• Fadi J Charchar, Lisa Ds Bloomer, Timothy A Barnes, Mark J Cowley, Christopher P Nelson, Yanzhong Wang, Matthew Denniff, Radoslaw Debiec, Paraskevi Christofidou, Scott Nankervis, Anna F Dominiczak, Ahmed Bani-Mustafa, Anthony J Balmforth, Alistair S Hall, Jeanette Erdmann, Francois Cambien, Panos Deloukas, Christian Hengstenberg, Chris Packard, Heribert Schunkert, Willem H Ouwehand, Ian Ford, Alison H Goodall, Mark A Jobling, Nilesh J Samani, and Maciej Tomaszewski.
• School of Health Sciences, University of Ballarat, Ballarat, VIC, Australia.
• Lancet. 2012 Mar 10; 379 (9819): 915922915-922.

BackgroundA 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.MethodsWe 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.FindingsOf 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.InterpretationThe human Y chromosome is associated with risk of coronary artery disease in men of European ancestry, possibly through interactions of immunity and inflammation.FundingBritish 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.Copyright © 2012 Elsevier Ltd. All rights reserved.

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