Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
Link to record
Permanent link

Direct link
Alternative names
Publications (10 of 285) Show all publications
Gustafsson, S., Lampa, E., Jensevik, K., Butterworth, A. S., Elmståhl, S., Engström, G., . . . Sundström, J. (2024). Markers of imminent myocardial infarction. Nature Cardiovascular Research
Open this publication in new window or tab >>Markers of imminent myocardial infarction
Show others...
2024 (English)In: Nature Cardiovascular Research, E-ISSN 2731-0590Article in journal (Refereed) Epub ahead of print
Abstract [en]

Myocardial infarction is a leading cause of death globally but is notoriously difficult to predict. We aimed to identify biomarkers of an imminent first myocardial infarction and design relevant prediction models. Here, we constructed a new case–cohort consortium of 2,018 persons without prior cardiovascular disease from six European cohorts, among whom 420 developed a first myocardial infarction within 6 months after the baseline blood draw. We analyzed 817 proteins and 1,025 metabolites in biobanked blood and 16 clinical variables. Forty-eight proteins, 43 metabolites, age, sex and systolic blood pressure were associated with the risk of an imminent first myocardial infarction. Brain natriuretic peptide was most consistently associated with the risk of imminent myocardial infarction. Using clinically readily available variables, we devised a prediction model for an imminent first myocardial infarction for clinical use in the general population, with good discriminatory performance and potential for motivating primary prevention efforts.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-523069 (URN)10.1038/s44161-024-00422-2 (DOI)
Note

These authors contributed equally: Stefan Gustafsson, Erik Lampa

Available from: 2024-02-13 Created: 2024-02-13 Last updated: 2024-02-13Bibliographically approved
Tängdén, T., Gustafsson, S., Rao, A. S. & Ingelsson, E. (2022). A genome-wide association study in a large community-based cohort identifies multiple loci associated with susceptibility to bacterial and viral infections. Scientific Reports, 12, Article ID 2582.
Open this publication in new window or tab >>A genome-wide association study in a large community-based cohort identifies multiple loci associated with susceptibility to bacterial and viral infections
2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 2582Article in journal (Refereed) Published
Abstract [en]

There is limited data on host-specific genetic determinants of susceptibility to bacterial and viral infections. Genome-wide association studies using large population cohorts can be a first step towards identifying patients prone to infectious diseases and targets for new therapies. Genetic variants associated with clinically relevant entities of bacterial and viral infections (e.g., abdominal infections, respiratory infections, and sepsis) in 337,484 participants of the UK Biobank cohort were explored by genome-wide association analyses. Cases (n = 81,179) were identified based on ICD-10 diagnosis codes of hospital inpatient and death registries. Functional annotation was performed using gene expression (eQTL) data. Fifty-seven unique genome-wide significant loci were found, many of which are novel in the context of infectious diseases. Some of the detected genetic variants were previously reported associated with infectious, inflammatory, autoimmune, and malignant diseases or key components of the immune system (e.g., white blood cells, cytokines). Fine mapping of the HLA region revealed significant associations with HLA-DQA1, HLA-DRB1, and HLA-DRB4 locus alleles. PPP1R14A showed strong colocalization with abdominal infections and gene expression in sigmoid and transverse colon, suggesting causality. Shared significant loci across infections and non-infectious phenotypes in the UK Biobank cohort were found, suggesting associations for example between SNPs identified for abdominal infections and CRP, rheumatoid arthritis, and diabetes mellitus. We report multiple loci associated with bacterial and viral infections. A better understanding of the genetic determinants of bacterial and viral infections can be useful to identify patients at risk and in the development of new drugs.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2022
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-470538 (URN)10.1038/s41598-022-05838-z (DOI)000757107700002 ()35173190 (PubMedID)
Funder
Swedish Research Council, 2019-05911Swedish Research Council, 2020-02320Knut and Alice Wallenberg Foundation, 2013.0126
Available from: 2022-03-29 Created: 2022-03-29 Last updated: 2024-01-15Bibliographically approved
Ramdas, S., Gustafsson, S., Lind, L., Ingelsson, E. & Brown, C. D. (2022). A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids. American Journal of Human Genetics, 109(8), 1366-1387
Open this publication in new window or tab >>A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids
Show others...
2022 (English)In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 109, no 8, p. 1366-1387Article in journal (Refereed) Published
Abstract [en]

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

Place, publisher, year, edition, pages
CELL PRESS, 2022
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-485348 (URN)10.1016/j.ajhg.2022.06.012 (DOI)000850681500003 ()35931049 (PubMedID)
Note

For complete list of authors see http://dx.doi.org/10.1016/j.ajhg.2022.06.012

De fem första författarna delar förstaförfattarskapet.

Available from: 2022-09-22 Created: 2022-09-22 Last updated: 2022-09-22Bibliographically approved
Kanoni, S., Gustafsson, S., Lind, L., Ingelsson, E. & Demirkan, A. (2022). Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. Genome Biology, 23, Article ID 268.
Open this publication in new window or tab >>Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis
Show others...
2022 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 23, article id 268Article in journal (Refereed) Published
Abstract [en]

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.

Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2022
Keywords
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-498949 (URN)10.1186/s13059-022-02837-1 (DOI)000927879600003 ()36575460 (PubMedID)
Funder
Wellcome trust, 201543/B/16/ZWellcome trust, 202802/Z/16/ZEU, FP7, Seventh Framework Programme, HEALTH-F2-2013-601456EU, FP7, Seventh Framework Programme, 608765EU, FP7, Seventh Framework Programme, 786833Novo Nordisk, NNF15CC0018486Academy of Finland, 312062
Note

For complete list of authors see http://dx.doi.org/10.1186/s13059-022-02837-1

Available from: 2023-03-22 Created: 2023-03-22 Last updated: 2023-03-22Bibliographically approved
Mahajan, A., Spracklen, C. N., Zhang, W., Ng, M. C. Y., Petty, L. E., Kitajima, H., . . . Morris, A. P. (2022). Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. Nature Genetics, 54(5), 560-572
Open this publication in new window or tab >>Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
Show others...
2022 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 54, no 5, p. 560-572Article in journal (Refereed) Published
Abstract [en]

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.

Place, publisher, year, edition, pages
Springer NatureSpringer Nature, 2022
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-476118 (URN)10.1038/s41588-022-01058-3 (DOI)000794118000004 ()35551307 (PubMedID)
Available from: 2022-06-07 Created: 2022-06-07 Last updated: 2024-01-15Bibliographically approved
Jhun, M.-A., Mendelson, M., Wilson, R., Gondalia, R., Joehanes, R., Salfati, E., . . . Assimes, T. L. (2021). A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids. Nature Communications, 12(1), Article ID 3987.
Open this publication in new window or tab >>A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids
Show others...
2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 3987Article in journal (Refereed) Published
Abstract [en]

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups. Abnormal blood lipid levels are important risk factors for cardiovascular and other various diseases. Here the authors conduct a large-scale multi-ethnic epigenome-wide association study combined with epigenetic (cis-QTL and eQTM) data, and identify CpG-lipid traits associations that are specific to or common across racial/ethnic groups.

Place, publisher, year, edition, pages
Springer NatureNATURE RESEARCH, 2021
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-451570 (URN)10.1038/s41467-021-23899-y (DOI)000669943800001 ()34183656 (PubMedID)
Funder
EU, FP7, Seventh Framework ProgrammeSwedish Research Council, 2012-1397Knut and Alice Wallenberg Foundation, 2013.0126Swedish Heart Lung Foundation, 20140422
Available from: 2021-09-16 Created: 2021-09-16 Last updated: 2024-01-15Bibliographically approved
Rydell, A., Nowak, C., Janson, C., Lisspers, K., Ställberg, B., Iggman, D., . . . Ärnlöv, J. (2021). Plasma proteomics and lung function in four community-based cohorts. Respiratory Medicine, 176, Article ID 106282.
Open this publication in new window or tab >>Plasma proteomics and lung function in four community-based cohorts
Show others...
2021 (English)In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 176, article id 106282Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Underlying mechanism leading to impaired lung function are incompletely understood.

OBJECTIVES: To investigate whether protein profiling can provide novel insights into mechanisms leading to impaired lung function.

METHODS: We used four community-based studies (n = 2552) to investigate associations between 79 cardiovascular/inflammatory proteins and forced expiratory volume in 1 s percent predicted (FEV1%) assessed by spirometry. We divided the cohorts into discovery and replication samples and used risk factor-adjusted linear regression corrected for multiple comparison (false discovery rate of 5%). We performed Mendelian randomization analyses using genetic and spirometry data from the UK Biobank (n = 421,986) to assess causality.

MEASUREMENTS AND MAIN RESULTS: In cross-sectional analysis, 22 proteins were associated with lower FEV1% in both the discovery and replication sample, regardless of stratification by smoking status. The combined proteomic data cumulatively explained 5% of the variation in FEV1%. In longitudinal analyses (n = 681), higher plasma levels of growth differentiation factor 15 (GDF-15) and interleukin 6 (IL-6) predicted a more rapid 5-year decline in lung function (change in FEV1% per standard deviation of protein level -1.4, (95% CI, -2.5 to -0.3) for GDF-15, and -0.8, (95% CI, -1.5 to -0.2) for IL-6. Mendelian randomization analysis in UK-biobank provided support for a causal effect of increased GDF-15 levels and reduced FEV1%.

CONCLUSIONS: Our combined approach identified GDF-15 as a potential causal factor in the development of impaired lung function in the general population. These findings encourage additional studies evaluating the role of GDF-15 as a causal factor for impaired lung function.

Place, publisher, year, edition, pages
Elsevier, 2021
Keywords
FEV1, Mendelian randomization, Protein expression, Proteomics
National Category
Cardiac and Cardiovascular Systems Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-430538 (URN)10.1016/j.rmed.2020.106282 (DOI)000618529000037 ()33310204 (PubMedID)
Funder
Region DalarnaSwedish Research CouncilSwedish Heart Lung Foundation
Available from: 2021-01-11 Created: 2021-01-11 Last updated: 2024-01-15Bibliographically approved
Lagou, V., Maegi, R., Hottenga, J.- . J., Grallert, H., Perry, J. R. B., Bouatia-Naji, N., . . . Prokopenko, I. (2021). Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. Nature Communications, 12(1), Article ID 24.
Open this publication in new window or tab >>Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
Show others...
2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 24Article in journal (Refereed) Published
Abstract [en]

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.

