The Y chromosome is present exclusively in men and is inherited along the paternal lineage (from fathers to sons). Apart from determining maleness and fertility, the other roles of the Y chromosome in health and disease were not clear for many years. Men develop coronary artery disease (CAD) approximately 10 years earlier than women. A study published Online First by The Lancet analyses whether the human Y chromosome may contribute to coronary artery disease in men and it concludes that that men with a particular variant on their Y-chromosome are at a 50% increased risk of CAD compared with men without it. Furthermore, this increased risk is not mediated by traditional cardiovascular risk factors such as high blood pressure or cholesterol. The study was led by Dr Maciej Tomaszewski, Department of Cardiovascular Sciences, University of Leicester, UK and Dr Fadi J Charchar, University of Ballarat, Australia and colleagues.
The authors 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.
Of nine haplogroups identified, two (R1b1b2 and I) accounted for roughly 90% of the Y chromosome variants among British men. Carriers of haplogroup I (15% to 20% of the British male population) had about a 50% higher age-adjusted risk of CAD than did men with other Y chromosome lineages in BHF-FHS,WOSCOPS, and joint analysis of both populations.
The association between haplogroup I and increased risk of CAD was independent of traditional cardiovascular and socioeconomic risk factors, such as age, body-mass index, blood pressure, lipids, diabetes, smoking, alcohol consumption, socioeconomic status, or circulating concentrations of C-reactive protein.
Further analysis showed that men with haplogroup I showed downregulation of adaptive immunity as well as upregulation of inflammatory response pathways in their macrophages (immune system cells) compared with carriers of other Y chromosome types. These data show that predisposition to CAD 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 the immune response.
The authors conclude: "Our study is the first to evaluate associations between main European Y chromosome lineages and CAD as well as its underlying risk factors…[it has] 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."
In a linked Comment, Dr Virginia Miller, Mayo Clinic, Rochester, MN, USA, says: "Avenues for future research should include exploration of potential interconnections among pathways relating immunity to other forms of cardiovascular disease, such as those identified for various cardiomyopathies (see full Comment). Finally, it would be interesting to examine whether existing algorithms assessing individual risk of coronary artery disease for men could be improved by changing the question 'Did your mother or father have a heart attack before age 60?' to 'Did your father have a heart attack before the age of 60?' Both sex and family do matter in inheritance of coronary artery disease."
Dr Maciej Tomaszewski, Department of Cardiovascular Sciences, University of Leicester, UK. T) +44 (0) 116 258 7546 / +44 (0) 116 256 3031/ +44 (0) 116 256 3019 E) mt142@le.ac.uk
Dr Fadi J Charchar, University of Ballarat, Australia. T) +61 3 5327 6098 E) f.charchar@ballarat.edu.au
Dr Virginia Miller, Mayo Clinic, Rochester, MN, USA. T) +1-507-284 2290 E) miller.virginia@mayo.edu / nellis.robert@mayo.edu
Journal
The Lancet