| 1. |
- Thompson, Deborah J, et al.
(författare)
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Genetic predisposition to mosaic Y chromosome loss in blood
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 575, s. 652-657
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Tidskriftsartikel (refereegranskat)abstract
- Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.
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| 2. |
- Forsberg, Lars A., 1974-, et al.
(författare)
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Mosaic loss of chromosome Y in leukocytes matters
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:1, s. 4-7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Danielsson, Marcus, et al.
(författare)
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Longitudinal changes in the frequency of mosaic chromosome Y loss in peripheral blood cells of aging men varies profoundly between individuals
- 2020
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 28:3, s. 349-357
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Tidskriftsartikel (refereegranskat)abstract
- Mosaic loss of chromosome Y (LOY) is the most common somatic genetic aberration and is associated with increased risk for all-cause mortality, various forms of cancer and Alzheimer's disease, as well as other common human diseases. By tracking LOY frequencies in subjects from which blood samples have been serially collected up to five times during up to 22 years, we observed a pronounced intra-individual variation of changes in the frequency of LOY within individual men over time. We observed that in some individuals the frequency of LOY in blood clearly progressed over time and that in other men, the frequency was constant or showed other types of longitudinal development. The predominant method used for estimating LOY is calculation of the median Log R Ratio of probes located in the male specific part of chromosome Y (mLRRY) from intensity data generated by SNP-arrays, which is difficult to interpret due to its logarithmic and inversed scale. We present here a formula to transform mLRRY-values to percentage of LOY that is a more comprehensible unit. The formula was derived using measurements of LOY from matched samples analysed using SNP-array, whole genome sequencing and a new AMELX/AMELY-based assay for droplet digital PCR. The methods described could be applied for analyses of the vast amount of SNP-array data already generated in the scientific community, allowing further discoveries of LOY associated diseases and outcomes.
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| 4. |
- Dumanski, Jan P., et al.
(författare)
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A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors
- 2017
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Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 24:8, s. 427-443
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Tidskriftsartikel (refereegranskat)abstract
- The genetics behind predisposition to small intestinal neuroendocrine tumors (SI-NETs) is largely unknown, but there is growing awareness of a familial form of the disease. We aimed to identify germline mutations involved in the carcinogenesis of SI-NETs. The strategy included next-generation sequencing of exome- and/or whole-genome of blood DNA, and in selected cases, tumor DNA, from 24 patients from 15 families with the history of SI-NETs. We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients. The result was compared with the frequency of the candidate mutations in three control cohorts with a total of 35,688 subjects. A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038). We also found a statistically significant difference in age at diagnosis between familial and sporadic SI-NETs. MUTYH is involved in the protection of DNA from mutations caused by oxidative stress. The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals. Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.
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| 5. |
- Sano, Soichi, et al.
(författare)
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Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 377:6603, s. 292-297
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Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor β1–neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure–associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.
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| 6. |
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| 7. |
- Chase, Andrew, et al.
(författare)
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PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia
- 2019
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 33:5, s. 1184-1194
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Tidskriftsartikel (refereegranskat)abstract
- Acquired uniparental disomy (aUPD, also known as copy-neutral loss of heterozygosity) is a common feature of cancer cells and characterized by extended tracts of somatically-acquired homozygosity without any concurrent loss or gain of genetic material. The presumed genetic targets of many regions of aUPD remain unknown. Here we describe the association of chromosome 22 aUPD with mutations that delete the C-terminus of PRR14L in patients with chronic myelomonocytic leukemia (CMML), related myeloid neoplasms and age-related clonal hematopoiesis (ARCH). Myeloid panel analysis identified a median of three additional mutated genes (range 1-6) in cases with a myeloid neoplasm (n = 8), but no additional mutations in cases with ARCH (n = 2) suggesting that mutated PRR14L alone may be sufficient to drive clonality. PRR14L has very limited homology to other proteins and its function is unknown. ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype. RNA-Seq and cellular localization studies suggest a role for PRR14L in cell division. PRR14L is thus a novel, biallelically mutated gene and potential founding abnormality in myeloid neoplasms.
