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Lind, L., Salihovic, S., Ganna, A., Sundström, J., Broeckling, C. D., Magnusson, P. K., . . . Arnlov, J. (2020). A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke. Journal of Stroke & Cerebrovascular Diseases, 29(2), Article ID 104476.
Open this publication in new window or tab >>A Multi-Cohort Metabolomics Analysis Discloses Sphingomyelin (32:1) Levels to be Inversely Related to Incident Ischemic Stroke
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2020 (English)In: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 29, no 2, article id 104476Article in journal (Refereed) Published
Abstract [en]

Background and Purpose:

To search for novel pathophysiological pathways related to ischemic stroke using a metabolomics approach.

Methods:

We identified 204 metabolites in plasma by liquid chromatography mass spectrometry in 3 independent population-based samples (TwinGene, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) and Uppsala Longitudinal Study of Adult Men). TwinGene was used for discovery and the other 2 samples were meta-analyzed as replication. In PIVUS, traditional cardiovascular (CV) risk factors, multiple markers of subclinical CV disease, markers of coagulation/fibrinolysis were measured and analyzed in relation to top metabolites.

Results:

In TwinGene (177 incident cases, median follow-up 4.3 years), levels of 28 metabolites were associated with incident ischemic stroke at a false discover rate (FDR) of 5%. In the replication (together 194 incident cases, follow-up 10 and 12 years, respectively), only sphingomyelin (32:1) was significantly associated (HR.69 per SD change, 95% CI.57-0.83, P value = .00014; FDR <5%) when adjusted for systolic blood pressure, diabetes, smoking, low density lipoportein (LDL)- and high density lipoprotein (HDL), body mass index (BMI) and atrial fibrillation. In PIVUS, sphingomyelin (32:1) levels were significantly related to both LDL- and HDL-cholesterol in a positive fashion, and to serum triglycerides, BMI and diabetes in a negative fashion. Furthermore, sphingomyelin (32:1) levels were related to vasodilation in the forearm resistance vessels, and inversely to leukocyte count (P < .0069 and .0026, respectively).

Conclusions:

An inverse relationship between sphingomyelin (32:1) and incident ischemic stroke was identified, replicated, and characterized. A possible protective role for sphingomyelins in stroke development has to be further investigated in additional experimental and clinical studies.

Keywords
Epidemiology, metabolomics, stroke, risk factor
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-402618 (URN)10.1016/j.jstrokecerebrovasdis.2019.104476 (DOI)000505793800001 ()31806450 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2020-01-17 Created: 2020-01-17 Last updated: 2020-01-17Bibliographically approved
Carlsson, A. C., Nowak, C., Lind, L., Ostgren, C. J., Nystrom, F. H., Sundström, J., . . . Arnlov, J. (2020). Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach. Upsala Journal of Medical Sciences, 125(1), 37-43
Open this publication in new window or tab >>Growth differentiation factor 15 (GDF-15) is a potential biomarker of both diabetic kidney disease and future cardiovascular events in cohorts of individuals with type 2 diabetes: a proteomics approach
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2020 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 125, no 1, p. 37-43Article in journal (Refereed) Published
Abstract [en]

