- Christofidou, Paraskevi, Nelson, Christopher, Nikpay, Majid, Qu, Liming, Li, Mingyao, Loley, Christina, Debiec, Radoslaw, Braund, Peter, Denniff, Matthew, Charchar, Fadi, Arjo, Ares Rocanin, Trégouët, David-Alexandre, Goodall, Alison, Cambien, Francois, Ouwehand, Willem, Roberts, Robert, Schunkert, Heribert, Hengstenberg, Christian, Reilly, Muredach, Erdmann, Jeanette, McPherson, Ruth, König, Inke, Thompson, John, Samani, Nilesh, Tomaszewski, Maciej
- Authors: Christofidou, Paraskevi , Nelson, Christopher , Nikpay, Majid , Qu, Liming , Li, Mingyao , Loley, Christina , Debiec, Radoslaw , Braund, Peter , Denniff, Matthew , Charchar, Fadi , Arjo, Ares Rocanin , Trégouët, David-Alexandre , Goodall, Alison , Cambien, Francois , Ouwehand, Willem , Roberts, Robert , Schunkert, Heribert , Hengstenberg, Christian , Reilly, Muredach , Erdmann, Jeanette , McPherson, Ruth , König, Inke , Thompson, John , Samani, Nilesh , Tomaszewski, Maciej
- Date: 2015
- Type: Text , Journal article
- Relation: American Journal of Human Genetics Vol. 97, no. 2 (2015), p. 228-237
- Full Text: false
- Reviewed:
- Description: Runs of homozygosity (ROHs) are recognized signature of recessive inheritance. Contributions of ROHs to the genetic architecture of coronary artery disease and regulation of gene expression in cells relevant to atherosclerosis are not known. Our combined analysis of 24,320 individuals from 11 populations of white European ethnicity showed an association between coronary artery disease and both the count and the size of ROHs. Individuals with coronary artery disease had approximately 0.63 (95% CI: 0.4-0.8) excess of ROHs when compared to coronary-artery-disease-free control subjects (p = 1.49 x 10
Male-specific region of the y chromosome and cardiovascular risk phylogenetic analysis and gene expression studies
- Bloomer, Lisa, Nelson, Christopher, Eales, James, Denniff, Matthew, Christofidou, Paraskevi, Debiec, Radoslaw, Moore, Jasbir, Consortium, Cardiogenics, Zukowska-Szczechowska, Ewa, Goodall, Alison, Thompson, John, Samani, Nilesh, Charchar, Fadi, Tomaszewski, Maciej
- Authors: Bloomer, Lisa , Nelson, Christopher , Eales, James , Denniff, Matthew , Christofidou, Paraskevi , Debiec, Radoslaw , Moore, Jasbir , Consortium, Cardiogenics , Zukowska-Szczechowska, Ewa , Goodall, Alison , Thompson, John , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2013
- Type: Text , Journal article
- Relation: Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, no. 7 (2013), p. 1722-1727
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Objective-Haplogroup I of male-specific region of the human Y chromosome is associated with 50% increased risk of coronary artery disease. It is not clear to what extent conventional cardiovascular risk factors and genes of the malespecific region may explain this association. Approach and Results-A total of 1988 biologically unrelated men from 4 white European populations were genotyped using 11 Y chromosome single nucleotide polymorphisms and classified into 13 most common European haplogroups. Approximately 75% to 93% of the haplotypic variation of the Y chromosome in all cohorts was attributable to I, R1a, and R1b1b2 lineages. None of traditional cardiovascular risk factors, including body mass index, blood pressures, lipids, glucose, C-reactive protein, creatinine, and insulin resistance, was associated with haplogroup I of the Y chromosome in the joint inverse variance meta-analysis. Fourteen of 15 ubiquitous single-copy genes of the male-specific region were expressed in human macrophages. When compared with men with other haplogroups, carriers of haplogroup I had 0.61- and 0.64-fold lower expression of ubiquitously transcribed tetratricopeptide repeat, Y-linked gene (UTY) and protein kinase, Y-linked, pseudogene (PRKY) in macrophages (P=0.0001 and P=0.002, respectively). Conclusions-Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors. © 2013 American Heart Association, Inc.
- Description: 2003011132
- Authors: Bloomer, Lisa , Nelson, Christopher , Eales, James , Denniff, Matthew , Christofidou, Paraskevi , Debiec, Radoslaw , Moore, Jasbir , Consortium, Cardiogenics , Zukowska-Szczechowska, Ewa , Goodall, Alison , Thompson, John , Samani, Nilesh , Charchar, Fadi , Tomaszewski, Maciej
- Date: 2013
- Type: Text , Journal article
- Relation: Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, no. 7 (2013), p. 1722-1727
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text:
- Reviewed:
- Description: Objective-Haplogroup I of male-specific region of the human Y chromosome is associated with 50% increased risk of coronary artery disease. It is not clear to what extent conventional cardiovascular risk factors and genes of the malespecific region may explain this association. Approach and Results-A total of 1988 biologically unrelated men from 4 white European populations were genotyped using 11 Y chromosome single nucleotide polymorphisms and classified into 13 most common European haplogroups. Approximately 75% to 93% of the haplotypic variation of the Y chromosome in all cohorts was attributable to I, R1a, and R1b1b2 lineages. None of traditional cardiovascular risk factors, including body mass index, blood pressures, lipids, glucose, C-reactive protein, creatinine, and insulin resistance, was associated with haplogroup I of the Y chromosome in the joint inverse variance meta-analysis. Fourteen of 15 ubiquitous single-copy genes of the male-specific region were expressed in human macrophages. When compared with men with other haplogroups, carriers of haplogroup I had 0.61- and 0.64-fold lower expression of ubiquitously transcribed tetratricopeptide repeat, Y-linked gene (UTY) and protein kinase, Y-linked, pseudogene (PRKY) in macrophages (P=0.0001 and P=0.002, respectively). Conclusions-Coronary artery disease predisposing haplogroup I of the Y chromosome is associated with downregulation of UTY and PRKY genes in macrophages but not with conventional cardiovascular risk factors. © 2013 American Heart Association, Inc.
