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1.
J Neuropathol Exp Neurol ; 78(9): 854-864, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31360996

RESUMO

KLHL40-related nemaline myopathy is a severe autosomal recessive muscle disorder. The current study describes 4 cases of KLHL40-related nemaline myopathy in Hong Kong ethnic Chinese presenting within 3 years, which are confirmed with clinicopathologic features and genetic studies. The incidence is estimated to be at least 1 in 45 226 livebirths (at least 1 in 41 608 among ethnic Chinese livebirths) in Hong Kong. Hyponatremia appears to be another common feature in these patients. Salient histological features include nemaline bodies ranging from 200 to 500 nm in diameters on ultrastructural examination as well as negative KLHL40 immunohistochemistry; type II fiber predominance is obvious in 2 cases. We demonstrate the founder effect associated with genetic variant c.1516A>C (p.Thr506Pro) by polymorphic marker analysis, which revealed a 0.56-0.75-Mb or 0.41-0.78-cM shared haplotype encompassing the disease allele. The mutation is believed to have occurred around 412 generations ago or 6220 BCE, as estimated using DMLE+ and a formula described by Boehnke. We believe the founder variant might possibly underlie a sizable portion of nemaline myopathy in ethnic Chinese. Analysis of the KLHL40 gene may be considered as the first-tier testing of congenital myopathy in this ethnic group.


Assuntos
Hiponatremia/genética , Proteínas Musculares/genética , Músculo Esquelético/patologia , Miopatias da Nemalina/genética , Povo Asiático , Feminino , Predisposição Genética para Doença , Hong Kong , Humanos , Hiponatremia/patologia , Lactente , Recém-Nascido , Masculino , Mutação , Miopatias da Nemalina/patologia
2.
Atherosclerosis ; 258: 1-7, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28167353

RESUMO

BACKGROUND AND AIMS: Conventional coronary artery disease (CAD) risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of CAD risk prediction algorithms, but provide only modest discrimination. Genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors. Here we analyzed the genetic risk of CAD in subjects from Pakistan, using a GRS of 21 variants in 18 genes and examined whether the GRS is associated with blood lipid levels. METHODS: 625 (405 cases and 220 controls) subjects were genotyped for variants, NOS3 rs1799983, SMAD3 rs17228212, APOB rs1042031, LPA rs3798220, LPA rs10455872, SORT1 rs646776, APOE rs429358, GLUL rs10911021, FTO rs9939609, MIA3 rs17465637, CDKN2Ars10757274, DAB2IP rs7025486, CXCL12 rs1746048, ACE rs4341, APOA5 rs662799, CETP rs708272, MRAS rs9818870, LPL rs328, LPL rs1801177, PCSK9 rs11591147 and APOE rs7412 by TaqMan and KASPar allele discrimination techniques. RESULTS: Individually, the single SNPs were not associated with CAD except APOB rs1042031 and FTO rs993969 (p = 0.01 and 0.009 respectively). However, the combined GRS of 21 SNPs was significantly higher in cases than controls (19.37 ± 2.56 vs. 18.47 ± 2.45, p = 2.9 × 10-5), and compared to the bottom quintile, CAD risk in the top quintile of the GRS was 2.96 (95% CI 1.71-5.13). Atherogenic blood lipids showed significant positive association with GRS. CONCLUSIONS: The GRS was quantitatively associated with CAD risk and showed association with blood lipid levels, suggesting that the mechanism of these variants is likely to be, in part at least, through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles.


Assuntos
Doença da Artéria Coronariana/genética , Testes Genéticos/métodos , Polimorfismo de Nucleotídeo Único , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Fatores de Risco
3.
Cardiovasc Diabetol ; 15(1): 141, 2016 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-27716211

RESUMO

BACKGROUND: The coronary risk in diabetes (CoRDia) trial (n = 211) compares the effectiveness of usual diabetes care with a self-management intervention (SMI), with and without personalised risk information (including genetics), on clinical and behavioural outcomes. Here we present an assessment of randomisation, the cardiac risk genotyping assay, and the genetic characteristics of the recruits. METHODS: Ten-year coronary heart disease (CHD) risk was calculated using the UKPDS score. Genetic CHD risk was determined by genotyping 19 single nucleotide polymorphisms (SNPs) using Randox's Cardiac Risk Prediction Array and calculating a gene score (GS). Accuracy of the array was assessed by genotyping a subset of pre-genotyped samples (n = 185). RESULTS: Overall, 10-year CHD risk ranged from 2-72 % but did not differ between the randomisation groups (p = 0.13). The array results were 99.8 % concordant with the pre-determined genotypes. The GS did not differ between the Caucasian participants in the CoRDia SMI plus risk group (n = 66) (p = 0.80) and a sample of UK healthy men (n = 1360). The GS was also associated with LDL-cholesterol (p = 0.05) and family history (p = 0.03) in a sample of UK healthy men (n = 1360). CONCLUSIONS: CHD risk is high in this group of T2D subjects. The risk array is an accurate genotyping assay, and is suitable for estimating an individual's genetic CHD risk. Trial registration This study has been registered at ClinicalTrials.gov; registration identifier NCT01891786.