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| 8. |
- Danielsson, Marcus, 1985-
(författare)
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Mosaic loss of chromosome Y : methods for detection and consequences for affected leukocytes and men
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It has been known for centuries that men live shorter lives than women, but until recently, the biological mechanisms driving this sex bias has been poorly understood. Mosaic loss of chromosome Y (mLOY) refers to chromosome Y aneuploidy, a male specific and the most common somatic mutation in human blood cells. Known risk factors include age, smoking and genetic predisposition. Men with mLOY carry a fraction of blood cells without the Y chromosome, due to its loss from hematopoietic progenitor cells during life. Hence, in a single cell LOY is a binary event causing the absence of almost 2% of the male haploid nuclear genome. When measured in bulk samples, it is present as a continuous mosaicism affecting a fraction of cells. A paper published in 1963 demonstrated that mLOY is frequent in cells of the hematopoietic system in aging men, but it was long viewed as a neutral event. In contrast, recent discoveries demonstrate that mLOY in blood is associated with various forms of cancer, autoimmune conditions, Alzheimer’s disease, cardiovascular events, diabetes as well as age-related macular degeneration. Studies support the hypothesis that mLOY in leukocytes may exacerbate disease processes in other organs. Thus, given the associations with several common diseases, mLOY in blood cells could help explain reduced male longevity.A main aim and a long term goal of the work presented in this thesis is the development of novel methods for improved mLOY detection. Focus here is exploration of analytes such as DNA, RNA and proteins, including studies of bulk samples as well as single cell approaches. Among the evaluated methods are SNP-arrays, ddPCR, WGS, RNA-seq and CITE-seq. Furthermore, a novel method called SPARC was developed for co-detection of the transcriptome and a panel of 92 proteins in single cells. Future methods with clinical utility for mLOY should, in addition to robust detection, be able to simultaneously discriminate mLOY in different types of immune cells. The latter builds on recent results showing cell type specificity with regard to disease associations. To meet these needs, single cell analyses using mLOY associated cell surface proteins have been pursued and proof-of-concept established. Implementation of mLOY screening in general populations has the potential to identify men with increased risk for various disease. It could be envisioned that further medical examination of men affected with mLOY would enable earlier diagnoses of ongoing disease processes as well as serving to guide targeted interventions.
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| 9. |
- Danielsson, Marcus, et al.
(författare)
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Reply to Veitia
- 2021
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Ingår i: European Journal of Human Genetics. - : Springer Nature. - 1018-4813 .- 1476-5438. ; 29:9, s. 1323-1324
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Dumanski, Jan P., et al.
(författare)
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Immune cells lacking Y chromosome show dysregulation of autosomal gene expression
- 2021
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 78:8, s. 4019-4033
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.
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| 11. |
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| 12. |
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| 13. |
- Forsberg, Lars A., 1974-, et al.
(författare)
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Influence of genetic dissimilarity in the reproductive success and mate choice of brown trout – females fishing for optimal MHC dissimilarity
- 2007
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Ingår i: Journal of Evolutionary Biology. - : Wiley. - 1010-061X .- 1420-9101. ; 20:5, s. 1859-1869
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Tidskriftsartikel (refereegranskat)abstract
- We examined the reproductive success of 48 adult brown trout (Salmo trutta L.) which were allowed to reproduce in a stream that was controlled for the absence of other trout. Parentage analyses based on 11 microsatellites permitted us to infer reproductive success and mate choice preferences in situ. We found that pairs with intermediate major histocompatibility complex (MHC) dissimilarity mated more often than expected by chance. It appears that female choice was the driving force behind this observation because, compared with other individuals, males with intermediate MHC dissimilarity produced a larger proportion of offspring, whereas female reproductive output did not show this pattern. Hence, rather than seeking mates with maximal MHC dissimilarity, as found in several species, brown trout seemed to prefer mates of intermediate MHC difference, thus supporting an optimality-based model for MHC-dependent mate choice.
