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Garcia-Calzon, S., Schrader, S., Perfilyev, A., Martinell, M., Ahlqvist, E. & Ling, C. (2023). DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes. Diabetes Research and Clinical Practice, 202, Article ID 110807.
Open this publication in new window or tab >>DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes
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2023 (English)In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 202, article id 110807Article in journal (Refereed) Published
Abstract [en]

Aims: Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newlydiagnosed individuals with type 2 diabetes.

Methods and Results: We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for similar to 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin's effects on HbA1c.

Conclusion: Metformin-associated alterations in DNA methylation partially mediates metformin's antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes.

Place, publisher, year, edition, pages
Elsevier BV, 2023
Keywords
Epigenetics, Epigenomics, Pharmacoepigenetics, Therapy, Glycemia, Mechanism, EWAS
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-509057 (URN)10.1016/j.diabres.2023.110807 (DOI)001031815000001 ()37356726 (PubMedID)
Funder
Swedish Research Council, 2020-02191Swedish Research Council, 2015-2558Swedish Research Council, 2010-5983Swedish Research Council, 2012-5538Swedish Research Council, 2014-6395Swedish Heart Lung Foundation
Available from: 2023-08-16 Created: 2023-08-16 Last updated: 2023-08-16Bibliographically approved
Kennedy, B., Varotsis, G., Hammar, U., Nguyen, D., Carrasquilla, G. D., van Zoest, V., . . . Fall, T. (2023). Sociodemographic characteristics and COVID-19 testingrates: spatiotemporal patterns and impact of testaccessibility in Sweden. European Journal of Public Health
Open this publication in new window or tab >>Sociodemographic characteristics and COVID-19 testingrates: spatiotemporal patterns and impact of testaccessibility in Sweden
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2023 (English)In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360XArticle in journal (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-517057 (URN)
Available from: 2023-12-01 Created: 2023-12-01 Last updated: 2024-01-12Bibliographically approved
Kennedy, B., Fitipaldi, H., Hammar, U., Maziarz, M., Tsereteli, N., Oskolkov, N., . . . Fall, T. (2022). App-based COVID-19 syndromic surveillance and prediction of hospital admissions in COVID Symptom Study Sweden. Nature Communications, 13, Article ID 2110.
Open this publication in new window or tab >>App-based COVID-19 syndromic surveillance and prediction of hospital admissions in COVID Symptom Study Sweden
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2022 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 13, article id 2110Article in journal (Refereed) Published
Abstract [en]

The app-based COVID Symptom Study was launched in Sweden in April 2020 to contribute to real-time COVID-19 surveillance. We enrolled 143,531 study participants (≥18 years) who contributed 10.6 million daily symptom reports between April 29, 2020 and February 10, 2021. Here, we include data from 19,161 self-reported PCR tests to create a symptom-based model to estimate the individual probability of symptomatic COVID-19, with an AUC of 0.78 (95% CI 0.74–0.83) in an external dataset. These individual probabilities are employed to estimate daily regional COVID-19 prevalence, which are in turn used together with current hospital data to predict next week COVID-19 hospital admissions. We show that this hospital prediction model demonstrates a lower median absolute percentage error (MdAPE: 25.9%) across the five most populated regions in Sweden during the first pandemic wave than a model based on case notifications (MdAPE: 30.3%). During the second wave, the error rates are similar. When we apply the same model to an English dataset, not including local COVID-19 test data, we observe MdAPEs of 22.3% and 19.0% during the first and second pandemic waves, respectively, highlighting the transferability of the prediction model.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2022
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Epidemiology
Identifiers
urn:nbn:se:uu:diva-473382 (URN)10.1038/s41467-022-29608-7 (DOI)000785003900026 ()35449172 (PubMedID)
Projects
eSSENCE - An eScience Collaboration
Funder
Swedish Research Council, 2018-05973
Available from: 2022-04-26 Created: 2022-04-26 Last updated: 2024-01-15Bibliographically approved
Rosman, J., Eriksson, J., Martinell, M., Lindholm Olinder, A. & Leksell, J. (2022). Individual goal-based plan based on nursing theory for adults with type 2 diabetes and self-care deficits: a study protocol of a randomised controlled trial. BMJ Open, 12(3), Article ID e053955.
Open this publication in new window or tab >>Individual goal-based plan based on nursing theory for adults with type 2 diabetes and self-care deficits: a study protocol of a randomised controlled trial
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2022 (English)In: BMJ Open, E-ISSN 2044-6055, Vol. 12, no 3, article id e053955Article in journal (Refereed) Published
Abstract [en]

