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Hägg, Sara
Alternative names
Publications (7 of 7) Show all publications
Bjorkegren, J. L. M., Hägg, S., Talukdar, H. A., Asl, H. F., Jain, R. K., Cedergren, C., . . . Skogsberg, J. (2014). Plasma Cholesterol-Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis. PLOS Genetics, 10(2), e100420
Open this publication in new window or tab >>Plasma Cholesterol-Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis
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2014 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 10, no 2, p. e100420-Article in journal (Refereed) Published
Abstract [en]

Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (>= 80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob(100/100)Mttp(flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions. Author Summary The main underlying cause of heart attacks and strokes is atherosclerosis. One strategy to prevent these often deadly clinical events is therefore either to slow atherosclerosis progression or better, induce regression of atherosclerotic plaques making them more stable. Plasma cholesterol lowering (PCL) is the most efficient way to induce atherosclerosis regression but sometimes fails to do so. In our study, we used a mouse model with elevated LDL cholesterol levels, similar to humans who develop early atherosclerosis, and a genetic switch to lower plasma cholesterol at any time during atherosclerosis progression. In this model, we examined atherosclerosis gene expression and regression in response to PCL at three different stages of atherosclerosis progression. PCL led to complete regression in mice with early lesions but was incomplete in mice with mature and advanced lesions, indicating that early prevention with PCL in individuals with increased risk for heart attack or stroke would be particularly useful. In addition, by inferring PCL-responsive gene networks in early, mature and advanced atherosclerotic lesions, we identified key drivers specific for regression of early (PPARG), mature (MLL5) and advanced (SRSF10/XRN2) atherosclerosis. These key drivers should be interesting therapeutic targets to enhance PCL-mediated regression of atherosclerosis.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-227138 (URN)10.1371/journal.pgen.1004201 (DOI)000332021500024 ()
Funder
Swedish Research Council, 521-2012-2581, 522-2007-5792
Available from: 2014-06-24 Created: 2014-06-24 Last updated: 2017-12-05Bibliographically approved
Gao, H., Hägg, S., Sjögren, P., Lambert, P. C., Ingelsson, E. & van Dam, R. M. (2014). Serum selenium in relation to measures of glucose metabolism and incidence of Type 2 diabetes in an older Swedish population. Diabetic Medicine, 31(7), 787-793
Open this publication in new window or tab >>Serum selenium in relation to measures of glucose metabolism and incidence of Type 2 diabetes in an older Swedish population
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2014 (English)In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 31, no 7, p. 787-793Article in journal (Refereed) Published
Abstract [en]

Aims The relation between selenium status and risk of Type2 diabetes is controversial. We aimed to evaluate associations of serum selenium, a marker of dietary selenium, with measures of glucose metabolism and risk of diabetes. Methods We used data from a population-based, longitudinal cohort of 1925 Swedish men who were 50years old and did not have diabetes at baseline in the 1970s. At baseline, an intravenous glucose tolerance test was performed and, at a follow-up examination after 20years, an oral glucose tolerance test and a hyperinsulinaemic euglycaemic clamp for the assessment of insulin sensitivity were conducted. Results At baseline, the mean (standard deviation) selenium concentration was 75.6 (14.3) g/l. During 20years of follow-up, 88 incident cases of diabetes occurred in 1024 participants with follow-up data. Baseline serum selenium levels were not associated with risk of diabetes (odds ratio1.06; 95%CI 0.83-1.38). Higher selenium levels were associated with lower early insulin response (standardized -0.08; 95%CI -0.14 to -0.03) at baseline after adjusting for potential confounders, but not with any other measures of -cell function or insulin sensitivity at baseline or follow-up. The association with early insulin response was non-significant after taking multiple testing into account. Conclusions Our results do not support a role of dietary selenium in the development of disturbances in glucose metabolism or diabetes in older individuals.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-228532 (URN)10.1111/dme.12429 (DOI)000337621100006 ()
Funder
Swedish Research Council, 2009-2298Swedish Heart Lung Foundation, 20100401Swedish Foundation for Strategic Research , ICA08-0047
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2014-07-17 Created: 2014-07-16 Last updated: 2017-12-05Bibliographically approved
Albrecht, E., Sillanpaa, E., Karrasch, S., Alves, A. C., Codd, V., Hovatta, I., . . . Schulz, H. (2014). Telomere length in circulating leukocytes is associated with lung function and disease. European Respiratory Journal, 43(4), 983-992
Open this publication in new window or tab >>Telomere length in circulating leukocytes is associated with lung function and disease
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2014 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 43, no 4, p. 983-992Article in journal (Refereed) Published
Abstract [en]

