| 1. |
- Dakhel, Ardwan, et al.
(författare)
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Novel cardiovascular biomarkers associated with peripheral arterial disease in men screened for abdominal aortic aneurysm
- 2022
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Ingår i: Vasa - European Journal of Vascular Medicine. - : Hogrefe Publishing Group. - 0301-1526. ; 51:3, s. 167-173
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral arterial disease (PAD) is a common atherosclerotic disease with severity ranging from asymptomatic to chronic limb threatening ischemia. The aim of the present cross-sectional study was to identify novel biomarkers associated with PAD. Patients and methods: Levels of 91 cardiovascular specific proteins in plasma samples were measured by the Proseek Multiplex CVD III96x96 panel from a cohort consisting of 267 65-year-old men recruited from a screening program for abdominal aortic aneurysm (AAA) Levels of protein biomarkers were compared in men with and without PAD (defined as an ankle brachial index of <0.9) and their diagnostic potential was calculated by receiver-operating characteristic analysis. Results: The prevalence of PAD was 14.2% (38/267). After adjustment for multiple comparisons, levels of the following 11 biomarkers remained significantly higher (p<0.0001) in patients with PAD: secretoglobin family 3A member 2, osteoprotegerin, urokinase-type plasminogen activator surface receptor, serum macrophage chemokine ligand 16, matrix metalloproteinase 9, p-selectin, growth differentiation factor 15, elafin, cystatin B, trefoil factor 3, and fatty acid-binding protein 4. Multivariable logistic regression analysis (adjusted for smoking, use of antihypertensive and lipid-lowering medication, and metformin) showed that 11 biomarkers were significantly associated with higher risk of PAD with odds ratios ranging from 1.6 to 2.4. Area under curve calculated by receiver operating characteristic curve analysis (diagnostic value) for each protein biomarker ranged from 0.63 to 0.74. Conclusions: We have identified multiple proteins with a potential to be diagnostic biomarkers for PAD, and further research is warranted to clarify their potential predictive and prognostic value.
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| 2. |
- Jansåker, Filip, et al.
(författare)
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Examining the causal effect of type 2 diabetes on ischemic heart disease : - a longitudinal study with four measurements (1980-2017)
- 2023
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 1872-8227 .- 0168-8227. ; 198
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This longitudinal study examines a possible causal effect between type 2 diabetes and ischemic heart disease (IHD) by using measurements on four occasions from the Swedish Statistics on Income and Living Conditions (SILC) together with nationwide healthcare registers.METHODS: This was a longitudinal study based on a random sample of men and women (n = 2014) from the Swedish population with four measurements in the SILC every eight years. Baseline was 1980/81 and the participants were followed for up to 37 years. The mean age and age range at baseline were 36.5 and 20-59 years, respectively. The study used Marginal Structural Modeling (MSM-Cox) to account for time-varying exposures by implementing inverse probability weighting (IPTW). MSM-Cox with IPTW was compared with Cox proportional hazard modelling.RESULTS: The hazard ratio (HR) for IHD (369 cases) with 95% confidence interval (CI) in participants with type 2 diabetes (11.1%) compared to participants without type 2 diabetes (88.9%) was significantly higher (1.99; CI = 1.15 - 3.44) when using MSM-Cox with IPTW after adjustments for clinical and sociodemographic risk factors. When applying Cox proportional hazard models adjusted for the same variables, the HR was lower and non-significant at 1.34 (CI = 0.94 - 1.98).CONCLUSIONS: This longitudinal study with four measurements assessed a possible causal association between type 2 diabetes and IHD by applying MSM-Cox with IPTW. Although causality cannot be determined due to the remaining risk of residual bias, the results may help to elucidate a potential causal relationship between type 2 diabetes and IHD. Further causal studies on possible underlying mechanisms are, however, needed.
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| 3. |
- Li, Yanni, et al.
