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

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• 作者：Fadi J Charchar ; PhD^a ; Lisa DS Bloomer ; MSc^b ; Timothy A Barnes ; PhD^b ; Mark J Cowley ; PhD^d ; Christopher P Nelson ; PhD^b ; ^o ; Yanzhong Wang ; PhD^e ; Matthew Denniff ; BSc^b ; Radoslaw Debiec ; MD^b ; Paraskevi Christofidou ; MSc^b ; Scott Nankervis ; PhD^a ; Anna F Dominiczak ; MD^f ; Ahmed Bani-Mustafa ; PhD^a ; Anthony J Balmforth ; MDⁱ ; Alistair S Hall ; MDⁱ ; Jeanette Erdmann ; PhD^j ; Francois Cambien ; PhD^k ; Panos Deloukas ; PhD^l ; Christian Hengstenberg ; MD^m ; Chris Packard ; MD^h ; Heribert Schunkert ; MD^j ; Willem H Ouwehand ; MD^l ; ⁿ ; Ian Ford ; PhD^g ; Alison H Goodall ; PhD^b ; ^o ; Mark A Jobling ; PhD^c ; Nilesh J Samani ; MD^b ; ^o ; Dr Maciej Tomaszewski ; MD^b ; ^o ; ^{mt142@le.ac.uk}
• 刊名：The Lancet
• 出版年：2012
• 期刊代码：182_01406736
• 类别：med
• 出版时间：10-16 March, 2012
• 卷：379
• 期：9819
• 页码：915-922
• 文件大小：213 K

摘要

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Summary

Background

A sexual dimorphism exists in the incidence and prevalence of coronary artery disease鈥攎en 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路75, 95%CI 1路20-2路54, p=0路004), WOSCOPS (1路45, 1路08-1路95, p=0路012), and joint analysis of both populations (1路56, 1路24-1路97, p=0路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.