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- Ganna, Andrea
(författare)
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Risk prediction models for cardiovascular disease and overall mortality
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prediction or prognostication is at the core of modern evidence-based medicine. Prediction of overall mortality and cardiovascular disease can be improved by a systematic evaluation of measurements from large-scale epidemiological studies or by using nested sampling designs to discover new markers from omics technologies. In study I, we investigated if prediction measures such as calibration, discrimination and reclassification could be calculated within traditional sampling designs and which of these designs were the most efficient. We found that is possible to calculate prediction measures by using a proper weighting system and that a stratified casecohort design is a reasonable choice both in terms of efficiency and simplicity. In study II, we investigated the clinical utility of several genetic scores for incident coronary heart disease. We found that genetic information could be of clinical value in improving the allocation of patients to correct risk strata and that the assessment of a genetic risk score among intermediate risk subjects could help to prevent about one coronary heart disease event every 318 people screened. In study III, we explored the association between circulating metabolites and incident coronary heart disease. We found four new metabolites associated with coronary heart disease independently of established cardiovascular risk factors and with evidence of clinical utility. By using genetic information we determined a potential causal effect on coronary heart disease of one of these novel metabolites. In study IV, we compared a large number of demographics, health and lifestyle measurements for association with all-cause and cause-specific mortality. By ranking measurements in terms of their predictive abilities we could provide new insights about their relative importance, as well as reveal some unexpected associations. Moreover we developed and validated a prediction score for five-year mortality with good discrimination ability and calibrated it for the entire UK population. In conclusion, we applied a translational approach spanning from the discovery of novel biomarkers to their evaluation in terms of clinical utility. We combined this effort with methodological improvements aimed to expand prediction measures in settings that were not previously explored. We identified promising novel metabolomics markers for cardiovascular disease and supported the potential clinical utility of a genetic score in primary prevention. Our results might fuel future studies aimed to implement these findings in clinical practice.
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| 2. |
- Mattisson, Jonas, 1994-
(författare)
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The role of hematopoietic chromosome Y loss in health and disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mosaic loss of chromosome Y (mLOY) is the most common somatic mutation, and affected men have increased risk for all major causes of death, including cardiovascular diseases and cancer. As a male specific mutation, it helps explain why men live shorter lives than women. However, the causality is debated, and contrasting models have been proposed to explain how Y loss in blood could be linked with disease in other organs. In this thesis, I provide results contributing to this debate.In Paper I, we identify 156 loci associated with genetic susceptibility for mLOY. Enrichment of loci involved in processes such as cell-cycle regulation and cancer susceptibility suggest that mLOY could be viewed as a barometer of genomic instability. In Paper II, we used the mLOY-associated variants identified in Paper I to calculate a PRS for mLOY in an independent cohort. We found that men with high PRS displayed a five-fold increased risk in an age dependent manner.In Paper III, we showed that mLOY and CHIP driving SNVs often co-occur in leukocytes. Considering that they share clinical manifestations, further studies are necessary to elucidate how these mutations contributes to disease risk. In Paper IV, we studied transcriptional effects of mLOY in leukocytes and identified almost 500 dysregulated autosomal genes, varying between cell types. We also report that mLOY in specific leukocytes might be linked with different types of disease. In Paper V, regulatory T cells are shown to be affected with Y loss to a greater extent than other CD4+ T lymphocytes. We propose that mLOY might drive T lymphocytes towards the regulatory phenotype, known to exhibit immunosuppressive functions. In Paper VI, we used CITE-seq to show that expression and cell surface abundance of the immunoprotein CD99 is lower in leukocytes with Y loss. This finding provides a possible explanation how mLOY could influence normal immune response, since CD99 is essential is for the mobility and cell-to-cell interactions of leukocytes. In Paper VII, it is shown that hematological mLOY cause disease directly in other organs. Mice with mLOY was shown to have a reduced survival, increased fibrosis and cardiac dysfunction, while men in UK biobank with mLOY in blood was found to die from diseases of the circulatory system in a dose dependent manner. Treatment with TGFβ1-inhibitors could restore cardiac function in mLOY-mice. Together, the presented results show that mLOY both reflect genomic instability overall, while also causing disease directly.
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