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Helte, E., Akesson, A. & Larsson, S. C. (2019). Assessing Causality in Associations of Serum Calcium and Magnesium Levels With Heart Failure: A Two-Sample Mendelian Randomization Study. Frontiers in Genetics, 10, Article ID 1069.
Open this publication in new window or tab >>Assessing Causality in Associations of Serum Calcium and Magnesium Levels With Heart Failure: A Two-Sample Mendelian Randomization Study
2019 (English)In: Frontiers in Genetics, ISSN 1664-8021, E-ISSN 1664-8021, Vol. 10, article id 1069Article in journal (Refereed) Published
Abstract [en]

Evidence from observational studies suggests that increased exposure to calcium may increase the risk of coronary heart disease and stroke whereas magnesium might have a protective effect on disease risk. However, studies of the associations of these minerals with heart failure are scarce and limited by potential biases introduced by confounding and reverse causality. We applied a two-sample Mendelian randomization design using summary estimates to assess whether serum calcium and magnesium concentrations are causally associated with heart failure. Summary statistics data were collected for seven and six single-nucleotide polymorphisms associated with calcium and magnesium, respectively, from the hitherto largest genome-wide association studies on these minerals. Corresponding summary statistics for genetic associations with heart failure were available from publicly available data based on the UK Biobank study and based on participants of European ancestry. The findings showed that neither serum calcium nor magnesium concentrations were associated with heart failure. In the standard inverse-variance weighted analysis, the odds ratios of heart failure per genetically predicted one standard deviation increase in mineral concentrations were 0.89 (95% confidence interval 0.67-1.17; p = 0.41) for serum calcium and 0.89 (95% confidence interval 0.72-1.10; p = 0.28) for serum magnesium. Results were robust in sensitivity analyses, including the weighted median and Mendelian randomization Egger analyses. In conclusion, these findings do not support previous findings suggesting a link between serum calcium and magnesium and heart failure, but this study was underpowered to detect weak associations.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
calcium, heart failure, magnesium, minerals, Mendelian randomization
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-397594 (URN)10.3389/fgene.2019.01069 (DOI)000494683900001 ()31708976 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-11-22 Created: 2019-11-22 Last updated: 2019-11-22Bibliographically approved
Yuan, S., Michaëlsson, K., Wan, Z. & Larsson, S. C. (2019). Associations of Smoking and Alcohol and Coffee Intake with Fracture and Bone Mineral Density: A Mendelian Randomization Study. Calcified Tissue International, 105(6), 582-588
Open this publication in new window or tab >>Associations of Smoking and Alcohol and Coffee Intake with Fracture and Bone Mineral Density: A Mendelian Randomization Study
2019 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 6, p. 582-588Article in journal (Refereed) Published
Abstract [en]

The causal associations of smoking and alcohol and coffee intake with fracture and bone mineral density are unknown. We investigated the associations using Mendelian randomization (MR). Summary-level data from UK Biobank for bone fractures (main outcome) (53,184 cases; 373,611 non-cases) and estimated bone mineral density (eBMD) (n = 426,824 individuals) were used. Single-nucleotide polymorphisms associated with smoking initiation (n = 378) and alcohol (n = 99) and coffee (n = 15) intake at the genome-wide significance threshold (P = 5 x 10(-8)) were identified from published genome-wide association studies. Univariable and multivariable inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO methods were used for statistical analyses. Genetic predisposition to smoking initiation was associated with fracture but not eBMD. The odds ratio of fracture per one-unit increase in log odds of smoking was 1.09 (95% confidence interval 1.04, 1.15; P = 8.58 x 10(-4)) after adjustment for alcohol intake in the multivariable MR analysis. The association remained in complementary analyses. Genetically predicted alcohol and coffee intake was not associated with fracture or eBMD. Nevertheless, genetic liability to alcohol dependence, based on variants in the ALD1B gene, was associated with fracture and lower eBMD. The odds ratio was 1.06 (95% confidence interval 1.01, 1.12; P = 0.018) per genetically predicted one-unit higher log odds of liability to alcohol dependence. This MR study strengthens the causal inference on an association between smoking and higher fracture risk but found no linear association of modestly higher alcohol and coffee intake with fracture or BMD. However, alcohol dependence may increase fracture risk.

