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Richa Saxena,
Clara C Elbers,
Yiran Guo,
Inga Peter,
Tom R Gaunt,
Jessica L Mega,
Matthew B Lanktree,
Archana Tare,
Berta Almoguera Castillo,
Yun R Li, [......],
Paul I W de Bakker,
Jeanne McCaffery,
Cisca Wijmenga,
Marc S Sabatine,
James G Wilson,
Alex Reiner,
Donald W Bowden,
Hakon Hakonarson,
David S Siscovick,
Brendan J Keating
[show abstract]
[hide abstract]
ABSTRACT: To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
The American Journal of Human Genetics 02/2012; 90(3):410-25. · 10.60 Impact Factor
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Matthew B Lanktree,
Yiran Guo,
Muhammed Murtaza,
Joseph T Glessner,
Swneke D Bailey,
N Charlotte Onland-Moret,
Guillaume Lettre,
Halit Ongen,
Ramakrishnan Rajagopalan,
Toby Johnson, [......],
Wolfgang Koenig,
Tom R Gaunt,
Sonia S Anand,
Yvonne T van der Schouw,
Nicole Soranzo,
Garret A Fitzgerald,
Alex Reiner,
Robert A Hegele,
Hakon Hakonarson,
Brendan J Keating
[show abstract]
[hide abstract]
ABSTRACT: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
The American Journal of Human Genetics 01/2011; 88(1):6-18. · 10.60 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Retroperitoneal hemorrhage (RPH) is an infrequent but occasionally fatal complication of percutaneous coronary intervention (PCI). Therefore, it has been studied in relatively small numbers of patients.
Prospectively collected data on 28,378 consecutive patients treated between 1992 and 2003 were examined, supplemented by a date-based case control cohort study (76 RPH and 76 non-RPH patients) to examine elements not routinely recorded prospectively. Independent correlates of RPH were determined using logistical regression analysis.
One hundred sixty-three patients (0.57%) developed RPH; of these 73.5% required blood transfusions and 10.4% expired during hospitalization (P < 0.001 for both compared with patients without RPH). RPH was independently associated with femoral artery sheath placement superior to the inferior epigastric artery (P < 0.001), female sex (P < 0.001), use of Angioseal Device (P < 0.001), glycoprotein IIb/IIIa inhibitor use (P = 0.001), and patient presentation with the acute myocardial infarction (P = 0.035), and was inversely related to patient weight (P = 0.014). Of the 17 patient deaths, 6 were directly related to RPH, 2 of which occurred in association with delays in resuscitation efforts consequent to attempts to obtain diagnostic confirmation with CT imaging.
RPH remains an infrequent but serious complication of PCI. Appropriate management of the femoral access site and the patient once this complication is suspected may minimize adverse outcomes.
Catheterization and Cardiovascular Interventions 05/2006; 67(4):541-5. · 2.29 Impact Factor
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ABSTRACT: The study defined the incidence of cerebral hyperperfusion syndrome and intracranial hemorrhage (ICH) and the risk factors for their development following carotid artery stenting (CAS).
Hyperperfusion syndrome and ICH can complicate carotid revascularization, be it endarterectomy or CAS. Although extensive effort has been devoted to reducing the incidence of ischemic stroke complicating CAS, little is known about the incidence, etiology, and prevention strategies for hyperperfusion and ICH following CAS.
We retrospectively reviewed the prospective database of 450 consecutive patients who were treated with CAS in our department to identify patients who developed hyperperfusion syndrome and/or ICH.
The mean age of the patients was 72.7 +/- 10.9 years, and the mean diameter narrowing was 84 +/- 12.8%. Five (1.1% [95% confidence interval 0.4% to 2.6%]) patients developed hyperperfusion. Three (0.67%) of the five developed ICH. Two of these patients died (0.44%). Symptoms developed within a median of 10 h (range, 6 h to 4 days) following stenting. All five patients had correction of a severe internal carotid stenosis (mean 95.6 +/- 3.7%) with a concurrent contralateral stenosis >80% or contralateral occlusion and peri-procedural hypertension. These same risk factors are involved in cerebral hyperperfusion following carotid endarterectomy. The use of platelet glycoprotein IIb/IIIa receptor blockers did not appear to increase the risk ICH.
The hyperperfusion syndrome occurs infrequently following CAS, and ICH occurs in 0.67% of patients. Patients with severe bilateral carotid stenoses may be predisposed to ICH, particularly if there is concurrent arterial hypertension. Patients with these factors may require more intensive hemodynamic monitoring after CAS, including prolongation of hospitalization in some cases.
Journal of the American College of Cardiology 06/2004; 43(9):1596-601. · 14.16 Impact Factor
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ABSTRACT: The significance of a history of heart failure (HF) in patients presenting with acute coronary syndromes and elevated cardiac markers is unclear. The authors performed an analysis of patients enrolled in the Internet Tracking Registry of Acute Coronary Syndromes (i*trACS). Cardiac marker measurement and cardiac catheterization were performed in 1174 patients. Of these, 116 (9.9%) had heart failure (HF). Coronary artery disease (CAD) was found in 61 (52.6%) patients in the HF group and 581 (54.9%) in the group without HF. In the non-HF cohort, positive markers occurred in 306 patients, in whom 217 (70.9%) had CAD at catheterization. In the HF subset, 24 patients had positive biomarkers and 15 (62.5%) had CAD. A history of HF did not lessen the likelihood of CAD as evidenced by angiography and does not diminish the utility of cardiac markers in diagnosing acute coronary syndromes.
Congestive Heart Failure 13(3):142-8.
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Richa Saxena,
Clara C Elbers,
Yiran Guo,
Inga Peter,
Tom R Gaunt,
Jessica L Mega,
Matthew B Lanktree,
Archana Tare,
Berta Almoguera Castillo,
Yun R Li, [......],
Paul I W,
Jeanne McCaffery,
Cisca Wijmenga,
Marc S Sabatine,
James G Wilson,
Alex Reiner,
Donald W Bowden,
Hakon Hakonarson,
David S Siscovick,
Brendan J Keating
[show abstract]
[hide abstract]
ABSTRACT: To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom <50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with <2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10�9) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10�6). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10�7) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10�15). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10�8). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
American journal of human genetics.
