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1.
J Am Coll Cardiol ; 73(24): 3118-3131, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221261

RESUMO

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.

2.
J Proteome Res ; 18(6): 2397-2410, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-30887811

RESUMO

Direct infusion high-resolution mass spectrometry (DIHRMS) is a novel, high-throughput approach to rapidly and accurately profile hundreds of lipids in human serum without prior chromatography, facilitating in-depth lipid phenotyping for large epidemiological studies to reveal the detailed associations of individual lipids with coronary heart disease (CHD) risk factors. Intact lipid profiling by DIHRMS was performed on 5662 serum samples from healthy participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS). We developed a novel semi-targeted peak-picking algorithm to detect mass-to-charge ratios in positive and negative ionization modes. We analyzed lipid partial correlations, assessed the association of lipid principal components with established CHD risk factors and genetic variants, and examined differences between lipids for a common genetic polymorphism. The DIHRMS method provided information on 360 lipids (including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and sterol lipids), with a median coefficient of variation of 11.6% (range: 5.4-51.9). The lipids were highly correlated and exhibited a range of associations with clinical chemistry biomarkers and lifestyle factors. This platform can provide many novel insights into the effects of physiology and lifestyle on lipid metabolism, genetic determinants of lipids, and the relationship between individual lipids and CHD risk factors.

3.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
5.
Nat Genet ; 50(10): 1412-1425, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30224653

RESUMO

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

6.
Arch Public Health ; 76: 20, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29619218

RESUMO

Background: Hypertension has been recognized as a global health concern for developing countries and is scarcely described in many of these countries. In Pakistan, few population-based surveys evaluated the prevalence of hypertension and there is no current nationally representative study (the latest nationwide survey was conducted more than two decades ago). Objective: The goal of the current study was to estimate the pooled prevalence of hypertension in Pakistani population using meta-analysis approach. Methods: We searched the published literature using PubMed, Google and Scopus supplemented by a manual search of bibliographies of retrieved articles for population studies providing estimates on the prevalence of hypertension between 1990 and 2017. Studies were included if they defined hypertension as ≥140/90 mmHg and conducted in adults (≥15 years). From the extracted results, the heterogeneity index of the studies was determined using Chi-squared I2 tests and on the basis of heterogeneity, a fixed or random effect model was used to estimates the pooled prevalence of hypertension. Meta-regression was performed to determine those factor of generating heterogeneity. Results: Of a total of 1240 articles, 18 studies comprising 42,618 participants met the eligibility criteria. The overall pooled prevalence of hypertension was 26.34% (25.93%, 26.75%). Subgroup analysis showed higher urban prevalence 26.61% (21.80%, 31.42%) than the rural dwellers 21.03% (10.18%, 31.87%). The prevalence by decade in 1990s was 19.55% (18.07%, 21.05%), in 2000s 23.95% (16.60%, 31.30%) and in 2010s 29.95% (24.13%, 35.77%). Similarly, the pooled prevalence was 24.99% (19.70%, 30.28%) in males and 24.76% (16.76%, 32.76%) in females. We recorded high burden of hypertension among the adult Pakistanis when compared to the data published in local and international journals 23.32% (18.9%, 27.74%) and 27.44% (20.97%, 33.91%). We also found differences in the prevalence of hypertension among small, medium and large studies. Conclusion: Comparing data from previous studies in Pakistan, we found a higher prevalence in urban areas and among males. The prevalence over time is likely to increase faster, further our results underscore the importance of good quality long-term studies that will help to understand hypertension better and implement effective prevention and management programs.

7.
Nat Genet ; 49(10): 1450-1457, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28869590

RESUMO

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Ásia/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores , Comorbidade , Doença das Coronárias/epidemiologia , Doença das Coronárias/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Cadeias HLA-DRB5/genética , Humanos , Redes e Vias Metabólicas/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Terapia de Alvo Molecular , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Hum Mol Genet ; 26(12): 2346-2363, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28379579

RESUMO

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.