Keywords
Alcohol, Bone mineral density, Coffee, Fracture, Mendelian randomization, Smoking
National Category
Orthopaedics
Identifiers
urn:nbn:se:uu:diva-397666 (URN)10.1007/s00223-019-00606-0 (DOI)000493763200002 ()31482193 (PubMedID)
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved
Warensjö Lemming, E., Byberg, L., Stattin, K., Ahmad, S., Lind, L., Elmsfahl, S., . . . Michaëlsson, K. (2019). Dietary Pattern Specific Protein Biomarkers for Cardiovascular Disease: A Cross-Sectional Study in 2 Independent Cohorts. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, 8(11), Article ID e011860.
Open this publication in new window or tab >>Dietary Pattern Specific Protein Biomarkers for Cardiovascular Disease: A Cross-Sectional Study in 2 Independent Cohorts
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2019 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 8, no 11, article id e011860Article in journal (Refereed) Published
Abstract [en]

Background: Mechanisms related to the influence of diet on the development of cardiovascular disease are not entirely understood, and protein biomarkers may help to understand these pathways. Studies of biomarkers identified with multiplex proteomic methods and dietary patterns are largely lacking.

Methods and Results: Dietary patterns were generated through principal component analysis in 2 population‐based Swedish cohorts, the EpiHealth (EpiHealth study; n=20 817 men and women) and the SMCC (Swedish Mammography Cohort Clinical [n=4650 women]). A set of 184 protein cardiovascular disease biomarkers were measured with 2 high‐throughput, multiplex immunoassays. Discovery and replication multivariable linear regression analyses were used to investigate the associations between the principal component analysis–generated dietary patterns and the cardiovascular disease–associated protein biomarkers, first in the EpiHealth (n=2240) and then in the Swedish Mammography Cohort Clinical. Four main dietary patterns were identified in the EpiHealth, and 3 patterns were identified in the Swedish Mammography Cohort Clinical. The healthy and the Western/traditional patterns were found in both cohorts. In the EpiHealth, 57 protein biomarkers were associated with 3 of the dietary patterns, and 41 of these associations were replicated in the Swedish Mammography Cohort Clinical, with effect estimates ranging from 0.057 to 0.083 (P‐value range, 5.0×10−2–1.4×10−9) for each SD increase in the relative protein concentration. Independent associations were established between dietary patterns and the 21 protein biomarkers. Two proteins, myeloperoxidase and resistin, were associated with both the healthy and the light meal pattern but in opposite directions.

Conclusions: We have discovered and replicated independent associations between dietary patterns and 21 biomarkers linked to cardiovascular disease, which have a role in the pathways related to inflammation, endothelial and immune function, cell adhesion, and metabolism

Keywords
cardiovascular disease, dietary patterns, EpiHealth study, inflammation, proteomics, Swedish Mammography Cohort Clinical
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-394981 (URN)10.1161/JAHA.118.011860 (DOI)000484576200019 ()31433701 (PubMedID)
Funder
Swedish Research Council, 2017-06100Swedish Research Council, 2015-05997Swedish Research Council, 2015-03257Forte, Swedish Research Council for Health, Working Life and Welfare, 2017-00721Swedish Research Council, 2017/49 (180)
Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2019-10-11Bibliographically approved
Larsson, S. C. & Markus, H. S. (2019). Genetic Liability to Insomnia and Cardiovascular Disease Risk [Letter to the editor]. Circulation, 140(9), 796-798
Open this publication in new window or tab >>Genetic Liability to Insomnia and Cardiovascular Disease Risk
2019 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 140, no 9, p. 796-798Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
Keywords
cardiovascular diseases, Mendelian randomization analysis, sleep, sleep initiation and maintenance disorders, stroke
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-394722 (URN)10.1161/CIRCULATIONAHA.119.041830 (DOI)000483552900019 ()31422675 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2018-00123Swedish Research Council
Available from: 2019-10-11 Created: 2019-10-11 Last updated: 2019-10-11Bibliographically approved
Yuan, S., Jiang, X., Michaëlsson, K. & Larsson, S. C. (2019). Genetic Prediction of Serum 25-Hydroxyvitamin D, Calcium, and Parathyroid Hormone Levels in Relation to Development of Type 2 Diabetes: A Mendelian Randomization Study. Diabetes Care, 42(12), 2197-2203
Open this publication in new window or tab >>Genetic Prediction of Serum 25-Hydroxyvitamin D, Calcium, and Parathyroid Hormone Levels in Relation to Development of Type 2 Diabetes: A Mendelian Randomization Study
2019 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 42, no 12, p. 2197-2203Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE We conducted a Mendelian randomization study to investigate the associations of genetically predicted serum 25-hydroxyvitamin D (S-25OHD), calcium (S-Ca), and parathyroid hormone (S-PTH) levels with type 2 diabetes (T2DM). RESEARCH DESIGN AND METHODS Seven, six, and five single nucleotide polymorphisms (SNPs) associated with S-25OHD, S-Ca, and S-PTH levels, respectively, were used as instrumental variables. Data on T2DM were available for 74,124 case subjects with T2DM and 824,006 control subjects. The inverse variance-weighted method was used for the primary analyses, and the weighted median and Mendelian randomization (MR)-Egger methods were used for supplementary analyses. RESULTS Genetically predicted S-25OHD but not S-Ca and S-PTH levels were associated with T2DM in the primary analyses. For 1 SD increment of S-25OHD levels, the odds ratio (OR) of T2DM was 0.94 (95% CI 0.88-0.99; P = 0.029) in an analysis based on all seven SNPs and 0.90 (95% CI 0.83-0.98; P = 0.011) in an analysis based on three SNPs within or near genes involved in vitamin D synthesis. Only the association based on the SNPs involved in vitamin D synthesis remained in the weighted median analysis, and no pleiotropy was detected (P = 0.153). Pleiotropy was detected in the analysis of S-Ca (P = 0.013). After correcting for this bias using MR-Egger regression, the OR of T2DM per 1 SD increment of S-Ca levels was 1.41 (95% CI 1.12-1.77; P = 0.003). CONCLUSIONS Modest lifelong higher S-25OHD levels were associated with reduced odds of T2DM, but the association was only robust for SNPs in the vitamin D synthesis pathway. The possible role of S-Ca levels for T2DM development requires further research.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC, 2019
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-400010 (URN)10.2337/dc19-1247 (DOI)000498634000014 ()31548248 (PubMedID)
Funder
Swedish Research CouncilForte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2019-12-19Bibliographically approved
Larsson, S. C., Traylor, M. & Markus, H. S. (2019). Homocysteine and small vessel stroke: A mendelian randomization analysis. Annals of Neurology, 85(4), 495-501
Open this publication in new window or tab >>Homocysteine and small vessel stroke: A mendelian randomization analysis
2019 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 85, no 4, p. 495-501Article in journal (Refereed) Published
Abstract [en]