Assuntos
Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/genética , Perfilação da Expressão Gênica/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/prevenção & controle , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/prevenção & controle , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Medicina de Precisão , Valor Preditivo dos Testes , Gravidez , Medição de Risco , Fatores de Risco , Fatores de Tempo , Reino Unido
4.
Am J Respir Crit Care Med ; 194(11): 1349-1357, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27248440

RESUMO

RATIONALE: Epidemiological studies in older individuals have found an association between the use of angiotensin-converting enzyme (ACE) inhibition (ACE-I) therapy and preserved locomotor muscle mass, strength, and walking speed. ACE-I therapy might therefore have a role in the context of pulmonary rehabilitation (PR). OBJECTIVES: To investigate the hypothesis that enalapril, an ACE inhibitor, would augment the improvement in exercise capacity seen during PR. METHODS: We performed a double-blind, placebo-controlled, parallel-group randomized controlled trial. Patients with chronic obstructive pulmonary disease, who had at least moderate airflow obstruction and were taking part in PR, were randomized to either 10 weeks of therapy with an ACE inhibitor (10 mg enalapril) or placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome measurement was the change in peak power (assessed using cycle ergometry) from baseline. Eighty patients were enrolled, 78 were randomized (age 67 ± 8 years; FEV1 48 ± 21% predicted), and 65 completed the trial (34 on placebo, 31 on the ACE inhibitor). The ACE inhibitor-treated group demonstrated a significant reduction in systolic blood pressure (Δ, -16 mm Hg; 95% confidence interval [CI], -22 to -11) and serum ACE activity (Δ, -18 IU/L; 95% CI, -23 to -12) versus placebo (between-group differences, P < 0.0001). Peak power increased significantly more in the placebo group (placebo Δ, +9 W; 95% CI, 5 to 13 vs. ACE-I Δ, +1 W; 95% CI, -2 to 4; between-group difference, 8 W; 95% CI, 3 to 13; P = 0.001). There was no significant between-group difference in quadriceps strength or health-related quality of life. CONCLUSIONS: Use of the ACE inhibitor enalapril, together with a program of PR, in patients without an established indication for ACE-I, reduced the peak work rate response to exercise training in patients with chronic obstructive pulmonary disease.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Enalapril/uso terapêutico , Tolerância ao Exercício/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/reabilitação , Idoso , Pressão Sanguínea/efeitos dos fármacos , Terapia Combinada/métodos , Método Duplo-Cego , Feminino , Humanos , Masculino , Qualidade de Vida , Resultado do Tratamento
5.
Lipids Health Dis ; 15: 83, 2016 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-27112212

RESUMO

BACKGROUND: Many SNPs have been identified in genes regulating LDL-C metabolism, but whether their influence is similar in subjects from different ethnicities is unclear. Effect of 4 such SNPs on LDL-C and coronary heart disease (CHD) was examined in Pakistani subjects and was compared with middle aged UK men from Northwick Park Heart Study II (NPHSII). METHODS: One thousand nine hundred sixty-five (1770 non CHD, 195 CHD) UK and 623 (219 non CHD, 404 CHD) Pakistani subjects were enrolled in the study. The SNPs SORT1 rs646776, APOB rs1042031 and APOE rs429358, rs7412 were genotyped by TaqMan/KASPar technique and their gene score was calculated. LDL-C was calculated by Friedewald equation, results were analyzed using SPSS. RESULTS: Allele frequencies were significantly different (p= <0.05) between UK and Pakistani subjects. However, the SNPs were associated with LDL-C in both groups. In UK non CHD, UK CHD, Pakistani non CHD and Pakistani CHD respectively, for rs646776, per risk allele increase in LDL-C(mmol/l) was 0.18(0.04), 0.06(0.11), 0.15(0.04) and 0.27(0.06) respectively. For rs1042031, per risk allele increase in LDL-C in four groups was 0.11(0.04), 0.04(0.14), 0.15(0.06) and 0.25(0.09) respectively. For APOE genotypes, compared to Ɛ3, each Ɛ2 decreased LDL-C by 0.11(0.06), 0.07(0.15), 0.20(0.08) and 0.38(0.09), while each Ɛ4 increased LDL-C by 0.43(0.06), 0.39(0.21), 0.19(0.11) and 0.39(0.14) respectively. Overall gene score explained a considerable proportion of sample variance in four groups (3.8%, 1.26% 13.7% and 12.3%). Gene score in both non-CHD groups was significantly lower than CHD subjects. CONCLUSIONS: The SNPs show a dose response association with LDL-C levels and risk of CHD in both populations.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Apolipoproteína B-100/genética , Apolipoproteínas E/genética , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único , Idoso , LDL-Colesterol/sangue , LDL-Colesterol/genética , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Reino Unido
6.
Circ Cardiovasc Genet ; 8(2): 356-62, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25583995

