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ABSTRACT: A paradigm shift towards biology occurred in the 1990's subsequently catalyzed by the sequencing of the human genome in 2000. The cost of DNA sequencing has gone from millions to thousands of dollars with sequencing of one's entire genome costing only $1,000. Rapid DNA sequencing is being embraced for single gene disorders, particularly for sporadic cases and those from small families. Transmission of lethal genes such as associated with Huntington's disease can, through in-vitro fertilization, avoid passing it on to one's offspring. DNA sequencing will meet the challenge of elucidating the genetic predisposition for common polygenic diseases, especially in determining the function of the novel common genetic risk variants and identifying the rare variants, which may also partially ascertain the source of the missing heritability. The challenge for DNA sequencing remains great, despite human genome sequences being 99.5% identical, the 3 million single nucleotide polymorphisms (SNPs) responsible for most of the unique features add up to 60 new mutations per person which, for 7 billion people, is 420 billion mutations. It is claimed that DNA sequencing has increased 10,000 fold while information storage and retrieval only 16 fold. The physician and health user will be challenged by the convergence of two major trends, whole genome sequencing and the storage/retrieval and integration of the data.
Journal of the American College of Cardiology 03/2013; · 14.16 Impact Factor
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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Sekar Kathiresan,
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer, Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani
[show abstract]
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ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer, Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani,
Klaus Stark
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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The CARDIoGRAMplusC4D Consortium,
Panos Deloukas,
Stavroula Kanoni,
Christina Willenborg,
Martin Farrall,
Themistocles L Assimes,
John R Thompson,
Erik Ingelsson,
Danish Saleheen,
Jeanette Erdmann, [......],
Sekar Kathiresan,
Anders Hamsten,
Jaspal S Kooner,
Unnur Thorsteinsdottir,
John Danesh,
Colin N A Palmer, Robert Roberts,
Hugh Watkins,
Heribert Schunkert,
Nilesh J Samani
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
Nature Genetics 12/2012; 45(1):25. · 35.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVES: Because post-transcriptional mechanisms modulate levels of p16 (encoded by CDKN2A) and p15 (encoded by CDKN2B), we tested whether interferon-γ regulates the expression of these proteins and the effect of the 9p21 genotype. BACKGROUND: The mechanism whereby the common variant at chromosome 9p21.3 confers risk for coronary artery disease (CAD) remains uncertain. A recent report proposed that 9p21.3 confers differential activation of adjacent genes in response to interferon-γ, and reported that mRNA levels of CDKN2B are reduced in response to interferon-γ. METHODS: Human umbilical vein endothelial cells (HUVECs), aortic smooth muscle cells, HeLa cells, HEK293 cells, and 16 human lymphoblastoid cell lines, all genotyped for the 9p21.3 locus, were treated with interferon-γ and analyzed by immunoblot. RESULTS: In all cells tested-except HUVECs where expression was not modulated by interferon-γ-regardless of 9p21.3 genotype, interferon-γ increased the expression of p16 and p15. Northern blot analysis confirmed that interferon-γ has little effect on mRNA levels of CDKN2A and CDKN2B. CONCLUSIONS: The 9p21.3 risk genotype does not affect the activation of cyclin-dependent kinase inhibitors p15 and p16 by interferon-γ. Thus, another mechanism is likely to account for the CAD risk associated with this locus.
Journal of the American College of Cardiology 11/2012; · 14.16 Impact Factor
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ABSTRACT: Personalized medicine is the tailoring of the diagnosis, prevention, and treatment to the characteristics of each individual patient. In this review, we provide a status report on genetic variants that influence therapy with antiplatelet agents, warfarin, and statins. Resistance to clopidogrel, an antiplatelet therapy, has been shown to be present in 25% to 30% of Caucasians and an even higher percentage in Asians. Part of this resistance is because of the CYP2C19*2 allele. Administering clopidogrel on the basis of previous genetic testing remains controversial. A recent breakthrough in point-of-care genetic testing for clopidogrel might be significant, not only for genetic testing for clopidogrel, but for the whole of personalized medicine. Genetic testing for aspirin resistance is not yet recommended because of incomplete genetic data. Studies to determine the value of genetic testing before the administration of warfarin are ongoing. Testing for SLCO1B1 allele for individuals with muscle cramps who are taking statins could be very helpful but is not yet recommended as routine. Pharmacogenetics has the potential to customize therapy and move away from the current model of 1 drug fits all.
