The Y chromosome in cardiovascular disease

Men develop coronary artery disease (CAD) approximately 10 years earlier and die of CAD more frequently (2:1) than age-matched women. This sexual dimorphism is even more striking in abdominal aortic aneurysms (AAA) – the ratio of affected men to women is as high as 6:1. A major biological difference between both sexes is the exclusive presence of the Y chromosome in men. Haplogroup I of the Y chromosome increases the risk of CAD by ~50% compared to other Y chromosome lineages. The analysis of ~1940 men from 3 cohorts recruited from the general European population revealed that the association between haplogroup I and CAD is not driven by conventional cardiovascular risk factors BMI, blood pressure, total cholesterol, HDL-C, triglycerides, LDL-C, glucose, aggression (total aggression, physical aggression, verbal aggression, hostility, anger) or sex steroids (testosterone, androstenedione, DHEA-S, estrone, oestradiol). Transcriptomic analysis revealed that none of “Kyoto Encyclopaedia of Genes and Genomes” (KEGG) pathways were differentially regulated in monocytes between men from haplogroup I and all other lineages. In contrast, 30 KEGG pathways showed differential expression between haplogroup I and other lineages of the Y chromosome in transcriptome-wide analysis of macrophages. Of these, 19 pathways were interconnected by common genes of adaptive immunity and the inflammatory response. In gene-centred analysis of the Y chromosome, carriers of haplogroup I also showed significant down-regulation of two X-degenerate male specific Y chromosome genes (PRKY and UTY) in macrophages (P=0.001 and P=0.0001) but not in monocytes (P=0.181, and P=0.611). Meta-analysis of 3 cohorts of British and Irish men revealed that the presence of haplogroup I was not associated with predisposition to AAA. Neither conventional CAD risk factors nor male-associated/sex-specific phenotypes appear to drive the increased risk of CAD in carriers of haplogroup I. Furthermore, these results show that immune system and response to inflammation may mediate the association between Y chromosome and CAD. The absence of association between the Y chromosome and AAA suggest differences in the pathogenesis of sexual dimorphism of AAA and CAD.