Inheritance of Coronary Artery Disease in Men: An Analysis of the Role of the Y Chromosome

Study Questions:

Does the Y chromosome contribute to coronary artery (CAD) risk in males?

Methods:

Genetic markers on the Y chromosome were used to group 3,233 unrelated men (from the BHF-FHS, WOSCOPS, and Cardiogenics Study) into different haplogroups. Associations were then examined between CAD risk and common Y haplogroups. In addition, a functional analysis of Y chromosome effects on monocyte and macrophage transcriptomes in British men from the Cardiogenics Study was performed.

Results:

Nine haplogroups were identified, but two haplogroups (R1b1b2 and I) accounted for 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted independent risk of CAD than did men with other Y chromosome lineages (odds ratio, 1.56; 95% confidence interval, 1.24-1.97; p = 0.0002). Analysis of macrophage transcriptomes in the Cardiogenics Study revealed that 19 molecular pathways showing strong differential expression between men with haplogroup I and other lineages of the Y chromosome were interconnected by common genes related to inflammation and immunity.

Conclusions:

The authors concluded that the human Y chromosome is associated with risk of CAD in men of European ancestry, possibly through interactions of immunity and inflammation.

Perspective:

The increased risk of age-adjusted CAD in men is largely unexplained. This study indicates that increased male risk of CAD could be mediated by genes on the Y chromosome and that this risk could be related to exaggerated adaptive immune responses. Risk stratification for males might also be better assessed by focusing on the paternal history of CAD. If confirmed in other populations/databases, these exciting results may eventually lead to new therapeutic targets for prevention of CAD.

Clinical Topics: Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), Heart Failure and Cardiac Biomarkers

Keywords: Inflammation, Coronary Artery Disease, Macrophages, Biological Markers, Cardiology, Heterozygote, Haplotypes, Risk Factors, Genetic Markers, Coronary Vessels, Chromosomes, Y Chromosome


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