Loss of chromosome Y in elderly men is not associated with cardiovascular risk following acute myocardial infarction
T Opstad, S Palmero, K B Rypdal, A A Kalstad, S Tveit, K Laake, A Tveit, S Solheim, P Myhre, I G LundeAbstract
Background
Genome instability is considered a hallmark of ageing, cellular senescence and age-related diseases, e.g., shortening of chromosome telomeres. Mosaic loss of chromosome Y (LOY) is relatively common in blood cells of ageing men, and LOY is increasingly being recognized as a male-specific genetic risk factor for disease.
Purpose
To assess LOY frequency in elderly men with acute myocardial infarction (AMI) and evaluate associations with comorbidities and major adverse cardiovascular events (MACE).
Methods
OMEMI was a multicenter randomized controlled trial of omega-3 supplements vs placebo, that included elderly patients with a recent (2-8 weeks) AMI between 2012 and 2020. The overall trial was neutral. This sub-study included all male participants (n=709, mean age 75, range 70-82). LOY frequency (%) was analyzed in blood leukocytes by digital PCR through absolute quantification of AMEL X and AMEL Y gene copy numbers using digital PCR at baseline (two-eight weeks post-MI), calculated by AMEL (X-Y)/X*100. LOY< 5% was interpreted as LOY absence according to previous studies. Leukocyte telomere length (LTL) was measured by qPCR (n=208). Cox proportional hazards regression was used to analyze time to event data for MACE, including stroke, AMI, heart failure (HF), unscheduled revascularization, and death during two years follow-up. Adjustment variables included age, sex, current smoking, body mass index (BMI), systolic blood pressure (SBP), hypertension, diabetes, heart failure, and creatinine at baseline.
Results
Median leukocyte LOY was 7% (Q1, Q3; 1.3, 15.4) and 425 men (60%) presented with LOY≥5%. Higher LOY correlated with older age (r=0.078, p=0.038) and shorter LTL (r=-0.185, p=0.007). Cigarette smoking, lower SBP, lower triglycerides, and absence of diabetes were also associated with higher LOY quartile (Table). During two years of follow-up, 159 (22.5%) of men experienced a MACE. Men with LOY<5% had higher rates of MACE (26.1%) compared to those with LOY≥5% (20.0%). In multivariable Cox models, the risk of MACE decreased with increasing LOY (aHR 0.95 (0.90-0.99) per % increase, p=0.048), and patients in Q1 had the highest risk (aHR 1.44 (1.04-1.98), p=0.026, compared to Q2-4; Figure).
Conclusion
Leukocyte LOY was relatively low (median 7%) in elderly male patients with a recent AMI, and higher LOY was associated with higher age and shorter telomeres. Unexpectedly, higher leukocyte LOY associated with a lower risk of MACE over the two following years. These findings warrant further exploration of LOY and genomic instability in elderly men with established cardiovascular disease.