Objective

Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization.

Methods

We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B-6 (n = 1), and vitamin B-12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases).

Results

Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 x 10(-4)) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B-6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 x 10(-4)) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B-12 levels were not associated with any stroke subtype.

Interpretation

These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-383517 (URN)10.1002/ana.25440 (DOI)000466415500006 ()30785218 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare, 2018-00123EU, Horizon 2020, 667375
Available from: 2019-05-16 Created: 2019-05-16 Last updated: 2019-05-16Bibliographically approved
Yuan, S. & Larsson, S. C. (2019). No association between coffee consumption and risk of atrial fibrillation: A Mendelian randomization study. NMCD. Nutrition Metabolism and Cardiovascular Diseases, 29(11), 1185-1188
Open this publication in new window or tab >>No association between coffee consumption and risk of atrial fibrillation: A Mendelian randomization study
2019 (English)In: NMCD. Nutrition Metabolism and Cardiovascular Diseases, ISSN 0939-4753, E-ISSN 1590-3729, Vol. 29, no 11, p. 1185-1188Article in journal (Refereed) Published
Abstract [en]

Background and aims: Some observational studies have found that habitual coffee and caffeine consumption might reduce the risk of atrial fibrillation (AF). We conducted a two-sample Mendelian randomization study to explore the potential association between coffee consumption and AF.

Methods and results: This study was based on summary-level data from the Atrial Fibrillation Consortium, including 588 190 individuals (65 446 cases and 522 744 non-cases). Nine single-nucleotide polymorphisms associated with coffee consumption at significance level of P < 5 x 10(-8) were used as instrumental variables and were obtained from a genome-wide association study that included up to 375 833 individuals. The odds ratio of AF per genetically-predicted 50% increase of coffee consumption was 0.98 (95% confidence interval, 0.88, 1.10; P = 0.80) in the standard inverse-variance weighted analysis. Results were consistent in sensitivity analyses using the weighted median and MR-Egger methods, and no directional pleiotropy (P = 0.37) was observed. Moreover, complementary analyses that separated the coffee-related single-nucleotide polymorphisms based on their association with blood levels of caffeine metabolites (lower, higher, unrelated or unknown association) revealed no association with AF.

Conclusions: This study does not support a causal association between habitual coffee consumption and risk of AF. 

