Inheritance of coronary artery disease in men : An analysis of the role of the y chromosome
- 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
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- 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.
Pathway analysis shows association between FGFBP1 and hypertension
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Nelson, Christopher , Barnes, Timothy , Denniff, Matthew , Kaiser, Michael , Debiec, Radoslaw , Christofidou, Paraskevi , Rafelt, Suzanne , Van Harst, Pim Der , Wang, William , Maric, Christine , Zukowska-Szczechowska, Ewa , Samani, Nilesh
- Date: 2011
- Type: Text , Journal article
- Relation: Journal of the American Society of Nephrology Vol. 22, no. 5 (2011), p. 947-955
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- Description: Variants in the gene encoding fibroblast growth factor 1 (FGF1) co-segregate with familial susceptibility to hypertension, and glomerular upregulation of FGF1 associates with hypertension. To investigate whether variants in other members of the FGF signaling pathway may also associate with hypertension, we genotyped 629 subjects from 207 Polish families with hypertension for 79 single nucleotide polymorphisms in eight genes of this network. Family-based analysis showed that parents transmitted the major allele of the rs16892645 polymorphism in the gene encoding FGF binding protein 1 (FGFBP1) to hypertensive offspring more frequently than expected by chance (P = 0.005). An independent cohort of 807 unrelated Polish subjects validated this association. Furthermore, compared with normotensive subjects, hypertensive subjects had approximately 1.5- and 1.4-fold higher expression of renal FGFBP1 mRNA and protein (P = 0.04 and P = 0.001), respectively. By immunohistochemistry, hypertensionrelated upregulation of FGFBP1 was most apparent in the glomerulus and juxtaglomerular space. Taken together, these data suggest that FGFBP1 associates with hypertension and that systematic analysis of signaling pathways can identify previously undescribed genetic associations. Copyright © 2011 by the American Society of Nephrology.
The epithelial sodium channel y-subunit gene and blood pressure : Family based association, renal gene expression, and physiological analyses
- Authors: Büsst, Cara , Bloomer, Lisa , Scurrah, Katrina , Ellis, Justine , Barnes, Timothy , Charchar, Fadi , Braund, Peter , Hopkins, Paul , Samani, Nilesh , Hunt, Steven , Tomaszewski, Maciej , Harrap, Stephen
- Date: 2011
- Type: Text , Journal article
- Relation: Hypertension Vol. 58, no. 6 (2011), p. 1073-1078
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- Description: Variants in the gene encoding the y-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination. © 2011 American Heart Association, Inc.
FGF21 signalling pathway and metabolic traits - genetic association analysis
- Authors: Kaess, Bernhard , Barnes, Timothy , Stark, Klaus , Charchar, Fadi , Waterworth, Dawn , Song, Kijoung , Wang, William , Vollenweider, Peter , Waeber, Gerard , Mooser, Vincent , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Hengstenberg, Christian , Tomaszewski, Maciej
- Date: 2010
- Type: Text , Journal article
- Relation: European Journal of Human Genetics Vol. 18, no. 12 (2010), p. 1344-1348
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- Description: Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol-LDL-C, HDL-cholesterol-HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry
Fibroblast growth factor binding protein 1 gene (FGFBP1) and hypertension d from pathway analysis to renal glomerulus
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Maric, Christine , Zukowska-Szczechowska, Ewa , Samani, Nilesh
- Date: 2010
- Type: Text , Conference paper
- Relation: Paper presented at British Cardiovascular Society Annual Conference 2010, Manchester Central, Manchester, UK : 7th-9th June 2010
- Full Text: false