Assuntos
Frequência Cardíaca/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Feminino , Frequência do Gene/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
9.
J Am Coll Cardiol ; 67(4): 407-416, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26821629

RESUMO

BACKGROUND: Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain. OBJECTIVES: Through a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF). METHODS: This study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls. RESULTS: Serum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations. CONCLUSIONS: Evidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Acidente Vascular Cerebral/genética , Ácido Úrico/sangue , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Saúde Global , Humanos , Morbidade/tendências , Razão de Chances , Prognóstico , Fatores de Risco , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/epidemiologia
10.
BMC Med Genet ; 16: 114, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26683835

RESUMO

BACKGROUND: Multiple genetic variants have been reliably associated with obesity-related traits in Europeans, but little is known about their associations and interactions with lifestyle factors in South Asians. METHODS: In 16,157 Pakistani adults (8232 controls; 7925 diagnosed with myocardial infarction [MI]) enrolled in the PROMIS Study, we tested whether: a) BMI-associated loci, individually or in aggregate (as a genetic risk score--GRS), are associated with BMI; b) physical activity and smoking modify the association of these loci with BMI. Analyses were adjusted for age, age(2), sex, MI (yes/no), and population substructure. RESULTS: Of 95 SNPs studied here, 73 showed directionally consistent effects on BMI as reported in Europeans. Each additional BMI-raising allele of the GRS was associated with 0.04 (SE = 0.01) kg/m(2) higher BMI (P = 4.5 × 10(-14)). We observed nominal evidence of interactions of CLIP1 rs11583200 (P(interaction) = 0.014), CADM2 rs13078960 (P(interaction) = 0.037) and GALNT10 rs7715256 (P(interaction) = 0.048) with physical activity, and PTBP2 rs11165643 (P(interaction) = 0.045), HIP1 rs1167827 (P(interaction) = 0.015), C6orf106 rs205262 (P(interaction) = 0.032) and GRID1 rs7899106 (P(interaction) = 0.043) with smoking on BMI. CONCLUSIONS: Most BMI-associated loci have directionally consistent effects on BMI in Pakistanis and Europeans. There were suggestive interactions of established BMI-related SNPs with smoking or physical activity.


Assuntos
Predisposição Genética para Doença/genética , Atividade Motora/fisiologia , Infarto do Miocárdio/genética , Fumar/fisiopatologia , Adulto , Alelos , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Obesidade/genética , Obesidade/fisiopatologia , Razão de Chances , Paquistão , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
J Stroke Cerebrovasc Dis ; 23(8): 2174-2182, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25088165

RESUMO

BACKGROUND: Intracranial atherosclerosis (ICAD) is a frequent underlying mechanism of ischemic stroke. There is little direct evidence on its frequency and determinants from regions of high prevalence. This study explores the conventional and socioeconomic risk factors of ICAD in a South Asian population. METHODS: The Karachi Intracranial Stenosis Study is a case-control study of 313 cases of ischemic stroke secondary to ICAD and 331 controls enrolled from 4 major hospitals in Karachi, Pakistan. Stroke subtype was verified by a vascular neurologist using the Trial of Org 10172 in Acute Stroke Treatment classification. Relationships of conventional and socioeconomic risk factors with ICAD-related strokes are reported by calculating odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: ICAD was the cause of stroke in 81.1% cases with large-artery atherosclerosis and 19.5% of all stroke events. Along with risk factors like history of hypertension (OR, 3.33; CI, 2.31-4.78), history of diabetes (OR, 2.29; CI, 1.56-3.35), use of tobacco (OR, 1.49; CI, 1.03-2.16), waist-to-hip ratio (OR, 1.58; CI, 1.04-2.41), and family history of stroke (OR, 1.89; CI, 1.21-2.95), other significant social determinants of ICAD strokes were monthly income (OR, 1.59; CI, 1.01-2.51), unemployment (OR, 2.15; CI, 1.21-3.83), and chronic stress (OR, 3.67; CI, 2.13-6.34). These social determinants were independent predictors of the risk of ICAD, in addition to those described in other world populations. CONCLUSIONS: ICAD accounted for one fifth of all strokes making it the most common ischemic stroke mechanism. In addition to aggressive risk factor control, data also indicated broader holistic efforts on ameliorating inequity, unemployment, and stress reduction to reduce stroke because of ICAD.


