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- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- Vats, Sakshi, et al.
(författare)
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Characterization of the Mitochondrial Genetic Landscape in Abdominal Aortic Aneurysm
- 2023
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Ingår i: Journal of the American Heart Association. - 2047-9980. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Abdominal aortic aneurysm (AAA) is a vascular disease with a mortality rate of >80% if ruptured. Mitochondrial dysfunction has been previously implicated in AAA pathogenesis. In this study, we aimed to characterize the mitochondrial genetic landscape in AAA.Methods and Results: Whole mitochondrial genome sequencing and bioinformatics analysis were performed in comorbidity matched 48 cases without AAA and 48 cases with AAA, objectively diagnosed, and selected from a cohort of 65‐year‐old men recruited for a screening program. We identified differential mutational landscapes in men with and without AAA, with errors in mitochondrial DNA replication or repair as potential sources. Heteroplasmic insertions and overall heteroplasmy of structural rearrangements were significantly elevated in AAA cases. Three heteroplasmic variants were associated with risk factors of AAA: leukocyte concentration, plasma glucose, and cholesterol levels, respectively. Interestingly, mutations were more prevalent in regulatory part of the mitochondria, the displacement loop region, in AAA as compared with controls (P value <0.05), especially in the conserved and critical mitochondrial extended termination‐associated sequence region. Moreover, we report a novel 24 bp mitochondrial DNA duplication present exclusively in cases with AAA (4%) and 75% of the unmatched AAA biopsies. Finally, the haplogroup cluster JTU was overrepresented in AAA and significantly associated with a positive family history of AAA (odds ratio, 2.9 [95% CI, 1.1–8.1]).Conclusions: This is the first study investigating the mitochondrial genome in AAA, where important genetic alterations and haplogroups associated with AAA and clinical risk factors were identified. Our findings have the potential to fill in gaps in the missing genetic information on AAA.
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| 5. |
- Wang, Xiao, et al.
(författare)
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Association of Circulating Long Noncoding 7S RNA with Deep Vein Thrombosis
- 2023
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Ingår i: Seminars in Thrombosis and Hemostasis. - 1098-9064. ; 49:7, s. 702-708
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial dysfunction is a recognized factor in the pathogenesis of deep vein thrombosis (DVT). The role of 7S RNA, a long noncoding RNA that plays an important role in mitochondrial function, in DVT remains unclear. In this study, we aimed to investigate the potential use of 7S RNA as a biomarker in DVT. Plasma samples were obtained from 237 patients (aged 16-95 years) with suspected DVT recruited in a prospective multicenter management study (SCORE) where 53 patients were objectively confirmed with a diagnosis of DVT and the rest were diagnosed as non-DVT. 7S RNA was measured using quantitative real-time polymerase chain reaction in plasma samples. The plasma expression of 7S RNA was significantly lower in DVT compared with non-DVT (0.50 vs. 0.95, p = 0.043). With the linear regression analysis, we showed that the association between the plasma expression of 7S RNA and DVT (β = -0.72, p = 0.007) was independent of potential confounders. Receiver-operating characteristic curve analysis showed the area under the curve values of 0.60 for 7S RNA. The findings of the present study showed a notable association between 7S RNA and DVT. However, further investigations are needed to fully elucidate the exact role of 7S RNA in the pathophysiology of DVT and its diagnostic value.
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