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in is (FEV1), forced vital capacity (PVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (beta= -0.0452, p= 0.024) as well as COPD (beta= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07 x 10(-7)), FVC (p=2.07 x 10(-5)), and FEV1/FVC (p =5.27 x 10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-224752 (URN)10.1183/09031936.00046213 (DOI)000334261900013 ()
Available from: 2014-05-20 Created: 2014-05-19 Last updated: 2017-12-05Bibliographically approved
Gao, H., Fall, T., van Dam, R. M., Flyvbjerg, A., Zethelius, B., Ingelsson, E. & Hägg, S. (2013). Evidence of a Causal Relationship Between Adiponectin Levels and Insulin Sensitivity: A Mendelian Randomization Study. Diabetes, 62(4), 1338-1344
Open this publication in new window or tab >>Evidence of a Causal Relationship Between Adiponectin Levels and Insulin Sensitivity: A Mendelian Randomization Study
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2013 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 4, p. 1338-1344Article in journal (Refereed) Published
Abstract [en]

The adipocyte-secreted protein adiponectin is associated with insulin sensitivity in observational studies. We aimed to evaluate whether this relationship is causal using a Mendelian randomization approach. In a sample of Swedish men aged 71 years (n = 942) from the Uppsala Longitudinal Study of Adult Men (ULSAM), insulin sensitivity (M/I ratio) was measured by the euglycemic insulin clamp. We used three genetic variants in the ADIPOQ locus as instrumental variables (IVs) to estimate the potential causal effect of adiponectin on insulin sensitivity and compared these with results from conventional linear regression. The three ADIPOQ variants, rs17300539, rs3774261, and rs6444175, were strongly associated with serum adiponectin levels (all P ≤ 5.3 × 10−9) and were also significantly associated with M/I ratio in the expected direction (all P ≤ 0.022). IV analysis confirmed that genetically determined adiponectin increased insulin sensitivity (β = 0.47–0.81, all P ≤ 0.014) comparable with observational estimates (β = 0.50, all Pdifference ≥ 0.136). Adjustment for BMI and waist circumference partly explained the association of both genetically determined and observed adiponectin levels with insulin sensitivity. The observed association between higher adiponectin levels and increased insulin sensitivity is likely to represent a causal relationship partly mediated by reduced adiposity.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-189285 (URN)10.2337/db12-0935 (DOI)000316526000044 ()23274890 (PubMedID)
Note

De två sista författarna delar sistaförfattarskapet.

Available from: 2013-03-05 Created: 2013-01-01 Last updated: 2017-12-06Bibliographically approved
Rietveld, C. A., Medland, S. E., Derringer, J., Yang, J., Esko, T., Martin, N. W., . . . Koellinger, P. D. (2013). GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment. Science, 340(6139), 1467-1471
Open this publication in new window or tab >>GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment
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2013 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 340, no 6139, p. 1467-1471Article in journal (Refereed) Published
Abstract [en]

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R-2 approximate to 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for approximate to 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-204277 (URN)10.1126/science.1235488 (DOI)000320647000046 ()
Available from: 2013-07-30 Created: 2013-07-29 Last updated: 2017-12-06Bibliographically approved
Lagou, V., Maegi, R., Surakka, I., Sarin, A.-P. -., Horikoshi, M., Thorleifsson, G., . . . Prokopenko, I. (2013). Pleiotropic effects on lipid levels and obesity identified in multi-trait meta-analysis of genome-wide association studies (GWAS) of type 2 diabetes related traits. Paper presented at 49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 23-27, 2013, Barcelona, SPAIN. Diabetologia, 56, S60-S60
Open this publication in new window or tab >>Pleiotropic effects on lipid levels and obesity identified in multi-trait meta-analysis of genome-wide association studies (GWAS) of type 2 diabetes related traits
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2013 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, p. S60-S60Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-218007 (URN)000329196900131 ()
Conference
49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 23-27, 2013, Barcelona, SPAIN
Available from: 2014-02-07 Created: 2014-02-06 Last updated: 2017-12-06Bibliographically approved
Fall, T., Hägg, S., Maegi, R., Ploner, A., Fischer, K., Horikoshi, M., . . . Prokopenko, I. (2013). The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis. PLoS Medicine, 10(6), e1001474
Open this publication in new window or tab >>The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis
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2013 (English)In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 6, p. e1001474-Article in journal (Refereed) Published
Abstract [en]

Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-206759 (URN)10.1371/journal.pmed.1001474 (DOI)000321034800017 ()
Note

De fyra sista författarna delar sistaförfattarskapet.

Available from: 2013-09-04 Created: 2013-09-04 Last updated: 2017-12-06Bibliographically approved
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