- Description: 2003011132
Inheritance of coronary artery disease in men : An analysis of the role of the y chromosome
- Charchar, Fadi, Bloomer, Lisa, Barnes, Timothy, Cowley, Mark, Nelson, Christopher, Wang, Yanzhong, Denniff, Matthew, Debiec, Radoslaw, Christofidou, Paraskevi, Nankervis, Scott, Dominiczak, Anna, Bani-Mustafa, Ahmed, Balmforth, Anthony, Hall, Alistair, Erdmann, Jeanette, Cambien, Francois, Deloukas, Panos, Hengstenberg, Christian, Packard, Chris, Schunkert, Heribert, Ouwehand, Willem, Ford, Ian, Goodall, Alison, Jobling, Mark, Samani, Nilesh, Tomaszewski, Maciej
- Authors: Charchar, Fadi , Bloomer, Lisa , Barnes, Timothy , Cowley, Mark , Nelson, Christopher , Wang, Yanzhong , Denniff, Matthew , Debiec, Radoslaw , Christofidou, Paraskevi , Nankervis, Scott , Dominiczak, Anna , Bani-Mustafa, Ahmed , Balmforth, Anthony , Hall, Alistair , Erdmann, Jeanette , Cambien, Francois , Deloukas, Panos , Hengstenberg, Christian , Packard, Chris , Schunkert, Heribert , Ouwehand, Willem , Ford, Ian , Goodall, Alison , Jobling, Mark , Samani, Nilesh , Tomaszewski, Maciej
- Date: 2012
- Type: Text , Journal article
- Relation: The Lancet Vol. 379, no. 9819 (2012), p. 915-922
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
- Full Text: false
- Reviewed:
- Description: 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. 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 1·75, 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. 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. © 2012 Elsevier Ltd.
- Tomaszewski, Maciej, Charchar, Fadi, Barnes, Timothy, Gawron-Kiszka, Magdalena, Sedkowska, Agnieszka, Podolecka, Ewa, Kowalczyk, Jacek, Rathbone, Wendy, Kalarus, Zbigniew, Grzeszczak, Wladyslaw, Goodall, Alison, Samani, Nilesh, Zukowska-Szczechowska, Ewa
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Gawron-Kiszka, Magdalena , Sedkowska, Agnieszka , Podolecka, Ewa , Kowalczyk, Jacek , Rathbone, Wendy , Kalarus, Zbigniew , Grzeszczak, Wladyslaw , Goodall, Alison , Samani, Nilesh , Zukowska-Szczechowska, Ewa
- Date: 2009
- Type: Text , Journal article
- Relation: Arteriosclerosis Thrombosis and Vascular Biology Vol. 29, no. 9 (2009), p. 1316-1321
- Full Text: false
- Reviewed:
- Description: Objective-A rare mutation in low-density lipoprotein receptor-related protein 6 gene (LRP6) was identified as the primary molecular defect underlying monogenic form of coronary artery disease. We hypothesized that common variants in LRP6 could predispose subjects to elevated LDL-cholesterol (LDL-C). Methods and Results-Twelve common ( minor allele frequency >= 0.1) single nucleotide polymorphisms in LRP6 were genotyped in 703 individuals from 213 Polish pedigrees (Silesian Cardiovascular Study families). The family-based analysis revealed that the minor allele of rs10845493 clustered with elevated LDL-C in offspring more frequently than expected by chance (P=0.0053). The quantitative analysis restricted to subjects free of lipid-lowering treatment confirmed the association between rs10845493 and age-, sex-, and BMI-adjusted circulating levels of LDL-C in families as well as 2 additional populations - 218 unrelated subjects from Silesian Cardiovascular Study replication panel and 1138 individuals from Young Men Cardiovascular Association cohort (P=0.0268, P=0.0476, and P=0.0472, respectively). In the inverse variance weighted meta-analysis of the 3 populations each extra minor allele copy of rs10845493 was associated with 0.14 mmol/L increase in age-, sex-, and BMI-adjusted LDL-C (SE=0.05, P=0.0038). Conclusions-Common polymorphism in the gene underlying monogenic form of coronary artery disease impacts on risk of LDL-C elevation. (Arterioscler Thromb Vasc Biol. 2009;29:1316-1321.)
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