Introduction The prevalence and costs of type 2 diabetes are increasing worldwide. A cornerstone in the treatment and care of diabetes is supporting each patient in self-management. In Sweden, most patients with type 2 diabetes are cared for in the primary care setting, which is heavily burdened. Because of implementation difficulties regarding evidenced-based diabetes self-management education and support in this setting, there is a need for an instrument that is easy to use and implement. We developed an individual care plan based on the self-care deficit nursing theory of Dorothea Orem as an instrument to facilitate more individualised self-care support for patients with type 2 diabetes. In this study, we aim to determine whether a written, theory-based, individual goal-based plan for patients with type 2 diabetes and self-management deficits can affect their glycaemic control and health-related quality of life, as well as their experiences of living with diabetes and of support from diabetes care. Methods and analysis The study design is a randomised controlled trial using a quantitative approach. A total of 110 patients will be included. Additionally, a qualitative interview study will be conducted 12 months after the intervention. The primary outcome will be glycosylated haemoglobin levels. Secondary outcomes will be health-related quality of life measured using the RAND-36, and the patient's experience of living with diabetes and of the support from diabetes care measured using the Diabetes Questionnaire. Quantitative data will be analysed using the paired t-test, unpaired t-test, and Mann-Whitney U test with IBM SPSS V.26.0 software. Qualitative content analysis will be used for qualitative data. Ethics and dissemination This study has been approved by the Ethical Review Authority in Uppsala, Sweden (Etikprovningsmyndigheten, Uppsala, Sverige) (Dnr: 2020-03421). The results will be disseminated in peer-reviewed publications.

Place, publisher, year, edition, pages
BMJ Publishing Group LtdBMJ, 2022
National Category
Endocrinology and Diabetes Nursing
Identifiers
urn:nbn:se:uu:diva-473661 (URN)10.1136/bmjopen-2021-053955 (DOI)000777947200017 ()35351707 (PubMedID)
Available from: 2022-05-02 Created: 2022-05-02 Last updated: 2024-01-15Bibliographically approved
Martinell, M., Andersson, T., Mannsverk, S. S., Bergholm, J., Ellström, P., Hill, A., . . . Kaden, R. (2022). In-Flight Transmission of a SARS-CoV-2 Lineage B.1.617.2 Harbouring the Rare S:E484Q Immune Escape Mutation. Viruses, 14(3), Article ID 504.
Open this publication in new window or tab >>In-Flight Transmission of a SARS-CoV-2 Lineage B.1.617.2 Harbouring the Rare S:E484Q Immune Escape Mutation
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2022 (English)In: Viruses, E-ISSN 1999-4915, Vol. 14, no 3, article id 504Article in journal (Refereed) Published
Abstract [en]

We describe a flight-associated infection scenario of seven individuals with a B.1.617.2 (Delta) lineage, harbouring an S:E484Q point mutation. In Sweden, at least 10% of all positive SARS-CoV-2 samples were sequenced in each county; the B.1.717.2 + S:E484Q combination was not detected in Sweden before and was imported within the scenario described in this report. The high transmission rate of the delta lineage combined with the S:E484Q mutation, associated with immune escape in other lineages, makes this specific genetic combination a possible threat to the global fight against the COVID-19 pandemic. Even within the Omicron wave, the B.1.617.2 + S:E484Q variant appeared in community samples in Sweden, as it seems that this combination has an evolutionary gain compared to other B.1.617.2 lineages. The here described genomic combination was not detectable with the common fasta file-based Pango-lineage analysis, hence increasing the probability of the true global prevalence to be higher.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
SARS-CoV-2, delta, E484Q
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-472744 (URN)10.3390/v14030504 (DOI)000774280900001 ()35336908 (PubMedID)
Available from: 2022-04-19 Created: 2022-04-19 Last updated: 2024-01-17Bibliographically approved
Schrader, S., Perfilyev, A., Ahlqvist, E., Groop, L., Vaag, A., Martinell, M., . . . Ling, C. (2022). Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns That Associate With Future Diabetic Complications. Diabetes Care, 45(7), 1621-1630
Open this publication in new window or tab >>Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns That Associate With Future Diabetic Complications
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2022 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 45, no 7, p. 1621-1630Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE Type 2 diabetes (T2D) was recently reclassified into severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications. RESEARCH DESIGN AND METHODS Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications. RESULTS We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6-6.1 per 1-SD increase, P < 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4-1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue. CONCLUSIONS We identified differential epigenetic patterns between T2D subgroups that associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.