Place, publisher, year, edition, pages
Springer NatureNATURE RESEARCH, 2021
National Category
Medical Genetics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-435757 (URN)10.1038/s41467-020-19366-9 (DOI)000610431700001 ()33402679 (PubMedID)
Funder
EU, European Research Council, 284167EU, European Research Council, 771057EU, European Research Council, 230374EU, European Research Council, GA 269045Knut and Alice Wallenberg Foundation, KAW 2009.0243Swedish Foundation for Strategic Research , ICA08-0047Swedish Heart Lung Foundation, 201202729Swedish Research Council, 8691Swedish Research Council, 0593Swedish Research Council, M-2005-1112Swedish Research Council, 2009-2298Swedish Research Council, 521-2010-3490Swedish Research Council, 521-2007-4037Swedish Research Council, 521-2008-2974Swedish Research Council, 349 2006-237PSwedish Research Council, 12660Swedish Research Council, 521-2010-2633EU, FP7, Seventh Framework Programme, HEALTH-F2-2013-601456EU, Horizon 2020, QLG1-CT-2000-01643EU, Horizon 2020, 692145
Available from: 2021-03-09 Created: 2021-03-09 Last updated: 2024-01-15Bibliographically approved
Graham, S. E., Gustafsson, S., Lind, L., Ingelsson, E. & Willer, C. J. (2021). The power of genetic diversity in genome-wide association studies of lipids. Nature, 600(7890), 675-679
Open this publication in new window or tab >>The power of genetic diversity in genome-wide association studies of lipids
Show others...
2021 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 600, no 7890, p. 675-679Article in journal (Refereed) Published
Abstract [en]

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use(1). Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels(2), heart disease remains the leading cause of death worldwide(3). Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS(4-23) have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns(24). Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65 million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately 295,000 individuals from 7 ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine(25), we anticipate that increased diversity of participants will lead to more accurate and equitable(26) application of polygenic scores in clinical practice.

Place, publisher, year, edition, pages
Springer NatureNATURE PORTFOLIO, 2021
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-470195 (URN)10.1038/s41586-021-04064-3 (DOI)000728504500001 ()34887591 (PubMedID)
Note

For complete list of authors see http://dx.doi.org/10.1038/s41586-021-04064-3

Available from: 2022-03-21 Created: 2022-03-21 Last updated: 2024-01-15Bibliographically approved
Lind, L., Figarska, S., Sundström, J., Fall, T., Arnlov, J. & Ingelsson, E. (2020). Changes in Proteomic Profiles are Related to Changes in BMI and Fat Distribution During 10 Years of Aging. Obesity, 28(1), 178-186
Open this publication in new window or tab >>Changes in Proteomic Profiles are Related to Changes in BMI and Fat Distribution During 10 Years of Aging
Show others...
2020 (English)In: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 28, no 1, p. 178-186Article in journal (Refereed) Published
Abstract [en]

Objective

This study investigated how changes in 84 proteins over a 10‐year period of aging were related to changes in measures of body fat and distribution over the same period.

Methods

Cardiovascular candidate proteins were measured using the proximal extension assay technique, along with BMI and waist‐hip ratio (WHR), at ages 70, 75, and 80 in 1,016 participants of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort. Associations of changes in plasma protein levels, BMI, and WHR over time were analyzed using linear mixed models.

Results

Changes in 19 and 16 proteins were significantly associated with changes in BMI and WHR, respectively (P < 0.00059), over the investigated 10‐year period. Leptin and fatty acid‐binding protein 4 were among the proteins most strongly associated with changes in both BMI and WHR. Four of the proteins significantly tracked with change in BMI (P < 0.00059) but not WHR (P > 0.05): endothelial cell‐specific molecule 1, pentraxin‐related protein PTX3, ST2 protein (also known as interleukin‐1 receptor‐like 1), and spondin‐1. Five proteins tracked with change in WHR (P < 0.00059) but not BMI (P > 0.05): caspase‐8, cathepsin L1, oxidized low‐density lipoprotein receptor 1, interleukin‐6 receptor subunit alpha, and C‐C motif chemokine 20.

Conclusions

This is the first large longitudinal study of how changes in plasma protein signatures are associated with changes in measures of body fat and distribution over 10 years of aging.

Place, publisher, year, edition, pages
Wiley, 2020
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-423497 (URN)10.1002/oby.22660 (DOI)000500583200001 ()31804015 (PubMedID)
Funder
Swedish Research Council, 2015-03477Swedish Heart Lung Foundation, 20150429Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine, 1637
Available from: 2020-10-28 Created: 2020-10-28 Last updated: 2021-03-24Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2256-6972

Search in DiVA

Show all publications