Our study is the first to evaluate associations between main European Y chromosome lineages and coronary artery disease as well as its underlying risk factors. The most important finding from our analysis is that haplogroup I is associated with significantly increased risk of coronary artery disease compared with other ancient lineages of the Y chromosome and that this association, although independent of major cardiovascular risk factors and socioeconomic status, might be mediated through a genetically programmed profile of immunity and response to inflammation (panel
Panel. Research in context
We searched original English-language publications in PubMed to May, 2011, using “Y chromosome”, “haplogroup”, “haplotype”, and “coronary artery disease” as keywords and found no studies that investigated the association between paternal lineages of the Y chromosome (haplogroups) and predisposition to coronary artery disease.
Our study is the first robust analysis of association between different lineages of the Y chromosome and coronary artery disease. We show that men who inherit haplogroup I (one of the most common Y chromosome types in Europe) from their male ancestors have a roughly 50% higher risk of coronary artery disease than do men with other types of the Y chromosome. The effect of haplogroup I on coronary artery disease is not mediated by traditional cardiovascular risk factors such as age, body-mass index, blood pressure, lipids, diabetes, smoking, alcohol consumption, socioeconomic status, or circulating concentrations of C-reactive protein. However, we noted that men with haplogroup I showed downregulation of adaptive immunity as well as upregulation of inflammatory response pathways in their macrophages compared with carriers of other Y chromosome types. These data show that predisposition to coronary artery disease in men might, at least in part, be determined by the paternal lineage of their Y chromosome and that this effect on risk of coronary artery disease is most likely mediated through immune response.
Our transcriptomic analysis showed that several of 19 pathways interconnected by inflammation and immunity genes, and showing differential expression between men with haplogroup I and other lineages, might be relevant to atherosclerosis. Specifically, trafficking of leucocytes through the endothelial barrier is a well recognised process in both early27
stages of atherosclerosis, and leucocyte transendothelial migration (hsa04670) was identified as the most significantly upregulated pathway in gene expression profiling of atherosclerotic arterial wall.28
Focal adhesions (hsa04510) control cytoskeletal or adhesion dynamics and thus affect both leucocyte motility within intima and interactions between platelets and endothelium, all of which play a part in the pathogenesis of coronary artery disease.29–31
The balance between proinflammatory and anti-inflammatory cytokines (cytokine-cytokine receptor interaction pathway, hsa04060) is also a well recognised mechanism underlying atherosclerotic plaque development.32
Interestingly, four of seven upregulated pathways (focal adhesion, cytokine-cytokine receptor interaction, hypertrophic cardiomyopathy [hsa05410], and extracellular matrix-receptor interaction [hsa04512]) show the strongest enrichment for genes with previous evidence of association with coronary artery disease among more than 100 KEGG pathways.33
Pharmacological inhibitions of these pathways were suggested as treatments with a potential to reduce or even reverse the burden of atherosclerosis in coronary circulation.27,30,34
These molecular networks therefore represent possible mechanisms explaining the association of haplogroup I with coronary artery disease. Furthermore, upregulation of these pathways in macrophages (but not in monocytes) suggests that differentiation (activation) of monocytes to macrophages, one of the key steps in the pathogenesis of atherosclerosis,35
might be the stage at which haplogroup I exerts its molecular effects on coronary artery disease.