The Canadian journal of cardiology 10/2012; · 3.36 Impact Factor
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ABSTRACT: Susceptibility to coronary artery disease (CAD) is claimed to be 40% to 60% inherited, but until recently genetic risk factors predisposing to CAD have been elusive. Comprehensive prevention of CAD requires manipulation of genetic risk. The availability of microarrays of single-nucleotide polymorphisms enabling genome-wide association studies (GWAS) led to the discovery of 33 genetic risk variants for CAD. Surprisingly, 23 risk variants mediate their risk through unknown mechanisms, with only 10 associating with hypertension or lipids. Thus, there are several mechanisms contributing to the pathogenesis of CAD yet to be elucidated. The first risk variant discovered by GWAS was 9p21.3, which occurs in 75% of all populations except African, with a mean increased risk of 25% per copy. Of the 33 variants for CAD, the increased risk varies from 6% to 92% with a mean increased risk of 18%, occurring on average in 47% of the population. The maximum number of risk alleles per individual would be 66. In the CARDIoGRAM (Coronary Artery Disease Genome-wide Replication and Meta Analysis) study of 23 variants, the average per individual was 17, the minimum 7, and the maximum 37. The top 10th percentile has an odds ratio of 1.88 and the lowest percentile an odds ratio of 0.55. Routine genetic screening is unlikely until management is improved by genetic testing. Risk variants should provide pathophysiological insights and targets for novel therapy. While risk variants are less potent predictors of CAD, compared with biomarkers, they have the advantage of not changing in one's lifetime and are unaffected by diet, sex, age, or medication.
Journal of the American College of Cardiology 09/2012; 60(18):1715-21. · 14.16 Impact Factor
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W H Wilson Tang,
Jaana Hartiala,
Yiying Fan,
Yuping Wu,
Alexandre F R Stewart,
Jeanette Erdmann,
Sekar Kathiresan, Robert Roberts,
Ruth McPherson,
Hooman Allayee,
Stanley L Hazen
[show abstract]
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ABSTRACT: OBJECTIVE: Diminished serum paraoxonase and arylesterase activities (measures of paraoxonase-1 [PON-1] function) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk. The clinical prognostic use of measuring distinct PON-1 activities has not been established, and the genetic determinants of PON-1 activities are not known. METHODS AND RESULTS: We established analytically robust high-throughput assays for serum paraoxonase and arylesterase activities and measured these in 3668 stable subjects undergoing elective coronary angiography without acute coronary syndrome and were prospectively followed for major adverse cardiovascular events (MACE= death, myocardial infarction, stroke) over 3 years. Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE, with arylesterase activity showing greatest prognostic value (quartile 4 versus quartile 1; hazard ratio 2.63; 95% CI, 1.97-3.50; P<0.01). Arylesterase remained significant after adjusting for traditional risk factors, C-reactive protein, and creatinine clearance (hazard ratio, 2.20; 95% CI, 1.60-3.02; P<0.01), predicted future development of MACE in both primary and secondary prevention populations, and reclassified risk categories incrementally to traditional clinical variables. A genome-wide association study identified distinct single nucleotide polymorphisms within the PON-1 gene that were highly significantly associated with serum paraoxonase (1.18×10(-303)) or arylesterase (4.99×10(-116)) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort (n=2136) or history of either coronary artery disease or myocardial infarction in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis consortium (n≈80 000 subjects). CONCLUSIONS: Diminished serum arylesterase activity, but not the genetic determinants of PON-1 functional measures, provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE.
Arteriosclerosis Thrombosis and Vascular Biology 09/2012; 32(11):2803-2812. · 6.37 Impact Factor
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Tanya M Teslovich,
Kiran Musunuru,
Albert V Smith,
Andrew C Edmondson,
Ioannis M Stylianou,
Masahiro Koseki,
James P Pirruccello,
Samuli Ripatti,
Daniel I Chasman,
Cristen J Willer, [......],
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Cornelia M van Duijn,
Leena Peltonen,
Gonçalo R Abecasis,
Michael Boehnke,
Sekar Kathiresan
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Benjamin F Voight,
Gina M Peloso,
Marju Orho-Melander,
Ruth Frikke-Schmidt,
Maja Barbalic,
Majken K Jensen,
George Hindy,
Hilma Hólm,
Eric L Ding,
Toby Johnson, [......],
David Siscovick,
Roberto Elosua,
Kari Stefansson,
Christopher J O'Donnell,
Veikko Salomaa,
Daniel J Rader,
Leena Peltonen,
Stephen M Schwartz,
David Altshuler,
Sekar Kathiresan
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ABSTRACT: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
The Lancet 05/2012; 380(9841):572-80. · 38.28 Impact Factor
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ABSTRACT: Coronary artery disease (CAD) is still the number-one killer in the world, and clinical trials indicate that it is preventable. Mortality and morbidity can be reduced by at least 30% to 40% by treating known risk factors. Genetic susceptibility is claimed to account for 50% of predisposition. The challenge of preventing CAD in this century, as claimed by some investigators, will require a more comprehensive prevention and treatment of environmental and genetic risk factors. Part of that challenge has been met by genome-wide association studies, which have identified 36 genetic variants with increased risk for CAD. All of these genetic variants have reached genome-wide significance (5×10(-8) ) and replicate in independent populations with large sample sizes. More than 50% of these variants occur in >50% of the population, with 10 occurring in >75% of the population. The challenge and the opportunity lie in the observation that >66% of these risk variants do not mediate their risk through known conventional risk factors. These results suggest that genetic predisposition for CAD is conferred by common DNA variants and many factors contributing to the pathogenesis of CAD are yet to be determined. Comprehensive prevention of CAD will most likely require combating genetic and environmental risk factors. We are on the cusp of genetic screening, and new therapeutic targets are becoming available to manage both genetic and environmental risk factors for CAD. The authors are supported by grants from the Canadian Institutes of Health Research, nos. MOP82810 (RR) and MOP77682 (AFRS), and the Canada Foundation for Innovation, no. 11966 (RR). The authors have no other funding, financial relationships, or conflicts of interest to disclose.
