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

Abstract

Background: A sexual dimorphism exists in the incidence and prevalence of coronary artery disease--men are more commonly affected than are age-matched women. We explored the role of the Y chromosome in coronary artery disease in the context of this sexual inequity.

Methods: We genotyped 11 markers of the male-specific region of the Y chromosome in 3233 biologically unrelated British men from three cohorts: the British Heart Foundation Family Heart Study (BHF-FHS), West of Scotland Coronary Prevention Study (WOSCOPS), and Cardiogenics Study. On the basis of this information, each Y chromosome was tracked back into one of 13 ancient lineages defined as haplogroups. We then examined associations between common Y chromosome haplogroups and the risk of coronary artery disease in cross-sectional BHF-FHS and prospective WOSCOPS. Finally, we undertook functional analysis of Y chromosome effects on monocyte and macrophage transcriptome in British men from the Cardiogenics Study.

Findings: Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I had about a 50% higher age-adjusted risk of coronary artery disease than did men with other Y chromosome lineages in BHF-FHS (odds ratio 1·75, 95% CI 1·20-2·54, p=0·004), WOSCOPS (1·45, 1·08-1·95, p=0·012), and joint analysis of both populations (1·56, 1·24-1·97, p=0·0002). The association between haplogroup I and increased risk of coronary artery disease was independent of traditional cardiovascular and socioeconomic risk factors. Analysis of macrophage transcriptome 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, and that some of them have a strong relevance to atherosclerosis.

Interpretation: The human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.

Funding: British Heart Foundation; UK National Institute for Health Research; LEW Carty Charitable Fund; National Health and Medical Research Council of Australia; European Union 6th Framework Programme; Wellcome Trust.

Figure 1

Phylogenetic tree of the Y chromosome and frequency of haplogroups in the British Heart Foundation Family Heart Study (BHF-FHS) and West of Scotland Coronary Prevention Study (WOSCOPS) Each vertical line represents one branch (haplogroup) of the Y chromosome phylogenetic tree. The 13 most common Y chromosome haplogroups are shown and are lined up from the phylogentically oldest on the left (Y[xBR]) to the youngest on the right (R1b1b2). The vertical length or height of each line corresponds to the age of each haplogroup (the longest line being the oldest haplogroup). The symbols at the top of each line (SRY10831.1, M35, M89, M201, M170, M304, M9, M45, M207, M173, SRY10831.2, and M269) are the identification numbers of the single nucleotide polymorphisms that define specific haplogroups according to the Y Chromosome Consortium nomenclature. The numbers in boxes reflect prevalence (percentage) of each haplogroup in BHF-FHS (upper row) and WOSCOPS (lower row) populations.

Figure 2

Immune pathways showing significant (false discovery rate <20%) differential expression in macrophages from men with haplogroup I compared with carriers of all other haplogroups Red nodes show upregulated pathways and blue nodes show downregulated pathways in men with haplogroup I from the Kyoto Encyclopedia of Genes and Genomes. Node size is a function of the number of genes in each pathway (the larger the node, the more genes in the pathway) and the colour intensity of each node reflects the level of significance. Lines represent a network of biological links between the pathways; the thickness of each line is proportional to number of genes shared by pathways connected by the line. The high interconnection between these pathways suggests that they are not independent and represent different, yet overlapping, facets of immunity (webappendix pp 9–13). The image was generated with the Enrichment Map plugin for Cytoscape. ECM=extracellular matrix.