Inheritance of coronary artery disease in men: an analysis of the role of the Y chromosome

Of all human chromosomes, the haploid Y chromosome contains the smallest number of genes. The main part of the Y chromosome (male-specific region; MSY) is transmitted intact from father to son and contains single and multicopy genes that encode about 27 distinct proteins, The fundamental biological role of the Y chromosome is to impart male characteristics. However, there are also data linking the Y chromosome to the cardiovascular system. For example, polysomy of the Y chromosome (mostly 47, XYY karyotype) was linked to increased cardiovascular mortality, and a common biallelic polymorphism of the MSY was associated with blood pressure, circulating concentrations of total cholesterol, LDL cholesterol, proatherogenic B-phenotype of LDL cholesterol molecules, and paternal history of coronary artery disease. Although not all studies have replicated these associations, the accumulated evidence lends support to the notion that genetic variation within the MSY could play a part in determining cardiovascular risk in men. In view of the haploid nature of the MSY and its low level of recombination, the usual methods of linkage disequilibrium-based mapping applied to autosomal chromosomes cannot be used in investigation of its variation. The most appropriate strategy is the analysis of the Y chromosome phylogenetic tree. Defined by a series of biallelic single nucleotide polymorphisms (SNPs), MSY can be partitioned into 20 major haplogroups that descend from a common ancestor, Y-chromosomal Adam.

We directly examined association between the Y chromosome and coronary artery disease. We first examined whether common Y chromosome haplogroups were associated with risk of coronary artery disease in white British men recruited into the cross-sectional British Heart Foundation Family Heart Study (BHF-FHS). We next evaluated the association of Y chromosome lineages with prospective development of coronary artery disease in the West of Scotland Coronary Prevention Study (WOSCOPS), a clinical trial that examined the benefits of statin treatment for primary prevention of coronary artery disease in middle-aged Scottish men. Finally, we explored the signatures of Y-chromosomal evolution on the human transcriptome in monocytes and macrophages from British men recruited into the Cardiogenics Study.