Clinical Cardiology 05/2012; 35(9):536-40. · 2.15 Impact Factor
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Sonny Dandona,
Li Chen,
Meng Fan,
Md Afaque Alam,
Olivia Assogba,
Melanie Belanger,
Kathryn Williams,
George A. Wells,
W. H. Wilson Tang,
Stephen G. Ellis,
Stanley L. Hazen,
Ruth McPherson, Robert Roberts,
Alexandre F. R. Stewart
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ABSTRACT: The transcription factor GATA2 was reported to associate with coronary artery disease (CAD) in the family-based Genecard sample
(Connelly etal. in PLoS Genet 2:e139, 2006). We asked whether GATA2 associates with sporadic cases of CAD in the Ottawa Heart
Genomics Study (OHGS) and Cleveland Clinic (CC) populations. We genotyped the lead single nucleotide polymorphism (SNP) from
Genecard, rs2713604 which is located in intron 5–6 of GATA2 in 600 CAD cases and 625 controls, as well as a tag SNP rs1573949
(r
2=0.87 in Caucasians of European ancestry in Utah from HapMap) in 1,136 cases and 1,162 controls in the OHGS1 population.
A further 1,838 CAD cases and 913 controls derived from an independent sample combining genotypes from CC and OHGS2 populations
were genotyped for rs1573949. Neither of the genotyped SNPs associates with CAD in the OHGS1 or CC/OHGS2 populations. Our
data suggest that GATA2 does not contribute to the development of angiographic CAD among sporadic cases.
Human Genetics 04/2012; 127(1):101-105. · 5.07 Impact Factor
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Zari Dastani,
Marie-France Hivert,
Nicholas Timpson,
John R B Perry,
Xin Yuan,
Robert A Scott,
Peter Henneman,
Iris M Heid,
Jorge R Kizer,
Leo-Pekka Lyytikäinen, [......],
Eric E Schadt,
David P Strachan,
Muredach P Reilly,
Nilesh J Samani,
Heribert Schunkert,
L Adrienne Cupples,
Manjinder S Sandhu,
Paul M Ridker,
Daniel J Rader,
Sekar Kathiresan
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[hide abstract]
ABSTRACT: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
PLoS Genetics 03/2012; 8(3):e1002607. · 8.69 Impact Factor
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ABSTRACT: Prevention of coronary artery disease (CAD) is an appropriate goal for the 21st century. Randomized clinical studies consistently show a 30-40% reduction in mortality and morbidity by modifying known risk factors. However, genetic risk, estimated to account for 40-60% of susceptibility to CAD, has until recently been unknown. Comprehensive prevention will require knowledge of both.
The 21st century technology has responded to the challenge. Whereas the first genetic risk variant was not discovered until 2007 (9p21), a total of 36 genetic risk factors for CAD have been discovered and verified in large sample sizes. A startling discovery was that over two-thirds of these factors do not act through known risk factors or mechanisms. This obviously has great implications for the pathogenesis of CAD and presents many potential targets for new therapy. These genetic risk factors occur more commonly in the population than expected, with over half of them occurring in more than 50% of the population, and 10 of them occurring in at least 75% of the population.
The role of genetic risk factors in genetic screening for prevention of heart disease is yet to be defined. The technology is already available, but functional analysis may be a prerequisite for their clinical application.
