiding hospitalization for patients with heart failure (HF) and refers to those activities performed with the intention of improving or restoring health and well-being, as well as treating or preventing disease. The purpose was to study the effects of a home-based mobile device on self-care behavior and hospitalizations in a representative HF-population. Methods and Results: SMART-HF is a randomized controlled multicenter clinical trial, where patients were randomized 1:1 to receive standard care (control group [CG]) or intervention with a home-based tool designed to enhance self-care behavior (intervention group [IG]) and followed for 240 days. The tool educates the patient about HF, monitors objective and subjective symptoms and adjusts loop diuretics. The primary outcome is self-care as measured by the European Heart Failure Self-care behavior scale and the secondary outcome is HF related in-hospital days.A total of 124 patients were recruited and 118 were included in the analyses (CG: n = 60, IG: n = 58). The mean age was 79 years, 39% were female, and 45% had an ejection fraction of less than 40%. Self-care was significantly improved in the IG compared to the CG (median (interquartile range) (21.5 [13.25; 28] vs 26 [18; 29.75], p = 0.014). Patients in the IG spent significantly less time in the hospital admitted for HF (2.2 days less, relative risk 0.48, 95% confidence interval 0.32–0.74, P = .001). Conclusions: The device significantly improved self-care behavior and reduced in-hospital days in a relevant HF population.
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| 38. |
- Vissers, L.E.T., et al.
(författare)
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Milk intake and incident stroke and coronary heart disease in populations of European descent : a mendelian randomization study
- 2022
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Ingår i: British Journal of Nutrition. - : Cambridge University Press. - 0007-1145 .- 1475-2662. ; 128:9, s. 1789-1797
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Tidskriftsartikel (refereegranskat)abstract
- Higher milk intake has been associated with a lower stroke risk, but not with risk of coronary heart disease (CHD). Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29,328 participants (4,611 stroke; 9,828 CHD) of the EPIC-CVD (8 European countries) and EPIC-NL case-cohort studies. rs4988235, a lactase persistence (LP) single nucleotide polymorphism which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777,024 participants (50,804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483,966 participants (61,612 cases) from CARDIoGRAM, UK Biobank and EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (β=13.7 g/day; 95%CI: 8.4-19.1) and EPIC-NL (36.8 g/day; 20.0-53.5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/day 1.05; 95%CI: 0.94-1.16) or CHD (1.02; 0.96-1.08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (odds ratios 1.02; 0.99-1.05) or CHD (0.99; 0.95-1.03). Current Mendelian Randomization analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.
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| 39. |
- Wessman, T., et al.
(författare)
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Myocardial injury defined as elevated high-sensitivity cardiac troponin T is associated with higher mortality in patients seeking care at emergency departments with acute dyspnea
- 2023
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Ingår i: BMC Emergency Medicine. - 1471-227X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Elevated levels of cardiac troponin T has been observed in patients seeking care at the emergency department (ED) presenting with chest pain but without myocardial infarction (MI). The clinical importance of this observation remains, however, still unclear. Our main aim was to study the role of cardiac troponin T in patients admitted to the emergency department with acute dyspnea, a group of patients with a high cardiovascular comorbidity, but no primary acute MI. Population and methods: Patients from the age of 18 seeking care at the ED for dyspnea, without an acute cardiac syndrome, and with a recorded assessment of high-sensitivity cardiac troponin T (hs-cTnT), were included (n = 1001). Patients were categorized into 3 groups by hs-cTnT level, i.e. <15, 15–100 and > 100 µg/l. Cox regression with Hazard Ratios (HRs) and 95% Confidence Intervals (CI) for 3-months mortality was performed, with adjustment for sex, age, respiratory frequency, saturation, CHF, renal disease, and BMI. Results: Fully adjusted HRs (95% CI) for 3-month mortality, with hs-cTnT < 15 µg/l as reference level, showed for hs-cTnT 15–100 a HR of 3.682 (1.729–7.844), and for hs-cTnT > 100 a HR of 10.523 (4.465–24.803). Conclusion: Elevated hs-cTnT seems to be a relevant marker of poor prognosis in patients with acute dyspnea without MI and warrants further validation and clinical testing.
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| 40. |
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