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1.
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.

2.
PLoS One ; 13(11): e0206554, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383853

RESUMO

BACKGROUND AND PURPOSE: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication. METHODS: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base. RESULTS: Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity. CONCLUSION: PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.

3.
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
4.
Circulation ; 135(24): 2336-2353, 2017 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-28461624

RESUMO

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0×10-3 (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P=1.3×10-16) in comparison with 5% in ever-smokers (P=2.5×10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.


Assuntos
Doença das Coronárias/genética , Doença das Coronárias/prevenção & controle , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Fumar/genética , Proteína ADAMTS7/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Doença das Coronárias/epidemiologia , Vasos Coronários/patologia , Vasos Coronários/fisiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fumar/efeitos adversos , Fumar/epidemiologia
5.
J Am Coll Cardiol ; 69(16): 2054-2063, 2017 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-28385496

RESUMO

BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown. OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD. METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects. RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001). CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.


Assuntos
Angiopoietinas/deficiência , Doença da Artéria Coronariana/genética , Adulto , Proteínas Semelhantes a Angiopoietina , Angiopoietinas/sangue , Angiopoietinas/genética , Animais , Aterosclerose/genética , Estudos de Casos e Controles , Feminino , Humanos , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Infarto do Miocárdio/sangue , Fatores de Risco
6.
Nature ; 544(7649): 235-239, 2017 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-28406212

RESUMO

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.


Assuntos
Consanguinidade , Análise Mutacional de DNA , Deleção de Genes , Genes/genética , Estudos de Associação Genética/métodos , Homozigoto , Fenótipo , 1-Alquil-2-acetilglicerofosfocolina Esterase/deficiência , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Apolipoproteína C-III/deficiência , Apolipoproteína C-III/genética , Estudos de Coortes , Doença das Coronárias/sangue , Doença das Coronárias/genética , Família 2 do Citocromo P450/genética , Gorduras na Dieta/farmacologia , Exoma/genética , Jejum/sangue , Feminino , Frequência do Gene , Humanos , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Neurregulinas/genética , Paquistão , Linhagem , Fosfoproteínas/genética , Período Pós-Prandial , Sítios de Splice de RNA/genética , Genética Reversa/métodos , Trocadores de Sódio-Hidrogênio/genética , Triglicerídeos/sangue
7.
Lancet Diabetes Endocrinol ; 5(7): 524-533, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28408323

RESUMO

BACKGROUND: The lipoprotein(a) pathway is a causal factor in coronary heart disease. We used a genetic approach to distinguish the relevance of two distinct components of this pathway, apolipoprotein(a) isoform size and circulating lipoprotein(a) concentration, to coronary heart disease. METHODS: In this mendelian randomisation study, we measured lipoprotein(a) concentration and determined apolipoprotein(a) isoform size with a genetic method (kringle IV type 2 [KIV2] repeats in the LPA gene) and a serum-based electrophoretic assay in patients and controls (frequency matched for age and sex) from the Pakistan Risk of Myocardial Infarction Study (PROMIS). We calculated odds ratios (ORs) for myocardial infarction per 1-SD difference in either LPA KIV2 repeats or lipoprotein(a) concentration. In a genome-wide analysis of up to 17 503 participants in PROMIS, we identified genetic variants associated with either apolipoprotein(a) isoform size or lipoprotein(a) concentration. Using a mendelian randomisation study design and genetic data on 60 801 patients with coronary heart disease and 123 504 controls from the CARDIoGRAMplusC4D consortium, we calculated ORs for myocardial infarction with variants that produced similar differences in either apolipoprotein(a) isoform size in serum or lipoprotein(a) concentration. Finally, we compared phenotypic versus genotypic ORs to estimate whether apolipoprotein(a) isoform size, lipoprotein(a) concentration, or both were causally associated with coronary heart disease. FINDINGS: The PROMIS cohort included 9015 patients with acute myocardial infarction and 8629 matched controls. In participants for whom KIV2 repeat and lipoprotein(a) data were available, the OR for myocardial infarction was 0·93 (95% CI 0·90-0·97; p<0·0001) per 1-SD increment in LPA KIV2 repeats after adjustment for lipoprotein(a) concentration and conventional lipid concentrations. The OR for myocardial infarction was 1·10 (1·05-1·14; p<0·0001) per 1-SD increment in lipoprotein(a) concentration, after adjustment for LPA KIV2 repeats and conventional lipids. Genome-wide analysis identified rs2457564 as a variant associated with smaller apolipoprotein(a) isoform size, but not lipoprotein(a) concentration, and rs3777392 as a variant associated with lipoprotein(a) concentration, but not apolipoprotein(a) isoform size. In 60 801 patients with coronary heart disease and 123 504 controls, OR for myocardial infarction was 0·96 (0·94-0·98; p<0·0001) per 1-SD increment in apolipoprotein(a) protein isoform size in serum due to rs2457564, which was directionally concordant with the OR observed in PROMIS for a similar change. The OR for myocardial infarction was 1·27 (1·07-1·50; p=0·007) per 1-SD increment in lipoprotein(a) concentration due to rs3777392, which was directionally concordant with the OR observed for a similar change in PROMIS. INTERPRETATION: Human genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein(a) concentration are independent and causal risk factors for coronary heart disease. Lipoprotein(a)-lowering interventions could be preferentially effective in reducing the risk of coronary heart disease in individuals with smaller apolipoprotein(a) isoforms. FUNDING: British Heart Foundation, US National Institutes of Health, Fogarty International Center, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, and Pfizer.