Background: Diabetic kidney disease (DKD) is a leading risk factor for end-stage renal disease and is one of the most important risk factors for cardiovascular disease in patients with diabetes. It is possible that novel markers portraying the pathophysiological underpinning processes may be useful. Aim: To investigate the associations between 80 circulating proteins, measured by a proximity extension assay, and prevalent DKD and major adverse cardiovascular events (MACE) in type 2 diabetes. Methods: We randomly divided individuals with type 2 diabetes from three cohorts into a two-thirds discovery and one-third replication set (total n = 813, of whom 231 had DKD defined by estimated glomerular filtration rate <60 mg/mL/1.73 m(2) and/or urinary albumin-creatinine ratio >= 3 g/mol). Proteins associated with DKD were also assessed as predictors for incident major adverse cardiovascular events (MACE) in persons with DKD at baseline. Results: Four proteins were positively associated with DKD in models adjusted for age, sex, cardiovascular risk factors, glucose control, and diabetes medication: kidney injury molecule-1 (KIM-1, odds ratio [OR] per standard deviation increment, 1.65, 95% confidence interval [CI] 1.27-2.14); growth differentiation factor 15 (GDF-15, OR 1.40, 95% CI 1.16-1.69); myoglobin (OR 1.57, 95% CI 1.30-1.91), and matrix metalloproteinase 10 (MMP-10, OR 1.43, 95% CI 1.17-1.74). In patients with DKD, GDF-15 was significantly associated with increased risk of MACE after adjustments for baseline age, sex, microalbuminuria, and kidney function and (59 MACE events during 7 years follow-up, hazard ratio per standard deviation increase 1.43 [95% CI 1.03-1.98]) but not after further adjustments for cardiovascular risk factors. Conclusion: Our proteomics approach confirms and extends previous associations of higher circulating levels of GDF-15 with both micro- and macrovascular disease in patients with type 2 diabetes. Our data encourage additional studies evaluating the clinical utility of our findings.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2020
Keywords
Albumin-creatinine ratio, biomarker, diabetic kidney disease, glomerular filtration rate, proteomics, risk factor, type 2 diabetes mellitus
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-408223 (URN)10.1080/03009734.2019.1696430 (DOI)000501063900001 ()31805809 (PubMedID)
Available from: 2020-04-06 Created: 2020-04-06 Last updated: 2020-04-06Bibliographically approved
Velders, M. A., Calais, F., Dahle, N., Fall, T., Hagström, E., Leppert, J., . . . Hedberg, P. (2019). Cathepsin D improves the prediction of undetected diabetes in patients with myocardial infarction. Upsala Journal of Medical Sciences, 124(3), 187-192
Open this publication in new window or tab >>Cathepsin D improves the prediction of undetected diabetes in patients with myocardial infarction
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2019 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 3, p. 187-192Article in journal (Refereed) Published
Abstract [en]

Background: Newer therapeutic agents for type 2 diabetes mellitus can improve cardiovascular outcomes, but diabetes remains underdiagnosed in patients with myocardial infarction (MI). We sought to identify proteomic markers of undetected dysglycaemia (impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus) to improve the identification of patients at highest risk for diabetes.

Materials and methods: In this prospective cohort, 626 patients without known diabetes underwent oral glucose tolerance testing (OGTT) during admission for MI. Proximity extension assay was used to measure 81 biomarkers. Multivariable logistic regression, adjusting for risk factors, was used to evaluate the association of biomarkers with dysglycaemia. Subsequently, lasso regression was performed in a 2/3 training set to identify proteomic biomarkers with prognostic value for dysglycaemia, when added to risk factors, fasting plasma glucose, and glycated haemoglobin A1c. Determination of discriminatory ability was performed in a 1/3 test set.

Results: In total, 401/626 patients (64.1%) met the criteria for dysglycaemia. Using multivariable logistic regression, cathepsin D had the strongest association with dysglycaemia. Lasso regression selected seven markers, including cathepsin D, that improved prediction of dysglycaemia (area under the receiver operator curve [AUC] 0.848 increased to 0.863). In patients with normal fasting plasma glucose, only cathepsin D was selected (AUC 0.699 increased to 0.704).