- Description: Essential hypertension is a complex, multifactorial disease with a strong genetic component. Fibroblast growth factor 1 gene (FGF1) is one of the most relevant candidates having been associated not only with familial susceptibility to hypertension but also with up-regulation within the glomerulus of the human hypertensive kidney/Circulation 2007;116:1915e24/. We have hypothesised that systematic analysis of genes interacting with FGF1 may uncover novel variants underlying essential hypertension. Seventy-nine common (minor allele frequency$0.1) tagging (r2$0.8) and functional single nucleotide polymorphisms (SNPs) spanning eight critical components of the FGF (fibroblast growth factor) pathway (FGF2, FGFR1, FGFR2, FGFR3, FGFR4, FGFBP1, FIBP, SPRY1) were genotyped by MALDI-TOF mass spectrometry in 629 subjects from 207 Polish hypertensive families (Silesian Hypertension Study d SHS). 83.5% of genotyped SNPs that passed quality control filters provided 92.9% genetic coverage of FGF pathway loci. Family-based analysis in SHS revealed that alleles of three SNPs (rs2956724, rs2245964 and rs16892645) in two loci (FGFR1 and FGFBP1) were transmitted to hypertensive offspring more frequently than expected by chance. However, only one association survived correction for multiple testing e major allele of rs16892645 in FGFBP1 was over-transmitted from heterozygous parents to hypertensive offspring more frequently than expected by chance (p¼0.0048, false discovery rate<0.25). The association between rs16892645 and hypertension was replicated in an independent cohort of 807 Polish subjects from Silesian Cardiovascular Study d each major allele copy of rs16892645 increased the odds of hypertension approximately by 1.5 (odds ratio: 1.5; 95% CI: 1.1 to to 2.2, p¼0.04). Association between FGFBP1 and hypertension was also apparent at the protein expression level d compared with normotensive patients, hypertensives from Silesian Renal Tissue Bank showed approximately 1.4-fold higher renal abundance of FGFBP1 in Western blotting (p¼0.001). Immunohistochemical analysis revealed that hypertension-related up-regulation of FGFBP1 was exclusive to renal glomeruli. These data show that FGFBP1da gene that encodes a carrier protein for FGF1 d is associated with human hypertension. We also reveal that up-regulation of FGFBP1 maps to the same histological compartment where FGF1 was shown to be most abundant (renal glomeruli). Our study also proves that systematic genetic analysis of signalling pathways is a strategy with a potential to identify novel molecular mechanisms underlying blood pressure elevation.
A common intronic variant in the gene underlying a rare monogenic form of coronary artery disease is associated with low-density lipoprotein cholesterol
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Nasmith, W. E. , Grzeszczak, Wladyslaw , Zukowska-Szczechowska, Ewa , Samani, Nilesh
- Date: 2009
- Type: Text , Journal article
- Relation: Heart Vol. 95, no. (2009), p. A83-A83
- Full Text: false
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A common variant in low-density lipoprotein receptor-related protein 6 gene (LRP6) is associated with LDL-Cholesterol
- 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
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- 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.)
Systematic genetic analysis of fibroblast growth factor signalling pathway uncovers fibroblast growth factor binding protein 1 (FGFBP1) as a novel gene of essential hypertension
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Maric, Christine , Samani, Nilesh , Zukowska-Szczechowska, Ewa
- Date: 2009
- Type: Text , Conference paper
- Relation: , p. S148
- Full Text: false
Y chromosome haplogroup as a novel biological risk factor for coronary artery disease - The results of tracking paternal lineages in the west of Scotland primary prevention study (WOSCOPS)
- Authors: Charchar, Fadi , Tomaszewski, Maciej , Barnes, Timothy , Wang, Y. , Brouilette, S. W. , Codd, Veryan , Bani-Mustafa, Ahmed , Padmanabhan, Sandosh , Dominiczak, Anna , Ford, I. , Samani, Nilesh
- Date: 2009
- Type: Text , Conference paper
- Relation: , p. S448-S448
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Common allelic variant in the gene underlying rare monogenic form of coronary artery disease cosegregates with elevated LDL cholesterol in families with high cardiovascular risk
- Authors: Tomaszewski, Maciej , Charchar, Fadi , Barnes, Timothy , Gawron-Kiszka, Magdalena , Sedkowska, Agnieszka , Grzeszczak, Wladyslaw , Samani, Nilesh , Zukowska-Szczechowska, Ewa
- Date: 2008
- Type: Text , Journal article
- Relation: Hypertension Vol. 52, no. 4 (Oct 2008), p. E129-E129
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- Description: C1