Assuntos
Arteriosclerose Intracraniana/complicações , Arteriosclerose Intracraniana/etiologia , Estresse Psicológico/complicações , Acidente Vascular Cerebral/etiologia , Desemprego , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diabetes Mellitus/epidemiologia , Família , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Paquistão/epidemiologia , Fatores de Risco , Fumar/efeitos adversos , Fatores Socioeconômicos , Relação Cintura-Quadril
12.
Int J Stroke ; 8 Suppl A100: 14-20, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23013556

RESUMO

BACKGROUND: There are no descriptions of stroke mechanisms from intracranial atherosclerotic disease in native South Asian Pakistanis. METHODS: Men and women aged ≥ 18 years with acute stroke presenting to four tertiary care hospitals in Karachi, Pakistan were screened using magnetic resonance angiography/transcranial Doppler scans. Trial of ORG 10172 in Acute Stroke Treatment criteria were applied to identify strokes from intracranial atherosclerotic disease. RESULTS: We studied 245 patients with acute stroke due to intracranial atherosclerotic disease. Two hundred thirty scans were reviewed. Also, 206/230 (89.0%) showed acute ischaemia. The most frequent presentation was with cortically based strokes in 42.2% (87/206) followed by border-zone infarcts (52/206, 25.2%). Increasing degrees of stenosis correlated with the development of both cortical and border-zone strokes (P = 0.002). Important associated findings were frequent atrophy (166/230, 72.2%), silent brain infarcts (66/230, 28%) and a marked lack of severe leukoaraiosis identified in only 68/230 (29.6%). A total of 1870 arteries were studied individually. Middle cerebral artery was the symptomatic stroke vessel in half, presenting with complete occlusion in 66%. Evidence of biological disease, symptomatic or asymptomatic was identified in 753 (40.2%) vessels of which 543 (72%) were significantly (>50%) stenosed at presentation. CONCLUSION: Intracranial atherosclerotic disease is a diffuse process in Pakistani south Asians, with involvement of multiple vessels in addition to the symptomatic vessel. The middle cerebral artery is the most frequent symptomatic vessel presenting with cortical embolic infarcts. There is a relative lack of leukoaraiosis. Concomitant atrophy, silent brain infarcts and recent ischaemia in the symptomatic territory are all frequently associated findings.


Assuntos
Isquemia Encefálica/patologia , Arteriosclerose Intracraniana/patologia , Acidente Vascular Cerebral/patologia , Adolescente , Adulto , Idoso , Isquemia Encefálica/etnologia , Estudos de Casos e Controles , Feminino , Humanos , Arteriosclerose Intracraniana/etnologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Paquistão/etnologia , Acidente Vascular Cerebral/etnologia , Tomografia Computadorizada por Raios X , Adulto Jovem
13.
Nat Genet ; 43(10): 984-9, 2011 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-21874001

RESUMO

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Genética Populacional , Genoma Humano , Humanos , Desequilíbrio de Ligação , Londres , Masculino , Paquistão , Polimorfismo de Nucleotídeo Único , Singapura
14.
Circ Cardiovasc Genet ; 3(4): 348-57, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20570915

RESUMO

BACKGROUND: Evidence is sparse about the genetic determinants of major lipids in Pakistanis. METHODS AND RESULTS: Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as CETP associated with HDL-C levels (rs711752; P<10(-13)), APOA5/ZNF259 (rs651821; P<10(-13)) and GCKR (rs1260326; P<10(-13)) with triglyceride levels; and CELSR2 variants with LDL-C levels (rs646776; P<10(-9)). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in APOA5 among Pakistanis was higher and its impact on triglyceride concentration was greater (P-value for difference <10(-4)). CONCLUSIONS: Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans.


Assuntos
Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Adulto , Idoso , Estudos de Casos e Controles , Europa (Continente) , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Transtornos do Metabolismo dos Lipídeos/sangue , Transtornos do Metabolismo dos Lipídeos/etnologia , Transtornos do Metabolismo dos Lipídeos/genética , Lipídeos/genética , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Paquistão , Polimorfismo de Nucleotídeo Único
15.
Arterioscler Thromb Vasc Biol ; 30(7): 1467-73, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20395598