Conclusions: Newly detected dysglycaemia, including manifest diabetes, is common in patients with acute MI. Cathepsin D improved the prediction of dysglycaemia, which may be helpful in the a priori risk determination of diabetes as a motivation for confirmatory OGTT.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2019
Keywords
Acute myocardial infarction, biomarkers, diabetes mellitus, proteomics
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-396110 (URN)10.1080/03009734.2019.1650141 (DOI)000482489400001 ()31429631 (PubMedID)
Available from: 2019-11-01 Created: 2019-11-01 Last updated: 2019-11-01Bibliographically approved
Feldreich, T., Nowak, C., Fall, T., Carlsson, A. C., Carrero, J.-J., Ripsweden, J., . . . Arnlov, J. (2019). Circulating proteins as predictors of cardiovascular mortality in end-stage renal disease. JN. Journal of Nephrology (Milano. 1992), 32(1), 111-119
Open this publication in new window or tab >>Circulating proteins as predictors of cardiovascular mortality in end-stage renal disease
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2019 (English)In: JN. Journal of Nephrology (Milano. 1992), ISSN 1121-8428, E-ISSN 1724-6059, Vol. 32, no 1, p. 111-119Article in journal (Refereed) Published
Abstract [en]

Proteomic profiling of end-stage renal disease (ESRD) patients could lead to improved risk prediction and novel insights into cardiovascular disease mechanisms. Plasma levels of 92 cardiovascular disease-associated proteins were assessed by proximity extension assay (Proseek Multiplex CVD-1, Olink Bioscience, Uppsala, Sweden) in a discovery cohort of dialysis patients, the Mapping of Inflammatory Markers in Chronic Kidney disease cohort [MIMICK; n=183, 55% women, mean age 63years, 46 cardiovascular deaths during follow-up (mean 43months)]. Significant results were replicated in the incident and prevalent hemodialysis arm of the Salford Kidney Study [SKS dialysis study, n=186, 73% women, mean age 62years, 45 cardiovascular deaths during follow-up (mean 12months)], and in the CKD5-LD-RTxcohort with assessments of coronary artery calcium (CAC)-score by cardiac computed tomography (n=89, 37% women, mean age 46years).

Results

In age and sex-adjusted Cox regression in MIMICK, 11 plasma proteins were nominally associated with cardiovascular mortality (in order of significance: Kidney injury molecule-1 (KIM-1), Matrix metalloproteinase-7, Tumour necrosis factor receptor 2, Interleukin-6, Matrix metalloproteinase-1, Brain-natriuretic peptide, ST2 protein, Hepatocyte growth factor, TNF-related apoptosis inducing ligand receptor-2, Spondin-1, and Fibroblast growth factor 25). Only plasma KIM-1 was associated with cardiovascular mortality after correction for multiple testing, but also after adjustment for dialysis vintage, cardiovascular risk factors and inflammation (hazard ratio) per standard deviation (SD) increase 1.84, 95% CI 1.26-2.69, p=0.002. Addition of KIM-1, or nine of the most informative proteins to an established risk-score (modified AROii CVM-score) improved discrimination of cardiovascular mortality risk from C=0.777 to C=0.799 and C=0.823, respectively. In the SKS dialysis study, KIM-1 predicted cardiovascular mortality in age and sex adjusted models (hazard ratio per SD increase 1.45, 95% CI 1.03-2.05, p=0.034) and higher KIM-1 was associated with higher CACscores in the CKD5-LD-RTx-cohort.

Conclusions

Our proteomics approach identified plasma KIM-1 as a risk marker for cardiovascular mortality and coronary artery calcification in three independent ESRD-cohorts. The improved risk prediction for cardiovascular mortality by plasma proteomics merit further studies.

Keywords
CVD, ESRD, Proteomics
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-378193 (URN)10.1007/s40620-018-0556-5 (DOI)000458699800013 ()30499038 (PubMedID)
Funder
Swedish Research CouncilEU, Horizon 2020, 722609EU, Horizon 2020, 634869Swedish Heart Lung FoundationSwedish Society for Medical Research (SSMF)
Available from: 2019-03-04 Created: 2019-03-04 Last updated: 2019-03-04Bibliographically approved
Landegren, N., Rosen, L. B., Freyhult, E., Eriksson, D., Fall, T., Smith, G., . . . Kampe, O. (2019). Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'. eLIFE, 8, Article ID e43578.
Open this publication in new window or tab >>Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'
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2019 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e43578Article in journal, Editorial material (Other academic) Published
Abstract [en]

The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE-deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.

