Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom

Abstract

AbstractBackgroundMosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear.MethodsWe estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190,613 men and 224,853 women with genotyping data from the UK Biobank. Among these participants, we analyzed 37,037 men with mLOY and 13,978 women with mLOX detected using Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization (MR) was conducted to estimate causal associations.ResultsAmong men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR=1.06, 95%CI:1.03-1.11). The associations were apparent in both never-smokers (HR=1.07, 95%:1.01-1.14) and ever-smokers (HR=1.05, 95%CI:1.01-1.11) as well as men > and ≤60 years of age. MR analyses supported causal associations between mLOY and atrial fibrillation (HRMR-PRESSO=1.15, 95%CI:1.13-1.18). Among post-menopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR=0.90, 95%CI:0.83-0.98). However, associations with mLOY and mLOX were not found for other heart diseases.ConclusionsOur findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.WHAT IS KNOWN?A previous population study found links between death from atrial fibrillation and heart failure, and mosaic loss of chromosome Y (mLOY) in leukocytes, which is a marker of genomic instability, environmental exposures, and aging. Additionally, mLOY has been associated cross-sectionally with prevalent cardiovascular and metabolic diseases.A similar but less common mosaic loss of chromosome X (mLOX) occurs among women but is role in disease pathogenesis is less characterized.The contributions of mLOY and mLOX to risk of hospitalization for incident atrial fibrillation, heart failure syndrome, and other heart diseases are unclear.WHAT THE STUDY ADDS?Among men, mLOY was associated with elevated risk of incident atrial fibrillation. Further, we found suggestive evidence linking mLOX to atrial fibrillation risk among women. Taken together, mLOY and mLOX potentially reflects sex-specific factors related to the pathogenesis of atrial fibrillation.