Current opinion in cardiology 02/2012; 27(3):221-7. · 2.66 Impact Factor
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Robert W Davies,
George A Wells,
Alexandre F R Stewart,
Jeanette Erdmann,
Svati H Shah,
Jane F Ferguson,
Alistair S Hall,
Sonia S Anand,
Mary S Burnett,
Stephen E Epstein, [......],
Stefan Schreiber,
W H Wilson Tang,
Stephen G Ellis,
Daniel J Rader,
Stanley L Hazen,
Muredach P Reilly,
Nilesh J Samani,
Heribert Schunkert, Robert Roberts,
Ruth McPherson
[show abstract]
[hide abstract]
ABSTRACT: Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with coronary artery disease (CAD) and/or myocardial infarction risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
We performed a discovery meta-analysis of 5 GWAS involving 13 949 subjects (7123 cases, 6826 control subjects) imputed at approximately 5 million single nucleotide polymorphisms, using pilot 1000 Genomes-based haplotypes. Promising loci were followed up in an additional 5 studies with 11 032 subjects (5211 cases, 5821 control subjects). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome-wide significance in the combined analysis (rs3869109; p(discovery)=3.3×10(-7), p(replication)=5.3×10(-4)p(combined)=1.12×10(-9)). A subanalysis combining discovery GWAS showed an attenuation of significance when stringent corrections for European population structure were used (P=4.1×10(-10) versus 3.2×10(-7)), suggesting that the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity, and self-cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T-cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
Circulation Cardiovascular Genetics 02/2012; 5(2):217-25. · 6.11 Impact Factor
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[show abstract]
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ABSTRACT: It has long been recognized that 50% of the susceptibility for coronary artery disease (CAD) is due to predisposing genetic factors. Comprehensive prevention is likely to require knowledge of these genetic factors.
Using a genomewide association study (GWAS), the Ottawa Heart Genomic Study and the deCODE group simultaneously identified the first genetic risk variant, at chromosome 9p21. The 9p21 variant became the first risk factor to be identified since 1964. 9p21 occurs in 75% of the population except for African Americans and is associated with a 25% increased risk for CAD with 1 copy and a 50% increased risk with 2 copies. Perhaps the most remarkable finding is that 9p21 is independent of all known risk factors, indicating there are factors contributing to the pathogenesis of CAD that are yet unknown. 9p21 in individuals with premature CAD is associated with a 2-fold increase in risk, similar to that of smoking and cholesterol. Routine genetic testing will probably remain controversial until a specific treatment is developed. Over a period of 5 years, however, GWASs have identified 30 genetic variants for CAD risk, of which only 6 act through the known risk factors.
The 9p21 variant has now been established as an independent risk factor for CAD and, along with the additional 29 risk genetic variants recently identified, is likely to provide the thrust for genetic testing and personalized medicine in the near future.
Clinical Chemistry 01/2012; 58(1):104-12. · 7.91 Impact Factor
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Harald Grallert,
Josée Dupuis,
Joshua C Bis,
Abbas Dehghan,
Maja Barbalic,
Jens Baumert,
Chen Lu,
Nicholas L Smith,
André G Uitterlinden, Robert Roberts, [......],
Jennifer F Yamamoto,
Jerome I Rotter,
Martin G Larson,
Alexandre F R Stewart,
Eric Boerwinkle,
Jacqueline C M Witteman,
Russell P Tracy,
Wolfgang Koenig,
Emelia J Benjamin,
Christie M Ballantyne
[show abstract]
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ABSTRACT: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.
In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 × 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study.
Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
European Heart Journal 01/2012; 33(2):238-51. · 10.48 Impact Factor
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ABSTRACT: The next decade will focus on identifying the missing heritability of coronary artery disease (CAD). This process will involve a more comprehensive interrogation of common single nucleotide polymorphisms (SNPs) that impart modest biologic effect and an interrogation of rare SNPs that impart profound biologic effect. In parallel, an investigation of the underlying biology of the described association will likely yield novel pathways that provide therapeutic targets. Once we obtain a more complete inventory of sequence variation that predisposes to CAD, a more realistic assessment of the role of genetic risk scoring allied with standard risk algorithms will be possible.
The Medical clinics of North America 01/2012; 96(1):113-22. · 2.18 Impact Factor
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Toby Johnson,
Tom R Gaunt,
Stephen J Newhouse,
Sandosh Padmanabhan,
Maciej Tomaszewski,
Meena Kumari,
Richard W Morris,
Ioanna Tzoulaki,
Eoin T O'Brien,
Neil R Poulter, [......], Robert Roberts,
Christopher Newton-Cheh,
Lude Franke,
Alice V Stanton,
Anna F Dominiczak,
Martin Farrall,
Aroon D Hingorani,
Nilesh J Samani,
Mark J Caulfield,
Patricia B Munroe
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ABSTRACT: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.
The American Journal of Human Genetics 11/2011; 89(6):688-700. · 10.60 Impact Factor