Place, publisher, year, edition, pages
American Diabetes Association, 2022
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-487988 (URN)10.2337/dc21-2489 (DOI)000867710600020 ()35607770 (PubMedID)
Funder
European Foundation for the Study of DiabetesSwedish Heart Lung FoundationSwedish Research CouncilEU, Horizon 2020, 725840EU, Horizon 2020, 706081Swedish Foundation for Strategic Research, IRC15-0067
Available from: 2022-11-17 Created: 2022-11-17 Last updated: 2022-11-17Bibliographically approved
van Zoest, V., Varotsis, G., Menzel, U., Wigren, A., Kennedy, B., Martinell, M. & Fall, T. (2022). Spatio-temporal predictions of COVID-19 test positivity in Uppsala County, Sweden: a comparative approach. Scientific Reports, 12(1), Article ID 15176.
Open this publication in new window or tab >>Spatio-temporal predictions of COVID-19 test positivity in Uppsala County, Sweden: a comparative approach
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2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 15176Article in journal (Refereed) Published
Abstract [en]

Previous spatio-temporal COVID-19 prediction models have focused on the prediction of subsequent number of cases, and have shown varying accuracy and lack of high geographical resolution. We aimed to predict trends in COVID-19 test positivity, an important marker for planning local testing capacity and accessibility. We included a full year of information (June 29, 2020-July 4, 2021) with both direct and indirect indicators of transmission, e.g. mobility data, number of calls to the national healthcare advice line and vaccination coverage from Uppsala County, Sweden, as potential predictors. We developed four models for a 1-week-window, based on gradient boosting (GB), random forest (RF), autoregressive integrated moving average (ARIMA) and integrated nested laplace approximations (INLA). Three of the models (GB, RF and INLA) outperformed the naïve baseline model after data from a full pandemic wave became available and demonstrated moderate accuracy. An ensemble model of these three models slightly improved the average root mean square error to 0.039 compared to 0.040 for GB, RF and INLA, 0.055 for ARIMA and 0.046 for the naïve model. Our findings indicate that the collection of a wide variety of data can contribute to spatio-temporal predictions of COVID-19 test positivity.

Place, publisher, year, edition, pages
Springer Nature, 2022
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-485063 (URN)10.1038/s41598-022-19155-y (DOI)000852630800046 ()36071066 (PubMedID)
Funder
Vinnova, 2020-03173Swedish Research Council, 2019-01471Swedish Heart Lung Foundation, 2019-0505EU, European Research Council, ERC-2018-STG 801965
Available from: 2022-09-19 Created: 2022-09-19 Last updated: 2023-01-25Bibliographically approved
Schrader, S., Perfilyev, A., Martinell, M., Garcia-Calzon, S. & Ling, C. (2021). Statin therapy is associated with epigenetic modifications in individuals with type 2 diabetes. Epigenomics, 13(12), 919-925
Open this publication in new window or tab >>Statin therapy is associated with epigenetic modifications in individuals with type 2 diabetes
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2021 (English)In: Epigenomics, ISSN 1750-1911, Vol. 13, no 12, p. 919-925Article in journal (Refereed) Published
Abstract [en]

Aim: Statins lower cholesterol and reduce the risk of cardiovascular disease. However, the exact mechanisms of statins remain unknown. We investigated whether statin therapy associates with epigenetics in type 2 diabetes (T2D) patients. Materials & methods: DNA methylation was analyzed in blood from newly diagnosed T2D patients in All New Diabetics in Scania (ANDIS) and a replication cohort All New Diabetics in Uppsala County (ANDiU). Results: Seventy-nine sites were differentially methylated between cases on statins and controls (false discovery rate <5%) in ANDIS. These include previously statin-associated methylation sites annotated to DHCR24 (cg17901584), ABCG1 (cg27243685) and SC4MOL (cg05119988). Differential methylation of two sites related to cholesterol biosynthesis and immune response, cg17901584 (DHCR24) and cg23011663 (ARIH2), were replicated in ANDiU. Conclusion: Statin therapy associates with epigenetic modifications in T2D patients.