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| 14. |
- Forsberg, Lars A., 1974-
(författare)
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Loss of chromosome Y (LOY) in blood cells is associated with increased risk for disease and mortality in aging men
- 2017
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Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 0340-6717 .- 1432-1203. ; 136:5, s. 657-663
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Forskningsöversikt (refereegranskat)abstract
- Recent discoveries have shown that harboring cells without the Y chromosome in the peripheral blood is associated with increased risk for all-cause mortality and disease such as different forms of cancer, Alzheimer’s disease,as well as other conditions in aging men. In the entire world, the life expectancy of men is shorter compared to women, a sex difference that has been known for centuries,but the underlying mechanism(s) are not well understood.As a male-specific genetic risk factor, an increased risk for pathology and mortality associated with mosaic loss of chromosome Y (LOY) in blood cells could help to explain that men on average live shorter lives compared to women.This review primarily focuses on observed associations between LOY in blood and various diseases in aging men.Other topics covered are known risk factors for LOY, methodsto detect LOY, and a discussion regarding mechanisms such as immunosurveillance, that could possibly explain how an acquired mutation in blood cells can be associated with disease processes in other organs.
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| 15. |
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| 16. |
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| 17. |
- Mattisson, Jonas, et al.
(författare)
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Leukocytes with chromosome Y loss have reduced abundance of the cell surface immunoprotein CD99
- 2021
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mosaic loss of chromosome Y (LOY) in immune cells is a male-specific mutation associated with increased risk for morbidity and mortality. The CD99 gene, positioned in the pseudoautosomal regions of chromosomes X and Y, encodes a cell surface protein essential for several key properties of leukocytes and immune system functions. Here we used CITE-seq for simultaneous quantification of CD99 derived mRNA and cell surface CD99 protein abundance in relation to LOY in single cells. The abundance of CD99 molecules was lower on the surfaces of LOY cells compared with cells without this aneuploidy in all six types of leukocytes studied, while the abundance of CD proteins encoded by genes located on autosomal chromosomes were independent from LOY. These results connect LOY in single cells with immune related cellular properties at the protein level, providing mechanistic insight regarding disease vulnerability in men affected with mosaic chromosome Y loss in blood leukocytes.
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| 18. |
- Mattisson, Jonas, 1994-, et al.
(författare)
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Loss of chromosome Y in regulatory T cells
- 2024
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Ingår i: BMC Genomics. - : BioMed Central (BMC). - 1471-2164. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMosaic loss of chromosome Y (LOY) in leukocytes is the most prevalent somatic aneuploidy in aging humans. Men with LOY have increased risks of all-cause mortality and the major causes of death, including many forms of cancer. It has been suggested that the association between LOY and disease risk depends on what type of leukocyte is affected with Y loss, with prostate cancer patients showing higher levels of LOY in CD4 + T lymphocytes. In previous studies, Y loss has however been observed at relatively low levels in this cell type. This motivated us to investigate whether specific subsets of CD4 + T lymphocytes are particularly affected by LOY. Publicly available, T lymphocyte enriched, single-cell RNA sequencing datasets from patients with liver, lung or colorectal cancer were used to study how LOY affects different subtypes of T lymphocyte. To validate the observations from the public data, we also generated a single-cell RNA sequencing dataset comprised of 23 PBMC samples and 32 CD4 + T lymphocytes enriched samples.ResultsRegulatory T cells had significantly more LOY than any other studied T lymphocytes subtype. Furthermore, LOY in regulatory T cells increased the ratio of regulatory T cells compared with other T lymphocyte subtypes, indicating an effect of Y loss on lymphocyte differentiation. This was supported by developmental trajectory analysis of CD4 + T lymphocytes culminating in the regulatory T cells cluster most heavily affected by LOY. Finally, we identify dysregulation of 465 genes in regulatory T cells with Y loss, many involved in the immunosuppressive functions and development of regulatory T cells.ConclusionsHere, we show that regulatory T cells are particularly affected by Y loss, resulting in an increased fraction of regulatory T cells and dysregulated immune functions. Considering that regulatory T cells plays a critical role in the process of immunosuppression; this enrichment for regulatory T cells with LOY might contribute to the increased risk for cancer observed among men with Y loss in leukocytes.