Despite this attractive possibility, a statistically more striking finding was the association of haplogroup I with downregulation of several pathways of the immune system. Indeed, some of the identified pathways are activated in exposure to pathogens (leishmaniasis [hsa05140], viral myocarditis [hsa05416]). Others directly represent immune response and processing (antigen processing and presentation [hsa04612] and intestinal immune network for IgA production [hsa04672]). Furthermore, some of the most significant pathways are in fact autoimmune disorders, including autoimmune thyroid disease (hsa05320) and type 1 diabetes (hsa09490). Most of the downregulated pathways interact together in regulation of adaptive immunity and operate mainly in lymphocytes or antigen-presenting cells, or both, possibly mostly through MHC class II cell surface receptors (HLA-DP, HLA-DQ, HLA-DR). Although not fully understood, dysfunction of immune response is a well established contributor to atherosclerosis and coronary artery disease.32
Previous studies suggested that the Y chromosome could play a part in regulation of the immune system—ie, men with haplogroup I of the Y chromosome were particularly vulnerable to HIV infection.36
In fact, carriers of haplogroup I on retroviral therapy took a longer time to HIV suppression and had more accelerated progression to AIDS compared with carriers of other MSY lineages.36
Mortality from AIDS in men of haplogroup I was also significantly higher than that in men with other haplogroups.36
Taken together, these findings suggest that downregulation of adaptive immunity in carriers of haplogroup I is accompanied by upregulation of pathways underlying inflammatory response. This conclusion implies that haplogroup I carriers might have chronic derangements in homoeostatic mechanisms of adaptive immunity, possibly with heightened inflammation affecting the cardiovascular system. A similar mechanism has been well documented in other complex disorders—ie, in inflammatory bowel disease, in which deficiencies in immunity status can lead to increased systemic inflammation.37
Interestingly, the association between haplogroup I and increased susceptibility to coronary artery disease was independent of C-reactive protein. This marker of inflammation is more closely related to innate than to adaptive defence mechanisms.38
Since the most distinct signature of haplogroup I in our study was identified on adaptive immunity pathways, we expect that studies with more robust markers of specific immune system will be necessary to explain the association between the Y chromosome and coronary artery disease. Such investigations should also take us closer to dissection of the mechanisms underlying the sex differences in regulation of human immunity. Indeed, there is a well recognised sexual dimorphism in response to immunisation39
as well as susceptibility to autoimmune disorders.40
The biological background of these differences is most likely multifactorial. Whether genes unique to the X chromosome, polymorphic variants of the MSY, their interactions with autosomal loci and environment, or all the above contribute to sex differences in regulation of the immune system will need further studies to elucidate.
Evolutionarily, the distinguishing feature of haplogroup I is its almost complete absence in indigenous populations outside Europe.2
The carriers of this haplogroup probably arrived from the Middle East as hunter-gatherers during the Paleolithic era roughly 25 000 years ago and it has been suggested that they spread throughout Europe together with diffusion of the Gravettian archaeological culture.41
The gradual Neolithic expansion of farmers 10 000 years ago led to the present dominance of R1b1b2 (over I and other MSY haplogroups) in most parts of northern and western Europe.2,42
The present geographical distribution of one of the major lineages of haplogroup I (I1) in western Europe correlates with the well established north–south gradient in prevalence of coronary artery disease. Indeed, in northern populations (Scandinavia, Germany, Netherlands) in which the prevalence of haplogroup I ranges between 15% and 40%, mortality from coronary artery disease is significantly higher than in southern Europe (France, Apennine peninsula, Spain, and Switzerland), where haplogroup I is less prevalent (3–15%).43,44
The north–south gradient in coronary artery disease morbidity was also reported in the UK
(2011). Unavailability of information about birthplace of participants and their male ancestors and lack of samples from different parts of the UK prevented us from examining whether men with haplogroup I are over-represented in regions known for particularly high prevalence of coronary artery disease and its modifiable lifestyle risk factors. Further studies should address the question of whether distribution of Y chromosome lineages could account (at least in part) for the geographic differences in predisposition to coronary artery disease in men.
We should acknowledge that similar to other common genetic variants associated with increased risk of cardiovascular disease, haplogroup I of the Y chromosome on its own is unlikely to offer sufficiently high positive predictive value of coronary artery disease. Indeed, single risk factors (both genetic and non-genetic) that are fairly common in both cases and controls and coupled with a 1·5-increase in the OR of a disease are not specific enough as individual risk predictors.45,46
Nevertheless, the relative estimates of coronary artery disease risk in carriers of haplogroup I are not trivial from the point of view of genetic association analysis. Indeed, they are larger than that of many common autosomal alleles identified in recent genome-wide association studies. Further replication of our results in large, prospective population-based studies is necessary to provide precise estimates of coronary artery disease risk attributable to variation in the Y chromosome. Such studies could have important public health implications in view of the significant lifetime risk of coronary artery disease in men47
and still imperfect risk stratification on the basis of traditional cardiovascular risk factors.46
A gap remains in the understanding of disease differences both within and between populations. Here, we have identified an association that supports the hypothesis that the Y chromosome determines interindividual differences in susceptibility to coronary artery disease among British men. We also showed that this association could be mediated through immunity and inflammation-related networks. Our study revealed that the Y chromosome might have a magnified effect on men beyond sex determination despite the small number of genes it harbours in the human genome. Future resequencing efforts and functional experiments will be needed to identify the causative variants underlying the increased susceptibility to coronary artery disease in carriers of haplogroup I and to decipher complex interplay between human Y chromosome, immunity, and cardiovascular disease.