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2019
Keywords
Atrial fibrillation, Coffee consumption, Mendelian randomization
National Category
Cardiac and Cardiovascular Systems Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-396954 (URN)10.1016/j.numecd.2019.07.015 (DOI)000492146700005 ()31558414 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-11-15 Created: 2019-11-15 Last updated: 2019-11-15Bibliographically approved
Yuan, S. & Larsson, S. C. (2019). Plasma Phospholipid Fatty Acids and Risk of Atrial Fibrillation: A Mendelian Randomization Study. Nutrients, 11(7), Article ID 1651.
Open this publication in new window or tab >>Plasma Phospholipid Fatty Acids and Risk of Atrial Fibrillation: A Mendelian Randomization Study
2019 (English)In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 11, no 7, article id 1651Article in journal (Refereed) Published
Abstract [en]

Available evidence on the associations of dietary and circulating levels of long-chain n-3 fatty acids, which have potential antiarrhythmic properties, and other fatty acids with atrial fibrillation is conflicting and limited. We conducted a Mendelian randomization study to assess the associations between plasma phospholipid fatty acid levels and atrial fibrillation. Summary-level data of atrial fibrillation were available from 65,446 cases and 522,744 non-cases included in the Atrial Fibrillation Consortium. Sixteen single-nucleotide polymorphisms associated with ten fatty acids at significance level of p < 5 x 10(-8) were identified as instrumental variables from the hitherto largest genome-wide association studies for plasma fatty acids. The fixed-effects inverse-variance weighted method was used to assess the association of individual plasma fatty acids and atrial fibrillation risk. The random-effects inverse-variance weighted method, weighted median method, and Mendelian randomization (MR)-Egger method were employed as the sensitivity analyses. Genetic predisposition to higher levels of any of the ten individual fatty acids was not associated with atrial fibrillation risk.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
atrial fibrillation, diet, fatty acids, Mendelian randomization
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-393131 (URN)10.3390/nu11071651 (DOI)000478885400200 ()31331006 (PubMedID)
Funder
Swedish Research Council
Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Larsson, S. C., Drca, N., Mason, A. M. & Burgess, S. (2019). Resting Heart Rate and Cardiovascular Disease Mendelian Randomization Analysis [Letter to the editor]. CIRCULATION-GENOMIC AND PRECISION MEDICINE, 12(3), 127-129
Open this publication in new window or tab >>Resting Heart Rate and Cardiovascular Disease Mendelian Randomization Analysis
2019 (English)In: CIRCULATION-GENOMIC AND PRECISION MEDICINE, ISSN 2574-8300, Vol. 12, no 3, p. 127-129Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2019
Keywords
atrial, fibrillation, cardiovascular disease, coronary, artery, disease, heart rate, risk
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-384091 (URN)10.1161/CIRCGEN.119.002459 (DOI)000466741300007 ()30919689 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and WelfareSwedish Research CouncilWellcome trust
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2019-06-12Bibliographically approved
Larsson, S. C. & Wolk, A. (2019). Sedentary leisure-time in relation to mortality and survival time. Journal of Science and Medicine in Sport, 22(5), 562-567
Open this publication in new window or tab >>Sedentary leisure-time in relation to mortality and survival time
2019 (English)In: Journal of Science and Medicine in Sport, ISSN 1440-2440, E-ISSN 1878-1861, Vol. 22, no 5, p. 562-567Article in journal (Refereed) Published
Abstract [en]

Objective: To examine the association between sedentary leisure-time and all-cause mortality and differences in survival time.

Design: Prospective cohort study.

Methods: Information on sedentary leisure-time, defined as TV viewing and/or sitting reading, was collected from 72 003 Swedish adults who were 45-83 (median 60) years of age and completed a self-administered questionnaire at baseline and were followed up for 17 years through linkage with the Swedish Death Register.

Results: The association between sedentary leisure-time and all-cause mortality was modified by age with a more pronounced association in middle-aged (<60 years of age) than in older adults (>= 60 years of age) (p-interaction <0.001). During follow-up, 3358 and 15 217 deaths occurred in the middle-aged and older age group, respectively. The multivariable-adjusted hazard ratios for the highest (>6 h/day) versus lowest category (<1 h/day) of sedentary leisure-time were 1.72 (95% confidence interval [CI] 1.29-2.30) in middle-aged adults and 1.19 (95% CI 1.05-1.36) in older adults. This corresponded to a difference in survival time of respectively 2.4 (95% CI -4.1 to -0.8) years and 1.5 (95% CI -2.2 to -0.7) years.

Conclusions: Prolonged sedentary leisure-time was associated with a significantly decreased survival time up to 2.4 years in middle-aged adults. 

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2019
Keywords
Cohort studies, Mortality, Sedentary leisure-time, Survival, TV viewing
National Category
Geriatrics Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:uu:diva-386182 (URN)10.1016/j.jsams.2018.11.020 (DOI)000468256300013 ()30522752 (PubMedID)
Funder
Swedish Research Council, 2017-00644
Available from: 2019-06-19 Created: 2019-06-19 Last updated: 2019-06-19Bibliographically approved
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Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-0118-0341

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