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


RESULTS
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.


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


BACKGROUND
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.
School of Health Sciences, University of Ballarat, Ballarat, VIC, Australia.
Fadi J
FJ
Charchar
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Lisa Ds
LD
Bloomer
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Timothy A
TA
Barnes
Peter Wills Bioinformatics Centre, Garvan Institute for Medical Research, Sydney, NSW, Australia.
Mark J
MJ
Cowley
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
Christopher P
CP
Nelson
Division of Health and Social Care Research, King's College London, London, UK.
Yanzhong
Y
Wang
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Matthew
M
Denniff
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Radoslaw
R
Debiec
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Paraskevi
P
Christofidou
School of Health Sciences, University of Ballarat, Ballarat, VIC, Australia.
Scott
S
Nankervis
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Anna F
AF
Dominiczak
School of Health Sciences, University of Ballarat, Ballarat, VIC, Australia.
Ahmed
A
Bani-Mustafa
Division of Epidemiology, LIGHT, School of Medicine, University of Leeds, Leeds, UK.
Anthony J
AJ
Balmforth
Division of Epidemiology, LIGHT, School of Medicine, University of Leeds, Leeds, UK.
Alistair S
AS
Hall
Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany.
Jeanette
J
Erdmann
INSERM UMRS 937, Pierre and Marie Curie University and Medical School, Paris, France.
Francois
F
Cambien
Wellcome Trust Sanger Institute, Cambridge, UK.
Panos
P
Deloukas
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany.
Christian
C
Hengstenberg
College of Medicine, Veterinary and Life Sciences, and Department of Vascular Biochemistry, University of Glasgow, Glasgow, UK.
Chris
C
Packard
Universität zu Lübeck, Medizinische Klinik II, Lübeck, Germany.
Heribert
H
Schunkert
Wellcome Trust Sanger Institute, Cambridge, UK; Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge, UK.
Willem H
WH
Ouwehand
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
Ian
I
Ford
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
Alison H
AH
Goodall
Department of Genetics, University of Leicester, Leicester, UK.
Mark A
MA
Jobling
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK.
Nilesh J
NJ
Samani
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK; National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK. Electronic address: mt142@le.ac.uk.
Maciej
M
Tomaszewski
D016022:Case-Control Studies; D041322:Chromosomes, Human, Y / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017678:Sex Distribution; D059467:Transcriptome