Place, publisher, year, edition, pages
Future MedicineFUTURE MEDICINE LTD, 2021
Keywords
cardiovascular disease, causal mediation analyses, DNA methylation, epigenetics, HDL, LDL, pharmacoepigenetics, statins, therapy, type 2 diabetes
National Category
Cardiac and Cardiovascular Systems Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-454398 (URN)10.2217/epi-2020-0442 (DOI)000647038700001 ()33947200 (PubMedID)
Funder
Swedish Research CouncilEU, Horizon 2020, 706081Swedish Foundation for Strategic Research , IRC15-0067EU, European Research Council, 725840Novo NordiskRegion SkåneSwedish Heart Lung FoundationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2021-09-28 Created: 2021-09-28 Last updated: 2024-01-15Bibliographically approved
Garcia-Calzon, S., Perfilyev, A., Martinell, M., Ustinova, M., Kalamajski, S., Franks, P. W., . . . Ling, C. (2020). Epigenetic markers associated with metformin response and intolerance in drug-naive patients with type 2 diabetes. Science Translational Medicine, 12(561), Article ID eaaz1803.
Open this publication in new window or tab >>Epigenetic markers associated with metformin response and intolerance in drug-naive patients with type 2 diabetes
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2020 (English)In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 12, no 561, article id eaaz1803Article in journal (Refereed) Published
Abstract [en]

Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naive patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin-related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naive patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.

Place, publisher, year, edition, pages
AMER ASSOC ADVANCEMENT SCIENCE, 2020
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-423368 (URN)10.1126/scitranslmed.aaz1803 (DOI)000570971200003 ()32938793 (PubMedID)
Funder
Swedish Research CouncilEU, European Research Council, 725840EU, Horizon 2020, 706081Swedish Heart Lung FoundationSwedish Foundation for Strategic Research Swedish Foundation for Strategic Research , IRC15-0067
Available from: 2020-10-23 Created: 2020-10-23 Last updated: 2020-10-23Bibliographically approved
Hjort, R., Ahlqvist, E., Andersson, T., Alfredsson, L., Carlsson, P.-O., Grill, V., . . . Carlsson, S. (2020). Physical Activity, Genetic Susceptibility, and the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes. Journal of Clinical Endocrinology and Metabolism, 105(11), e4112-e4123
Open this publication in new window or tab >>Physical Activity, Genetic Susceptibility, and the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes
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2020 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 105, no 11, p. e4112-e4123Article in journal (Refereed) Published
Abstract [en]

Purpose

Physical activity (PA) has been linked to a reduced risk of type 2 diabetes by reducing weight and improving insulin sensitivity. We investigated whether PA is associated with a lower incidence of latent autoimmune diabetes in adults (LADA) and whether the association is modified by genotypes of human leukocyte antigen (HLA), transcription factor 7-like 2 (TCF7L2)-rs7903146, or the fat mass and obesity-associated gene, FTO-rs9939609.

Methods

We combined data from a Swedish case-control study and a Norwegian prospective study including 621 incident cases of LADA and 3596 cases of type 2 diabetes. We estimated adjusted pooled relative risks (RRs) and 95% CI of diabetes in relation to high (≥ 30 minutes of moderate activity 3 times/week) self-reported leisure time PA, compared to sedentariness.

Results

High PA was associated with a reduced risk of LADA (RR 0.61; CI, 0.43-0.86), which was attenuated after adjustment for body mass index (BMI) (RR 0.90; CI, 0.63-1.29). The reduced risk applied only to noncarriers of HLA-DQB1 and -DRB1 (RR 0.49; CI, 0.33-0.72), TCF7L2 (RR 0.62; CI, 0.45-0.87), and FTO (RR 0.51; CI, 0.32-0.79) risk genotypes. Adjustment for BMI attenuated but did not eliminate these associations. For type 2 diabetes, there was an inverse association with PA (RR 0.49; CI, 0.42-0.56), irrespective of genotype.

Main Conclusions

Our findings indicate that high PA is associated with a reduced risk of LADA in individuals without genetic susceptibility.

Keywords
physical activity, gene-environment interaction, LADA, latent autoimmune diabetes in adults, type 2 diabetes, population-based
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-429000 (URN)10.1210/clinem/dgaa549 (DOI)000584540200031 ()32835373 (PubMedID)
Funder
Swedish Research Council, GA 2018-03035Forte, Swedish Research Council for Health, Working Life and Welfare, GA 2018-00337EU, European Research Council, GA 269045Swedish Diabetes AssociationNovo NordiskSwedish Rheumatism AssociationAFA InsuranceRegion StockholmNIH (National Institute of Health)The Research Council of Norway
Available from: 2020-12-18 Created: 2020-12-18 Last updated: 2022-10-31Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-6060-6229

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