Loss of Y and clonal hematopoiesis in blood—two sides of the same coin?

Ljungström, Viktor; Mattisson, Jonas; Halvardson, Jonatan; Pandzic, Tatjana; Davies, Hanna; Rychlicka-Buniowska, Edyta; Danielsson, Marcus; Lacaze, Paul; Cavelier, Lucia; Dumanski, Jan P.; Baliakas, Panagiotis; Forsberg, Lars A.

doi:10.1038/s41375-021-01456-2

Cited by 28 publications

(31 citation statements)

References 15 publications

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“…The observation of profibrotic signaling in mLOY is unexpected compared with findings of how CHIP mechanistically contributes to cardiovascular disease. Whereas there is a high co-occurrence of mLOY with CHIP ( 5 , 6 ), and both are associated with cardiovascular disease mortality, including heart failure ( 17 , 18 ), CHIP appears to largely promote pathological processes through the overactivation of IL-1β/IL-6 inflammatory signaling in myeloid cells ( 19 – 22 ). It is increasingly recognized that chronic diseases are caused by a spectrum of inflammation- and fibrosis-driven events ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon is the most prevalent postzygotic mutation in leukocytes ( 2 ). The frequency of hematopoietic mLOY increases with age and smoking status ( 3 , 4 ) and is associated with the condition of clonal hematopoiesis of indeterminate potential (CHIP) ( 5 , 6 ). Although the technology to assess mLOY is evolving, it has recently been reported that mLOY is detectable in 40% of 70-year-old males and 57% of 93-year-old males ( 4 , 7 ).…”

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confidence: 99%

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Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

Sano

Horitani

Ogawa

et al. 2022

Science

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104

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

Sano

Horitani

Ogawa

et al. 2022

Science

Self Cite

104

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“… 144 A recent study provided evidence that 75% of men with loss of chromosome Y also carried mutations in genes typically associated with CHIP. 145 The study of the mutational profile of the monocytes of 26 individuals with loss of chromosome Y showed frequent CHIP pathogenic variants in TET2, DNMT3A, SF3B1, ASXL1 and TP53 genes; furthermore, BCOR, ZRSF2, BCORL1, FBWW7, FLT3 and GATA2 gene resulted also to be frequently mutated. 145 Another recent study showed that patients with chromosome Y loss in their bone marrow cells often have mutations of DNMT3A, TET2 and ASXL1 genes.…”

Section: The Discovery Of Clonal Hematopoiesis Of Indeterminate Poten...mentioning

confidence: 99%

“… 145 The study of the mutational profile of the monocytes of 26 individuals with loss of chromosome Y showed frequent CHIP pathogenic variants in TET2, DNMT3A, SF3B1, ASXL1 and TP53 genes; furthermore, BCOR, ZRSF2, BCORL1, FBWW7, FLT3 and GATA2 gene resulted also to be frequently mutated. 145 Another recent study showed that patients with chromosome Y loss in their bone marrow cells often have mutations of DNMT3A, TET2 and ASXL1 genes. 146 The analysis of bone marrow cells of elderly subjects with loss of Y chromosome showed that individuals with ≥75% of metaphases with LOY have a greater likelihood of having myeloid-associated mutations and a higher risk of developing myeloid neoplasia.…”

Section: The Discovery Of Clonal Hematopoiesis Of Indeterminate Poten...mentioning

confidence: 99%

Clonal Hematopoiesis: Role in Hematologic Non-Hematologic

Testa¹,

Castelli²

2022

Mediterr J Hematol Infect Dis

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Hematopoietic stem cells (HSCs) ensure the coordinated and balanced production of all hematopoietic cell types throughout life. Aging is associated with a gradual decline of the self-renewal and regenerative potential of HSCs and with the development of clonal hematopoiesis. Clonal hematopoiesis of indeterminate potential (CHIP) is a term defining the clonal expansion of genetically variant hematopoietic cells bearing one or more gene mutations and/or structural variants (such as copy number alterations). CHIP increases exponentially with age and is associated with cancers, including hematologic neoplasia, cardiovascular and other diseases. The presence of CHIP consistently increases the risk of hematologic malignancy, particularly in individuals who have CHIP in association with peripheral blood cytopenia. Key words: hematopoiesis, hematopoietic stem cells, clonal hematopoiesis, gene mutations, next generation sequencing.

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“…15 LOY with large clone size has been linked to the presence of somatic mutations associated with hematological malignancies and an elevated risk of developing myeloid neoplasia in two recent, small studies of selected cases. 16,17 It has been suggested that LOY might be a broad marker of genomic instability across different tissues and may exert its effects by altering immune cell function. 2,18 Clonal hematopoiesis (CH) is a widespread phenomenon characterized by the presence of expanded clones of mutated blood cells, 19 predominantly in individuals over the age of 60.…”

Section: Introductionmentioning

confidence: 99%

Age-related loss of the Y chromosome is associated with sex hormone binding globulin and selected drivers of clonal hematopoiesis

Dawoud

Tapper

Cross

2022

Preprint

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Mosaic loss of the Y-chromosome (LOY) is the most common somatic alteration in men. We aimed to assess the relationship between LOY and serum biomarkers in UK Biobank and explore the interaction with constitutional and somatic genetics. LOY was strongly associated with levels of sex hormone binding globulin (SHBG, beta=0.12, PFDR= P = 7.44x10-36, adjusted for age, age squared, gender, smoking status, smoking intensity and principal genetic components), a key regulator of testosterone bioavailability associated with diverse disorders including cancer and autoimmune diseases. Furthermore, LOY was associated with total testosterone (TT, beta=0.09, PFDR=2.23 x 10-20), but not bioavailable testosterone (PFDR=0.46) or free testosterone (PFDR=0.75). These relationships remained significant after sensitivity analysis that included comorbidities and body mass index (SHBG, beta = 0.08, PFDR = 4.61x10-21; TT, beta=0.05, PFDR=4.13 x 10-9). Mendelian randomisation suggested a causal effect of SHBG on LOY in BioBank Japan (P=6.58x10-4) but there was no evidence for an effect of LOY on SHBG (P=0.46). Assessment of cis-eQTLs for 13 genes associated with LOY identified two SNPs that were also associated with levels of SHBG, however only rs7141210 (imprinted DLK1-MEG3 locus) modified the relationship between SHBG and LOY (rs7141210-T/T; Pinteraction=0.04) with low levels of SHBG seen specifically in men without LOY (beta=-0.02, P=0.001), but not those with LOY (P=0.41). Age-related clonal hematopoiesis (CH) defined by somatic driver mutations was not associated with sex hormone levels but was associated with LOY at clonal fractions >30% (OR=1.52, P=2.92x10-4). TET2, TP53, and CBL mutations were enriched in high level LOY cases, but not DNMT3A or ASXL1. Our findings thus identify independent relationships between LOY, sex hormones and CH.

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Loss of Y and clonal hematopoiesis in blood—two sides of the same coin?

Cited by 28 publications

References 15 publications

Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

Clonal Hematopoiesis: Role in Hematologic Non-Hematologic

Age-related loss of the Y chromosome is associated with sex hormone binding globulin and selected drivers of clonal hematopoiesis

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