Place, publisher, year, edition, pages
ELIFE SCIENCES PUBLICATIONS LTD, 2019
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-390333 (URN)10.7554/eLife.43578 (DOI)000473150200001 ()31244471 (PubMedID)
Funder
Swedish Research Council FormasSwedish Research CouncilKnut and Alice Wallenberg FoundationNovo NordiskSwedish Society for Medical Research (SSMF)
Available from: 2019-08-09 Created: 2019-08-09 Last updated: 2019-08-09Bibliographically approved
Mubanga, M., Byberg, L., Egenvall, A., Sundström, J., Magnusson, P. K., Ingelsson, E. & Fall, T. (2019). Dog ownership and Cardiovascular Risk Factors: a nationwide prospective register-based cohort study. BMJ Open, 9, Article ID 23447.
Open this publication in new window or tab >>Dog ownership and Cardiovascular Risk Factors: a nationwide prospective register-based cohort study
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2019 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 9, article id 23447Article in journal (Refereed) Published
Abstract [en]

Objective To study the association between dog ownership and cardiovascular risk factors.

Design A nationwide register–based cohort study and a cross-sectional study in a subset.

Setting A cohort of 2 026 865 participants was identified from the Register of the Total Population and linked to national registers for information on dog ownership, prescribed medication, hospital admissions, education level, income and country of birth. Participants were followed from 1 October, 2006, to the end of the study on 31 December, 2012, assessing medication for a cardiovascular risk factor, emigration and death. Cross-sectional associations were further assessed in 10 110 individuals from the TwinGene study with additional adjustment for professional level, employment status, Charlson comorbidity index, disability and tobacco use.

Participants All Swedish residents aged 45–80 years on 1 October, 2006.

Main outcome measures Initiation of medication for hypertension, dyslipidaemia and diabetes mellitus.

Results After adjustment for confounders, the results indicated slightly higher likelihood of initiating antihypertensive (HR, 1.02; 95% CI, 1.01 to 1.03) and lipid-lowering treatment (HR, 1.02; 95% CI, 1.01 to 1.04) in dog owners than in non-owners, particularly among those aged 45–60 years and in those owning mixed breed or companion/toy breed dogs. No association of dog ownership with initiation of treatment for diabetes was found in the overall analysis (HR, 0.98; 95% CI, 0.95 to 1.01). Sensitivity analyses in the TwinGene cohort indicated confounding of the association between dog ownership and prevalent treatment for hypertension, dyslipidaemia and diabetes mellitus, respectively, from factors not available in the national cohort, such as employment status and non cardiovascularchronic disease status.

Conclusions In this large cohort study, dog ownership was associated with a minimally higher risk of initiation of treatment for hypertension and dyslipidaemia implying that the previously reported lower risk of cardiovascular mortality among dog owners in this cohort is not explained by reduced hypertension and dyslipidaemia. These observations may suffer from residual confounding despite access to multiple important covariates, and future studies may add valuable information.

Keywords
cardiovascular risk, hypertension, dog ownership, diabetes, registers
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-357625 (URN)10.1136/bmjopen-2018-023447 (DOI)000471144900063 ()30850401 (PubMedID)
Funder
Swedish Research Council, 2017-00641Swedish Research Council Formas, 2013-1673Göran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2018-08-19 Created: 2018-08-19 Last updated: 2019-12-18Bibliographically approved
Mubanga, M., Byberg, L., Egenvall, A., Ingelsson, E. & Fall, T. (2019). Dog Ownership and Survival After a Major Cardiovascular Event: A Register-Based Prospective Study. Circulation. Cardiovascular Quality and Outcomes, 12(10), Article ID e005342.
Open this publication in new window or tab >>Dog Ownership and Survival After a Major Cardiovascular Event: A Register-Based Prospective Study
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2019 (English)In: Circulation. Cardiovascular Quality and Outcomes, ISSN 1941-7713, E-ISSN 1941-7705, Vol. 12, no 10, article id e005342Article in journal (Refereed) Published
Abstract [en]

Background: Dog ownership is associated with increased physical activity levels and increased social support, both of which could improve the outcome after a major cardiovascular event. Dog ownership may be particularly important in single-occupancy households where ownership provides substitutive companionship and motivation for physical activity.