(författare)
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Association of Mitochondrial DNA Copy Number and Telomere Length with Prevalent and Incident Cancer and Cancer Mortality in Women : A Prospective Swedish Population-Based Study
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:15
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Tidskriftsartikel (refereegranskat)abstract
- Changes in mitochondrial DNA copy number (mtDNA-CN) and telomere length have, separately, been proposed as risk factors for various cancer types. However, those results are conflicting. Here, mtDNA-CN and relative telomere length were measured in 3225 middle-aged women included in a large population-based prospective cohort. The baseline mtDNA-CN in patients with prevalent breast cancer was significantly higher (12.39 copies/µL) than cancer-free individuals. During an average of 15.2 years of follow-up, 520 patients were diagnosed with cancer. Lower mtDNA-CN was associated with decreased risk of genital organ cancer (hazard ratio (HR), 0.84), and shorter telomere length was associated with increased risk of urinary system cancer (HR, 1.79). Furthermore, mtDNA-CN was inversely associated with all-cause (HR, 1.20) and cancer-specific mortality (HR, 1.21) when considering all cancer types. Surprisingly, shorter telomere length was associated with decreased risk of cancer-specific mortality when considering all cancer types (HR, 0.85). Finally, lower mtDNA-CN and shorter telomere length were associated with increased risk of both all-cause and cancer-specific mortality in genital organ cancer patients. In this study population, we found that mtDNA-CN and telomere length were significantly associated with prevalent and incident cancer and cancer mortality. However, these associations were cancer type specific and need further investigation.
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| 4. |
- Li, Yanni, et al.
(författare)
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Mitochondrial heteroplasmic shifts reveal a positive selection of breast cancer
- 2023
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Ingår i: Journal of Translational Medicine. - 1479-5876. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially alternative to identify potential missing cancer information in circulation at an early stage.METHODS: To characterize mitochondrial mutation landscapes in breast cancer, whole mtDNA sequencing and bioinformatics analyses were performed on 86 breast cancer biopsies and 50 available matched baseline cancer-free whole blood samples from the same individuals, selected from a cohort of middle-aged women in Sweden. To determine whether the mutations can be detected in blood plasma prior to cancer diagnosis, we further designed a nested case-control study (n = 663) and validated the shortlisted mutations using droplet digital PCR.RESULTS: We detected different mutation landscapes between biopsies and matched whole blood samples. Compared to whole blood samples, mtDNA from biopsies had higher heteroplasmic mutations in the D-loop region (P = 0.02), RNR2 (P = 0.005), COX1 (P = 0.037) and CYTB (P = 0.006). Furthermore, the germline mtDNA mutations had higher heteroplasmy level than the lost (P = 0.002) and de novo mutations (P = 0.04). The nonsynonymous to synonymous substitution ratio (dN/dS) was higher for the heteroplasmic mutations (P = 7.25 × 10 -12) than that for the homoplasmic mutations, but the de novo (P = 0.06) and lost mutations (P = 0.03) had lower dN/dS than the germline mutations. Interestingly, we found that the critical regions for mitochondrial transcription: MT-HSP1 (odds ratio [OR]: 21.41), MT-TFH (OR: 7.70) and MT-TAS2 (OR: 3.62), had significantly higher heteroplasmic mutations than the rest of the D-loop sub-regions. Finally, we found that the presence of mt.16093T > C mutation increases 67% risk of developing breast cancer. CONCLUSIONS: Our findings show that mitochondrial genetic landscape changes during cancer pathogenesis and positive selection of mtDNA heteroplasmic mutations in breast cancer. Most importantly, the mitochondrial mutations identified in biopsies can be traced back in matched plasma samples and could potentially be used as early breast cancer diagnostic biomarkers.
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| 5. |
- Li, Yanni, et al.
(författare)
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Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types
- 2023
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 88
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mitochondrial dysfunction is a hallmark of cancer. However, it is unclear whether it is a cause of cancer. This two-sample Mendelian randomization (MR) analyses, uses genetic instruments to proxy the exposure of mitochondrial dysfunction and cancer summary statistics as outcomes, allowing for causal inferences.METHODS: Summary statistics from 18 common cancers (2107-491,974 participants), gene expression, DNA methylation and protein expression quantitative trait loci (eQTL, mQTL and pQTL, respectively, 1000-31,684 participants) on individuals of European ancestry, were included. Genetic variants located within or close to the 1136 mitochondrial-related genes (in cis) and robustly associated with the mitochondrial molecular alterations were used as instrumental variables, and their causal associations with cancers were examined using summary-data-based MR (SMR) analyses. An additional five MR methods were used as sensitivity analyses to confirm the casual associations. A Bayesian test for colocalization between mitochondrial molecular QTLs and cancer risk loci was performed to provide insights into the potential regulatory mechanisms of risk variants on cancers.FINDINGS: We identified potential causal relationships between mitochondrial-related genes and breast, prostate, gastric, lung cancer and melanoma by primary SMR analyses. The sensitivity and the colocalization analyses further refined four genes that have causal effects on three types of cancer. We found strong evidence of positive association of FDPS expression level with breast cancer risk (OR per SD, 0.66; 95% CI, 0.49-0.83; P = 9.77 × 10-7), NSUN4 expression level with both breast cancer risk (OR per SD, 1.05; 95% CI, 1.03-1.07; P = 5.24 × 10-6) and prostate cancer risk (OR per SD, 1.06; 95% CI, 1.03-1.09; P = 1.01 × 10-5), NSUN4 methylation level with both breast and prostate cancer risk, and VARS2 methylation level with lung cancer risk.INTERPRETATIONS: This data-driven MR study demonstrated the causal role of mitochondrial dysfunction in multiple cancers. Furthermore, this study identified candidate genes that can be the targets of potential pharmacological agents for cancer prevention.FUNDING: This work was supported by Styrelsen för Allmänna Sjukhusets i Malmö Stiftelse för bekämpande av cancer (20211025).