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| 19. |
- 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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| 20. |
- Riaz, Moeen, et al.
(författare)
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A polygenic risk score predicts mosaic loss of chromosome Y in circulating blood cells
- 2021
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Ingår i: Cell & Bioscience. - : Springer Nature. - 2045-3701. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mosaic loss of Y chromosome (LOY) is the most common somatic change that occurs in circulating white blood cells of older men. LOY in leukocytes is associated with increased risk for all-cause mortality and a range of common disease such as hematological and non-hematological cancer, Alzheimer’s disease, and cardiovascular events. Recent genome-wide association studies identified up to 156 germline variants associated with risk of LOY. The objective of this study was to use these variants to calculate a novel polygenic risk score (PRS) for LOY, and to assess the predictive performance of this score in a large independent population of older men.Results: We calculated a PRS for LOY in 5131 men aged 70 years and older. Levels of LOY were estimated using microarrays and validated by whole genome sequencing. After adjusting for covariates, the PRS was a significant predictor of LOY (odds ratio [OR] = 1.74 per standard deviation of the PRS, 95% confidence intervals [CI] 1.62–1.86, p < 0.001). Men in the highest quintile of the PRS distribution had > fivefold higher risk of LOY than the lowest (OR = 5.05, 95% CI 4.05–6.32, p < 0.001). Adding the PRS to a LOY prediction model comprised of age, smoking and alcohol consumption significantly improved prediction (AUC = 0.628 [CI 0.61–0.64] to 0.695 [CI 0.67–0.71], p < 0.001).Conclusions: Our results suggest that a PRS for LOY could become a useful tool for risk prediction and targeted intervention for common disease in men.
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| 21. |
- Tan, Xiao, et al.
(författare)
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Self-reported sleep disturbances and prostate cancer morbidity and mortality in Swedish men : A longitudinal study over 40 years
- 2018
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Ingår i: Journal of Sleep Research. - : Wiley. - 0962-1105 .- 1365-2869. ; 27:6
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Tidskriftsartikel (refereegranskat)abstract
- The present study, with an observational period of about 40 years, examined the association between self-reported sleep disturbances (i.e. problems with falling and staying asleep; use of hypnotics) and prostate cancer morbidity and mortality in initially 2322 men (all 50 years old at baseline). Self-reported sleep disturbances and established risk factors (e.g. age, lower urinary tract symptoms, smoking and family history of cancer) were measured at ages 50 and 70 years. Information about prostate cancer diagnosis and deaths as a result of prostate cancer was available from the National Cancer Registry and the Swedish Civil Registry of Morbidity. During the observational period, 263 participants developed prostate cancer (11% of the total cohort); 146 of them died as a result of prostate cancer. There was no association between sleep disturbances and prostate cancer morbidity or mortality (hazard ratio 1.09, 95% confidence interval (CI) 0.79, 1.52, and hazard ratio 1.21, 95% CI 0.77, 1.91, respectively). Similar findings were observed when examining associations between single sleep disturbance parameters and prostate cancer morbidity and mortality. Our study does not provide evidence that reports of sleep disturbances increase the risk of prostate cancer morbidity or mortality in middle to older-aged men. Therefore, assessing subjective sleep problems may not meaningfully help to identify men at risk of developing prostate cancer or dying of this devastating condition.
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