Assuntos
Apoproteína(a)/sangue , Biomarcadores/sangue , Doença das Coronárias/sangue , Lipoproteína(a)/sangue , Análise da Randomização Mendeliana/métodos , Infarto do Miocárdio/sangue , Polimorfismo de Nucleotídeo Único , Apoproteína(a)/genética , Estudos de Casos e Controles , Doença das Coronárias/epidemiologia , Doença das Coronárias/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Incidência , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Paquistão/epidemiologia , Fenótipo , Isoformas de Proteínas , Fatores de Risco
8.
Nat Genet ; 48(10): 1151-1161, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27618447

RESUMO

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.


Assuntos
Pressão Sanguínea/genética , Variação Genética , Hipertensão/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos
9.
Stroke ; 47(2): 307-16, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26732560

RESUMO

BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.


Assuntos
Isquemia Encefálica/genética , Serina Endopeptidases/genética , Acidente Vascular Cerebral/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idade de Início , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Isquemia Encefálica/complicações , Cromossomos Humanos Par 10 , Simulação por Computador , DNA Intergênico/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/metabolismo , Acidente Vascular Cerebral/etiologia
10.
Nat Commun ; 7: 10531, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26818947

RESUMO

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10(-8)), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Proteínas de Ligação a DNA/genética , Estudo de Associação Genômica Ampla , Humanos , Japão , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras da Sinalização de Citocina/genética , Fatores de Transcrição/genética
11.
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
12.
Curr Genet Med Rep ; 4(4): 207-212, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29082115

RESUMO

Integration of knowledge generated from genetic studies on intermediate biomarkers and CHD can provide a reliable approach to help assess causal pathways in coronary heart disease. Mendelian Randomization (MR) studies are a powerful tool to assess causal relevance of a range of pathways. These analyses use genetic variants as proxies for soluble biomarkers in association studies of disease risk. MR studies can provide unbiased estimates of causal effects and avoid distortions due to confounding factors arising later in life, because genetic variants are fixed at conception. MR studies have provided evidence pointing towards the likelihood of a causal relevance of a range of pathways in CHD, including LDL-C, triglycerides, lipoprotein (a), and interleukin-6 receptor. On the other hand, MR studies have refuted the causal relevance of a number of biomarkers, including C-reactive protein (CRP), fibrinogen, uric acid, LpPLA2 activity, and homocysteine. Carefully conducted MR studies should overcome the limitations that are inherent to other observational studies (e.g., residual confounding and reverse causality) to help assess causal relevance of a range of pathways in CHD.

13.
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
14.
J Coll Physicians Surg Pak ; 25 Suppl 1: S22-3, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25933453

RESUMO

Situs inversus totalis is a rare condition affecting intra abdominal and intra thoracic organs. Situs inversus usually remains asymptomatic. Life expectancy is normal in the absence of rare cardiac abnormalities. Left sided gallbladder can occur even without situs inversus totalis. Cholelithiasis is not more common in patients with situs inversus than the general population. However, these patients may pose a diagnostic difficulty. An ultrasound scan can confirm the presence of gallstones and the left-sided gallbladder. Here we present the case of a 40-year female with this diagnosis who was diagnosed on abdominal scanning and underwent laparoscopic cholecystectomy for left sided cholelithiasis.


Assuntos
Colecistectomia Laparoscópica/instrumentação , Colelitíase/cirurgia , Vesícula Biliar/anormalidades , Situs Inversus/complicações , Adulto , Colecistectomia Laparoscópica/métodos , Colelitíase/diagnóstico , Dextrocardia , Feminino , Doenças da Vesícula Biliar , Humanos , Resultado do Tratamento
15.
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
16.
Arterioscler Thromb Vasc Biol ; 34(9): 1811-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25035346