Methods and Results: We used the Swedish National Patient Register to identify all patients aged 40 to 85 presenting with an acute myocardial infarction (n=181 696; 5.7% dog ownership) or ischemic stroke (n=154 617; 4.8% dog ownership) between January 1, 2001 and December 31, 2012. Individual information was linked across registers for cause of death, sociodemographic, and dog ownership data. We evaluated all-cause mortality and risk of recurrent hospitalization for the same cause until December 31, 2012. Models were adjusted for socioeconomic, health, and demographic factors at study inclusion such as age, marital status, the presence of children in the home, area of residence, and income, as well as all registered comorbidities and hospitalization for cardiovascular disease in the past 5 years. Dog owners had a lower risk of death after hospitalization for acute myocardial infarction during the full follow-up period of 804 137 person-years, with an adjusted hazard ratio (HR) of 0.67 (95% CI, 0.61 to 0.75) for those who lived alone, and HR of 0.85 (95% CI, 0.80 to 0.90) for those living with a partner or a child. Similarly, after an ischemic stroke, dog owners were at lower risk of death during the full follow-up of 638 219 person-years adjusted HR of 0.73 (95% CI, 0.66 to 0.80) for those who lived alone and HR of 0.88 (95% CI, 0.83 to 0.93) for those living with a partner or a child. We further found an association of dog ownership with reduced risk of hospitalization for recurrent myocardial infarction (HR, 0.93; 95% CI, 0.87 to 0.99).

Conclusions: We found evidence of an association of dog ownership with a better outcome after a major cardiovascular event. Although our models are adjusted for many potential confounders, there are also unmeasured confounders such as smoking that prevent us from drawing conclusions regarding a possible causal effect.

Keywords
cardiovascular diseases, dog ownership, motivation, myocardial infarction
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-396741 (URN)10.1161/CIRCOUTCOMES.118.005342 (DOI)000490295200002 ()31592725 (PubMedID)
Funder
Swedish Research Council Formas, 2013-1673EU, European Research CouncilGöran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of Technology
Available from: 2019-11-19 Created: 2019-11-19 Last updated: 2019-11-19Bibliographically approved
Fall, T., Kuja-Halkola, R., Dobney, K., Westgarth, C. & Magnusson, P. K. E. (2019). Evidence of large genetic influences on dog ownership in the Swedish Twin Registry has implications for understanding domestication and health associations. Scientific Reports, 9, Article ID 7554.
Open this publication in new window or tab >>Evidence of large genetic influences on dog ownership in the Swedish Twin Registry has implications for understanding domestication and health associations
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 7554Article in journal (Refereed) Published
Abstract [en]

Dogs were the first domesticated animal and, according to the archaeological evidence, have had a close relationship with humans for at least 15,000 years. Today, dogs are common pets in our society and have been linked to increased well-being and improved health outcomes in their owners. A dog in the family during childhood is associated with ownership in adult life. The underlying factors behind this association could be related to experiences or to genetic influences. We aimed to investigate the heritability of dog ownership in a large twin sample including all twins in the Swedish Twin Registry born between 1926 and 1996 and alive in 2006. Information about dog ownership was available from 2001 to 2016 from national dog registers. The final data set included 85,542 twins from 50,507 twin pairs with known zygosity, where information on both twins were available in 35,035 pairs. Structural equation modeling was performed to estimate additive genetic effects (the heritability), common/shared environmental, and unique/non-shared environmental effects. We found that additive genetic factors largely contributed to dog ownership, with heritability estimated at 57% for females and 51% for males. An effect of shared environmental factors was only observed in early adulthood. In conclusion, we show a strong genetic contribution to dog ownership in adulthood in a large twin study. We see two main implications of this finding: (1) genetic variation may have contributed to our ability to domesticate dogs and other animals and (2) potential pleiotropic effects of genetic variation affecting dog ownership should be considered in studies examining health impacts of dog ownership.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-385976 (URN)10.1038/s41598-019-44083-9 (DOI)000468171100049 ()31101867 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Note

