Mosaic Loss of Chromosome Y Is Associated With Functional Outcome After Ischemic Stroke

Abstract

BACKGROUND: Mosaic loss of chromosome Y (LOY) is associated with cardiovascular and neurodegenerative diseases in men, and genetic predisposition to LOY is associated with poor poststroke outcome. We, therefore, tested the hypothesis that LOY itself is associated with functional outcome after ischemic stroke. METHODS: The study comprised male patients with ischemic stroke from the cohort studies SAHLSIS2 (Sahlgrenska Academy Study on Ischemic Stroke Phase 2; n=588) and LSR (Lund Stroke Register; n=735). We used binary logistic regression to analyze associations between LOY, determined by DNA microarray intensity data, and poor 3-month functional outcome (modified Rankin Scale score, >2) in each cohort separately and combined. Patients who received recanalization therapy were excluded from sensitivity analyses. RESULTS: LOY was associated with about 2.5-fold increased risk of poor outcome in univariable analyses ( P <0.001). This association withstood separate adjustment for stroke severity and diabetes in both cohorts but not age. In sensitivity analyses restricted to the nonrecanalization group (n=987 in the combined cohort), the association was significant also after separate adjustment for age (odds ratio, 1.6 [95% CI, 1.1–2.4]) and when additionally adjusting for stroke severity and diabetes (odds ratio, 1.6 [95% CI, 1.1–2.5]). CONCLUSIONS: We observed an association between LOY and poor outcome after ischemic stroke in patients not receiving recanalization therapy. Future studies on LOY and other somatic genetic alterations in larger stroke cohorts are warranted.

Tumor Predisposing Post-Zygotic Chromosomal Alterations in Bladder Cancer—Insights from Histologically Normal Urothelium

“…The basic premise of our study is the concept of aberrant clonal expansions of cells in morphologically normal tissues [ 45 ] and this is best studied in the hematopoietic system. It is termed clonal hematopoiesis [ 57 , 58 ], where the most prevalent alteration is LOY, a mutation also linked to various diseases in men [ 6 , 16 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. These aberrant clonal expansions have also been described in solid tissues, often in connection with cancer, and are commonly referred to as field cancerization [ 46 , 47 , 48 , 49 , 59 , 60 , 61 ].…”

“…Moreover, the dysregulation of autosomal gene expression in leukocytes with LOY in a pleiotropic fashion affects many of their immune cell functions [ 18 ]. Numerous studies have also shown a strong association between hematopoietic LOY and all-cause mortality [ 6 , 20 ] as well as an increased prevalence or poor outcome of many diseases in males, for instance, cardiovascular disease [ 21 , 22 ], Alzheimer’s disease [ 16 , 23 ], stroke [ 24 ], COVID-19 [ 25 ] and multiple types of cancer, among them BLCA [ 6 , 26 ].…”

Association of Plasma Brain-Derived Tau With Functional Outcome After Ischemic Stroke

“… 4 In brief, patients with first-ever or recurrent acute ischemic stroke aged 18–69 years were recruited between 1998 and 2003. For validation, a second observational longitudinal cohort study, the SAHLSIS phase 2 ( SAHLSIS2 ), 5 was used. This ongoing study includes first-ever or recurrent adult cases with acute stroke of all ages, and this study includes participants recruited during the period 2015–2020.…”

Molecular Mechanisms of the Failing Heart: A Fatal Regression?

“…45,46 In cardiovascular diseases, it has been reported as an adverse prognostic factor in some conditions, such as cerebral infarction and post-transcatheter aortic valve replacement. 47,48 Although studies on the association and mechanisms of mLOY with the development of HF are limited, Sano et al suggested the following possibilities. 49 The mice model with mLOY showed myocardial fibrosis, and the myocardial macrophages, induced by the loss of Y, were found to be in an activated inflammatory state.…”