RESUMO

All forms of tobacco lead to an increased risk of cardiovascular disorders. During the past few decades, the number of people who consume tobacco has increased worldwide because of an overall increase in the global population. It is estimated that close to 80% of the >1.3 billion people who smoke tobacco in the world are in low- and middle-income countries. Smokeless forms of tobacco are also widely consumed in low- and middle-income countries, including chewable and snuffed forms. Lack of targeted and effective strategies to control tobacco consumption contributes to a large burden of cardiovascular disorders in low- and middle-income countries, where cardiovascular disorders have become the leading cause of morbidity and mortality. In this review, we evaluate the epidemiology of tobacco use in low- and middle-income countries and assess the public health policies needed to control tobacco use in such regions for the prevention of cardiovascular disorders and other tobacco-related morbidities and mortality.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Política de Saúde , Promoção da Saúde , Saúde Pública , Uso de Tabaco/efeitos adversos , Adolescente , Adulto , Distribuição por Idade , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Criança , Países Desenvolvidos/economia , Países em Desenvolvimento/economia , Feminino , Guias como Assunto , Promoção da Saúde/legislação & jurisprudência , Promoção da Saúde/organização & administração , Humanos , Renda , Masculino , Nicotina/análise , Prevalência , Distribuição por Sexo , Fumar/efeitos adversos , Fumar/epidemiologia , Fumar/legislação & jurisprudência , Prevenção do Hábito de Fumar , Impostos , Tabaco/química , Indústria do Tabaco/economia , Indústria do Tabaco/legislação & jurisprudência , Poluição por Fumaça de Tabaco/efeitos adversos , Poluição por Fumaça de Tabaco/legislação & jurisprudência , Poluição por Fumaça de Tabaco/prevenção & controle , Poluição por Fumaça de Tabaco/estatística & dados numéricos , Uso de Tabaco/epidemiologia , Uso de Tabaco/legislação & jurisprudência , Tabaco sem Fumaça/efeitos adversos , Tabaco sem Fumaça/estatística & dados numéricos , Organização Mundial da Saúde
17.
Indian J Pharmacol ; 46(1): 105-8, 2014 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24550594

RESUMO

BACKGROUND: Ifosfamide (IFO) is widely used DNA-alkylating agents in cancer chemotherapy for management of solid tumors and hematological malignancies. However, hemorrhagic cystitis limits the use of IFO. OBJECTIVES: To compare the efficiency of reduced glutathione with 2-Mesna in reducing Ifosfamide (IFO) induced hemorrhagic cystitis (HC) in wistar rats. MATERIALS AND METHODS: Ifosfamide and 2-Mesna were dissolved in sterile water for injection and administered to wistar rats of albino strains. The rats were randomly assigned to one of the four groups of 6 rats each: Group I: Vehicle control; Group II: 120 mg/kg of IFO alone by intraperitoneal injection (i.p); Group III: 40 mg/kg Mesna i.p., at the same time and at 4 and 8 h after IFO administration; Group IV: 500 mg/kg of glutathione i.p., 30 min prior to IFO as above. The animals were observed for 5 days. On 6th day, rats were sacrificed by dissecting the intrajugular vein. The bladders were macroscopically and histopathologically evaluated. RESULTS: Control animals had normal bladders with assigned scores of '0' for the three parameters of edema, hemorrhage and histopathological changes. All the animals receiving IFO (group II) had evidence of HC as evidenced by alterations of edema and hemorrhages. These alterations were almost abolished (P < 0.001) by the glutathione (group III) or Mesna (group IV) in IFO-treated animals. CONCLUSION: Glutathione could be as useful as Mesna in the preventive management of IFO-induced HC.


Assuntos
Cistite/prevenção & controle , Glutationa/farmacologia , Hemorragia/prevenção & controle , Ifosfamida/efeitos adversos , Mesna/efeitos adversos , Bexiga Urinária/efeitos dos fármacos , Animais , Antineoplásicos Alquilantes/efeitos adversos , Cistite/induzido quimicamente , Hemorragia/induzido quimicamente , Substâncias Protetoras/efeitos adversos , Ratos , Ratos Wistar , Bexiga Urinária/patologia
18.
J Am Coll Cardiol ; 62(9): 789-98, 2013 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-23727086

RESUMO

OBJECTIVES: This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND: CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS: We performed a candidate gene study (∼2,100 genes; ∼50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). RESULTS: Of 268 SNPs reaching p < 5 × 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC. CONCLUSIONS: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways.


Assuntos
Vasos Coronários , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/complicações , Calcificação Vascular/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Estudos Prospectivos , Fatores de Risco , Calcificação Vascular/etiologia
20.
Diabetes ; 62(5): 1746-55, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23300278

RESUMO

We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10⁻³) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10⁻4) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10⁻8) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10⁻³) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10⁻4) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10⁻5 to < 10⁻7), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.


Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Sarcoglicanas/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Estudos de Coortes , Consanguinidade , Diabetes Mellitus Tipo 2/metabolismo , Europa (Continente) , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Índia , Masculino , Sarcoglicanas/metabolismo
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