The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641.

Available from: 2019-06-18 Created: 2019-06-18 Last updated: 2019-06-18Bibliographically approved
Salihovic, S., Fall, T., Ganna, A., Broeckling, C. D., Prenni, J. E., Hyötyläinen, T., . . . Lind, L. (2019). Identification of metabolic profiles associated with human exposure to perfluoroalkyl substances.. Journal of Exposure Science and Environmental Epidemiology, 29(2), 196-205
Open this publication in new window or tab >>Identification of metabolic profiles associated with human exposure to perfluoroalkyl substances.
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2019 (English)In: Journal of Exposure Science and Environmental Epidemiology, ISSN 1559-0631, E-ISSN 1559-064X, Vol. 29, no 2, p. 196-205Article in journal (Refereed) Published
Abstract [en]

Recent epidemiological studies suggest that human exposure to perfluoroalkyl substances (PFASs) may be associated with type 2 diabetes and other metabolic phenotypes. To gain further insights regarding PFASs exposure in humans, we here aimed to characterize the associations between different PFASs and the metabolome. In this cross-sectional study, we investigated 965 individuals from Sweden (all aged 70 years, 50% women) sampled in 2001-2004. PFASs were analyzed in plasma using isotope-dilution ultra-pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Non-target metabolomics profiling was performed in plasma using UPLC coupled to time-of-flight mass spectrometry (UPLC-QTOFMS) operated in positive electrospray mode. Multivariate linear regression analysis was used to investigate associations between circulating levels of PFASs and metabolites. In total, 15 metabolites, predominantly from lipid pathways, were associated with levels of PFASs following adjustment for sex, smoking, exercise habits, education, energy, and alcohol intake, after correction for multiple testing. Perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUnDA) were strongly associated with multiple glycerophosphocholines and fatty acids including docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). We also found that the different PFASs evaluated were associated with distinctive metabolic profiles, suggesting potentially different biochemical pathways in humans.

Keywords
Epidemiology, Metabolomics, PFOA, PFOS, Perfluoroalkyl substances, XCMS
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-366082 (URN)10.1038/s41370-018-0060-y (DOI)000459048700007 ()30185940 (PubMedID)
Available from: 2018-11-16 Created: 2018-11-16 Last updated: 2019-08-01Bibliographically approved
Beijer, K., Nowak, C., Sundström, J., Ärnlöv, J., Fall, T. & Lind, L. (2019). In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study. Diabetologia, 62(11), 1998-2006
Open this publication in new window or tab >>In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study
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2019 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 11, p. 1998-2006Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: The pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome 'diabetes' and whether these associations were causal.

Methods: In 2467 individuals of the population-based, cross-sectional EpiHealth study (45-75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of >= 7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study.

Results: Twenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, alpha-l-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes.

Conclusions/interpretation: The 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways.

Place, publisher, year, edition, pages
SPRINGER, 2019
Keywords
Diabetes, Genotyping, Mendelian randomisation, Proteomics, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-396951 (URN)10.1007/s00125-019-4960-8 (DOI)000491944900005 ()31446444 (PubMedID)
Funder
Swedish Research Council, 2015-03477Swedish Heart Lung Foundation, 20150429Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, 1637
Available from: 2019-11-15 Created: 2019-11-15 Last updated: 2019-11-15Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-2071-5866

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