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| 6. |
- Memon, Ashfaque A, et al.
(författare)
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Association of mitochondrial DNA copy number with prevalent and incident type 2 diabetes in women : A population-based follow-up study
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial dysfunction is an important factor of the aging process and may play a key role in various diseases. Mitochondrial DNA copy number (mtDNA-CN) is an indirect measure of mitochondrial dysfunction and is associated with type 2 diabetes mellitus (T2DM); however, whether mtDNA-CN can predict the risk of developing T2DM is not well-known. We quantified absolute mtDNA-CN in both prevalent and incident T2DM by well-optimized droplet digital PCR (ddPCR) method in a population-based follow-up study of middle aged (50-59 years) Swedish women (n = 2387). The median follow-up period was 17 years. Compared to those who were free of T2DM, mtDNA-CN was significantly lower in both prevalent T2DM and in women who developed T2DM during the follow-up period. Mitochondrial DNA-copy number was also associated with glucose intolerance, systolic blood pressure, smoking status and education. In multivariable Cox regression analysis, lower baseline mtDNA-CN was prospectively associated with a higher risk of T2DM, independent of age, BMI, education, smoking status and physical activity. Moreover, interaction term analysis showed that smoking increased the effect of low mtDNA-CN at baseline on the risk of incident T2DM. Mitochondrial DNA-copy number may be a risk factor of T2DM in women. The clinical usefulness of mtDNA-CN to predict the future risk of T2DM warrants further investigation.
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| 7. |
- Memon, Ashfaque A., et al.
(författare)
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Identification of novel diagnostic and prognostic biomarkers for abdominal aortic aneurysm
- 2020
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Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4873 .- 2047-4881. ; 27:2, s. 132-142
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Abdominal aortic aneurysm is a life-threatening condition due to the risk of aneurysm growth and rupture. There are no approved diagnostic or prognostic biomarkers for abdominal aortic aneurysm. We aimed to identify diagnostic and prognostic biomarkers for abdominal aortic aneurysm and to investigate their relationship with abdominal aortic aneurysm diameter and growth. Methods: In this case-control study, patients were included from an abdominal aortic aneurysm screening study on men aged ≥65 years. Of 24,589 examined men, 415 had abdominal aortic aneurysm, out of whom 134 consented to participate in the present study. One hundred and thirty-six screened men with aortic diameter <30 mm, matched for comorbidities and time of sampling were included as non-abdominal aortic aneurysm patients. Ninety-one cardiovascular specific proteins in plasma samples were measured by the Proseek Multiplex CVD III96x96 panel. Results: After Bonferroni correction, plasma levels of 21 proteins associated with proteolysis, oxidative-stress, lipid metabolism, and inflammation were significantly increased, whereas levels of paraoxonase 3, associated with high-density lipoprotein metabolism, were decreased in abdominal aortic aneurysm patients. Combination of growth/differentiation factor 15 and cystatin B had the best ability to discriminate abdominal aortic aneurysm from non-abdominal aortic aneurysm (area under the curve, 0.76; sensitivity, 80% and specificity, 52%). Myeloperoxidase showed the best prognostic value (area under the curve, 0.71; sensitivity, 80% and specificity, 59%) and higher baseline levels of myeloperoxidase were significantly associated with faster abdominal aortic aneurysm growth compared with lower levels, independent of baseline diameter. Conclusions: We have identified multiple proteins associated with abdominal aortic aneurysm diameter and growth with a potential to become novel diagnostic and prognostic biomarkers for abdominal aortic aneurysm.
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| 8. |
- Memon, Ashfaque A, et al.