RESUMO

OBJECTIVE: To examine variants at the 9p21 locus in a case-control study of acute myocardial infarction (MI) in Pakistanis and to perform an updated meta-analysis of published studies in people of European ancestry. METHODS AND RESULTS: A total of 1851 patients with first-ever confirmed MI and 1903 controls were genotyped for 89 tagging single-nucleotide polymorphisms at locus 9p21, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium. Minor allele frequencies and extent of linkage disequilibrium observed in Pakistanis were broadly similar to those seen in Europeans. In the Pakistani study, 6 variants were associated with MI (P<10(-2)) in the initial sample set, and in an additional 741 cases and 674 controls in whom further genotyping was performed for these variants. For Pakistanis, the odds ratio for MI was 1.13 (95% CI, 1.05 to 1.22; P=2 x 10(-3)) for each copy of the C allele at rs1333049. In comparison, a meta-analysis of studies in Europeans yielded an odds ratio of 1.31 (95% CI, 1.26 to 1.37) for the same variant (P=1 x 10(-3) for heterogeneity). Meta-analyses of 23 variants, in up to 38,250 cases and 84,820 controls generally yielded higher values in Europeans than in Pakistanis. CONCLUSIONS: To our knowledge, this study provides the first demonstration that variants at the 9p21 locus are significantly associated with MI risk in Pakistanis. However, association signals at this locus were weaker in Pakistanis than those in European studies.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Par 9 , Grupo com Ancestrais do Continente Europeu/genética , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Europa (Continente) , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etnologia , Razão de Chances , Paquistão , Fenótipo , Medição de Risco , Fatores de Risco
16.
BMC Neurol ; 9: 31, 2009 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-19604359

RESUMO

BACKGROUND: Intracranial stenosis is the most common cause of stroke among Asians. It has a poor prognosis with a high rate of recurrence. No effective medical or surgical treatment modality has been developed for the treatment of stroke due to intracranial stenosis. We aim to identify risk factors and biomarkers for intracranial stenosis and to develop techniques such as use of transcranial doppler to help diagnose intracranial stenosis in a cost-effective manner. METHODS/DESIGN: The Karachi Intracranial Stenosis Study (KISS) is a prospective, observational, case-control study to describe the clinical features and determine the risk factors of patients with stroke due to intracranial stenosis and compare them to those with stroke due to other etiologies as well as to unaffected individuals. We plan to recruit 200 patients with stroke due to intracranial stenosis and two control groups each of 150 matched individuals. The first set of controls will include patients with ischemic stroke that is due to other atherosclerotic mechanisms specifically lacunar and cardioembolic strokes. The second group will consist of stroke free individuals. Standardized interviews will be conducted to determine demographic, medical, social, and behavioral variables along with baseline medications. Mandatory procedures for inclusion in the study are clinical confirmation of stroke by a healthcare professional within 72 hours of onset, 12 lead electrocardiogram, and neuroimaging. In addition, lipid profile, serum glucose, creatinine and HbA1C will be measured in all participants. Ancillary tests will include carotid ultrasound, transcranial doppler and magnetic resonance or computed tomography angiogram to rule out concurrent carotid disease. Echocardiogram and other additional investigations will be performed at these centers at the discretion of the regional physicians. DISCUSSION: The results of this study will help inform locally relevant clinical guidelines and effective public health and individual interventions.


Assuntos
Artérias Cerebrais/patologia , Transtornos Cerebrovasculares/complicações , Protocolos Clínicos , Acidente Vascular Cerebral/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/patologia , Transtornos Cerebrovasculares/epidemiologia , Transtornos Cerebrovasculares/patologia , Constrição Patológica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
17.
Eur J Epidemiol ; 24(6): 329-38, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19404752

RESUMO

The burden of coronary heart disease (CHD) is increasing at a greater rate in South Asia than in any other region globally, but there is little direct evidence about its determinants. The Pakistan Risk of Myocardial Infarction Study (PROMIS) is an epidemiological resource to enable reliable study of genetic, lifestyle and other determinants of CHD in South Asia. By March 2009, PROMIS had recruited over 5,000 cases of first-ever confirmed acute myocardial infarction (MI) and over 5,000 matched controls aged 30-80 years. For each participant, information has been recorded on demographic factors, lifestyle, medical and family history, anthropometry, and a 12-lead electrocardiogram. A range of biological samples has been collected and stored, including DNA, plasma, serum and whole blood. During its next stage, the study aims to expand recruitment to achieve a total of about 20,000 cases and about 20,000 controls, and, in subsets of participants, to enrich the resource by collection of monocytes, establishment of lymphoblastoid cell lines, and by resurveying participants. Measurements in progress include profiling of candidate biochemical factors, assay of 45,000 variants in 2,100 candidate genes, and a genomewide association scan of over 650,000 genetic markers. We have established a large epidemiological resource for CHD in South Asia. In parallel with its further expansion and enrichment, the PROMIS resource will be systematically harvested to help identify and evaluate genetic and other determinants of MI in South Asia. Findings from this study should advance scientific understanding and inform regionally appropriate disease prevention and control strategies.


Assuntos
Predisposição Genética para Doença , Estilo de Vida , Infarto do Miocárdio/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria , Ásia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Paquistão , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários
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