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Mosaic loss of the Y chromosome in transthyretin (ATTR) cardiac amyloidosis

Award Number: R01AG093132
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Mosaic loss of the Y chromosome in transthyretin (ATTR) cardiac amyloidosis - PROJECT SUMMARY/ABSTRACT Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is associated with aging and is a commonly encountered, treatable cause of heart failure that affects over 150,000 older Americans. With an average age of onset of 75-80 years, ATTRwt-CA is characterized by the cardiac accumulation of misfolded TTR amyloid protein deposits. ATTRwt-CA has been mostly identified in men, with a male:female ratio of 4:1. While therapies improve survival and reduce heart failure hospitalizations in ATTRwt-CA, the mechanisms that underlie disease pathogenesis are incompletely understood. Mosaic loss of the Y chromosome (mLOY) in circulating white blood cells, a condition where the Y-chromosome is spontaneously deleted, is also a commonly observed feature in older men. Indeed, approximately 40% of men over the age of 70 years will have detectable mLOY, and the genetic abnormality has been associated with mortality from heart failure in large population studies. Given that both mLOY and ATTRwt-CA are diseases of older men, we demonstrated that, compared to patients with non-amyloid heart failure, ATTRwt-CA patients had almost a 2-fold higher prevalence of mLOY (58% vs. 30%). When ATTRwt-CA patients were divided into high and low burden of mLOY, those with high mLOY had a 2.8-fold increased risk of death and a 5-year mortality of 66% vs. 32% for those with low mLOY. Finally, using proteomics and single-cell RNA sequencing, our preliminary data suggests that mLOY is associated with dysregulation of immune pathways that impair macrophage scavenger functioning in the heart. Our central hypothesis is that the adverse outcomes observed in ATTRwt-CA with high mLOY are caused by a mechanism of immune dysregulation and impaired amyloid fibril clearance. In Aim 1 we will measure mLOY in archived blood samples from patients with ATTRwt-CA who were treated at the Boston University Amyloidosis Center and from non-amyloid patients with heart failure who are participants in the NIH- funded SCAN-MP study, directed by MPIs Ruberg and Maurer. We hypothesize that ATTRwt-CA patients will have higher mLOY and that mLOY will associate with survival, heart failure hospitalization, and quality of life both at baseline and over time. In Aim 2, we will describe the dysregulation of immune-mediated pathways using plasma proteomics from blood samples from Aim 1, and single-cell RNA sequencing transcriptomics using isolated white blood cells prospectively collected from patients with ATTRwt-CA and non-amyloid heart failure control patients. In Aim 3, we will collaborate with colleagues at the National Amyloidosis Centre (London, UK) to use cardiac magnetic resonance imaging to measure extracellular volume fraction (ECV), a clinical measure that captures the cardiac amyloid burden and predicts prognosis in ATTRwt-CA. We will demonstrate that mLOY is associated with increased ECV at baseline and increases over time. Successful completion of these Aims will provide critical insights into the course and prognosis of ATTRwt-CA, a common disease that impacts the health of older Americans, and inform treatment decisions.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $763,561 )
2026	2026	BOSTON MEDICAL CENTER CORPORATION	1 BOSTON MEDICAL CTR PL	BOSTON	MA	02118	SUFFOLK	USA	Aging Research	000	1	3/5/2026	NEW	$763,561
														Subtotal = $763,561

Grand Total All Awards = $763,561

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Mosaic loss of the Y chromosome in transthyretin (ATTR) cardiac amyloidosis

Award Number: R01AG093132

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/15/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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