(författare)
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Mitochondrial DNA Copy Number: Linking Diabetes and Cancer
- 2022
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Ingår i: Antioxidants and Redox Signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 37:16-18, s. 1168-1190
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Forskningsöversikt (refereegranskat)abstract
- Recent Advances: Various studies have suggested that mitochondrial DNA copy number (mtDNA-CN), a surrogate biomarker of mitochondrial dysfunction, is an easily quantifiable biomarker for chronic diseases, including diabetes and cancer. However, current knowledge is limited, and the results are controversial. This has been attributed mainly to methodology and study design.Critical Issues: The incidence of diabetes and cancer has increased significantly in recent years. Moreover, type 2 diabetes (T2D) has been shown to be a risk factor for cancer. mtDNA-CN has been associated with both T2D and cancer. However, it is not known whether mtDNA-CN plays any role in the association between T2D and cancer.Significance: In this review, we have discussed mtDNA-CN in diabetes and cancer, and reviewed the literature and methodology used in published studies so far. Based on the literature review, we have speculated how mtDNA-CN may act as a link between diabetes and cancer. Furthermore, we have provided some recommendations for reliable translation of mtDNA-CN as a biomarker.Future Directions: Further research is required to elucidate the role of mtDNA-CN in the association between T2D and cancer. If established, early lifestyle interventions, such as physical activity and diet control that improve mitochondrial function, may help preventing cancer in patients with T2D.
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| 9. |
- Nymberg, Peter, et al.
(författare)
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Mitochondria-DNA copy-number and incident venous thromboembolism among middle-aged women : a population-based cohort study
- 2021
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Ingår i: Journal of Thrombosis and Thrombolysis. - : Springer Science and Business Media LLC. - 1573-742X .- 0929-5305. ; 52:1, s. 148-157
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Tidskriftsartikel (refereegranskat)abstract
- Venous thromboembolism (VTE) is the third most common cardiovascular disease. Low amount of mitochondrial DNA copy number (mtDNA-CN) has been associated with arterial cardiovascular disease (CVD) and reflects mitochondrial dysfunctions. However, whether mtDNA-CN is associated with VTE has not been determined. To examine the association between mtDNA-CN and incident VTE among middle-aged women. 6917 women aged 50-64 years, followed for 20 years in the Women's Health In the Lund Area (WHILA) study. DNA samples for mtDNA quantification were available from 2521 women. Quantification of mtDNA-CN was performed using a well-optimized droplet digital PCR method. After exclusions of women with anticoagulant treatment, women living in nursing homes, and women who were diagnosed with cancer, stroke, VTE, or coronary heart disease at baseline, a cohort of 2117 women remained for analysis. Cox regression was used to analyze the relationship between mtDNA-CN and time to VTE (hazard ratio = HR). In total, 87 women were diagnosed with VTE during follow-up, corresponding to an incidence rate of 2.8 per 1000 person-years. Neither crude nor adjusted HR for mtDNA-CN were significantly associated with incident VTE. A sensitivity analysis with inclusion of excluded women did not change the results. MtDNA-CN was not significantly associated with VTE. The present study suggests that mtDNA-CN, reflecting mitochondrial dysfunction, should not be considered a biomarker that plays a major role for developing VTE. However, due to limited study size we may not exclude minor associations.
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| 10. |
- Roumans, Sanne, et al.
(författare)
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Association of circulating let-7b-5p with major depressive disorder : a nested case-control study
- 2021
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Ingår i: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 21:1, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Major depressive disorder (MDD) is one of the most common psychiatric disorders and is a great disease burden. However, its underlying pathophysiology and aetiology remain poorly understood. Available evidence suggests that circulating microRNAs (miRNAs) are associated with MDD, but it is still unknown whether miRNAs can predict subsequent incident MDD.METHODS: In this nested case-control study, a total of 104 individuals, who were free of MDD at baseline, from the Women's Health in Lund Area (WHILA) cohort were included. Among them, 52 individuals developed MDD (cases) during the 5 years follow-up and 52 individuals did not develop MDD (controls). Plasma expression levels of miR-17-5p, miR-134-5p, miR-144-5p, let-7b-5p and let-7c-5p at baseline were assessed using qRT-PCR. Logistic regression was used to estimate the odds of developing MDD among individuals with different levels of miRNA expression.RESULTS: Plasma expression levels of let-7b-5p were significantly lower (p = 0.02) at baseline in cases compared to controls. After adjustment for age and BMI, let-7b-5p was negatively associated with odds for developing MDD (OR = 0.33, p = 0.03, 95% CI = 0.12-0.91). Moreover, let-7b-5p expression levels showed a trend over time with larger differences between cases and controls for the earlier cases (MDD diagnosis <2 years from baseline) than MDD cases developed later (MDD diagnosis 2-5 years from baseline).CONCLUSIONS: These findings show that lower plasma levels of let-7b-5p are associated with a higher future risk of MDD. Results need to be validated in a large cohort to examine its potential as a peripheral biomarker for MDD.
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