RESUMO

BACKGROUND: Observational studies report that secretory phospholipase A2 (sPLA2) activity is a marker for coronary heart disease (CHD) risk, and activity measures are thought to represent the composite activity of sPLA2-IIA, -V, and -X. The aim of this study was to use genetic variants of PLA2G10, encoding sPLA2-X, to investigate the contribution of sPLA2-X to the measure of sPLA2 activity and coronary heart disease (CHD) risk traits and outcome. METHODS AND RESULTS: Three PLA2G10 tagging single-nucleotide polymorphisms (rs72546339, rs72546340, and rs4003232) and a previously studied PLA2G10 coding single-nucleotide polymorphism rs4003228, R38C, were genotyped in a nested case: control cohort drawn from the prospective EPIC-Norfolk Study (2175 cases and 2175 controls). Meta-analysis of rs4003228 (R38C) and CHD was performed using data from the Northwick Park Heart Study II and 2 published cohorts AtheroGene and SIPLAC, providing in total an additional 1884 cases and 3119 controls. EPIC-Norfolk subjects in the highest tertile of sPLA2 activity were older and had higher inflammatory markers compared with those in the lowest tertile for sPLA2 activity. None of the PLA2G10 tagging single-nucleotide polymorphism nor R38C, a functional variant, were significantly associated with sPLA2 activity, intermediate CHD risk traits, or CHD risk. In meta-analysis, the summary odds ratio for R38C was odds ratio=0.97 (95% confidence interval, 0.77-1.22). CONCLUSIONS: PLA2G10 variants are not significantly associated with plasma sPLA2 activity or with CHD risk.


Assuntos
Doença das Coronárias , Fosfolipases A2 do Grupo X , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Idoso , Idoso de 80 Anos ou mais , Doença das Coronárias/sangue , Doença das Coronárias/enzimologia , Doença das Coronárias/genética , Feminino , Seguimentos , Fosfolipases A2 do Grupo X/sangue , Fosfolipases A2 do Grupo X/genética , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
7.
Clin Chem ; 61(1): 231-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25414277

RESUMO

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples. METHODS: We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from a UK population sample (WHII). RESULTS: Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10(-16)). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C. CONCLUSIONS: A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.


Assuntos
LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/genética , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Apolipoproteínas B/genética , Canadá , Estudos de Casos e Controles , Criança , LDL-Colesterol/genética , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Israel , Masculino , Pessoa de Meia-Idade , Mutação , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Curva ROC , Receptores de LDL/genética , Fatores de Risco , Serina Endopeptidases/genética , Adulto Jovem
8.
Lancet ; 385(9965): 351-61, 2015 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-25262344

RESUMO

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING: The funding sources are cited at the end of the paper.


Assuntos
Peso Corporal/genética , Diabetes Mellitus Tipo 2/genética , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Polimorfismo de Nucleotídeo Único/genética , Idoso , Índice de Massa Corporal , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
9.
Atherosclerosis ; 237(1): 5-12, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25173947

RESUMO

BACKGROUND: Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD). METHODS AND RESULTS: We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification. CONCLUSIONS: In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.


Assuntos
Apolipoproteína E4/genética , Doença das Coronárias/genética , Genótipo , Fumar/efeitos adversos , Adulto , Idoso , Alelos , Estudos de Coortes , Feminino , Interação Gene-Ambiente , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
10.
J Med Genet ; 51(8): 537-44, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24987033

RESUMO

BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation. METHODS AND RESULTS: Exomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out. CONCLUSIONS: No major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.


Assuntos
LDL-Colesterol/genética , Hiperlipoproteinemia Tipo II/genética , Apolipoproteínas B/genética , Estudo de Associação Genômica Ampla , Humanos , Mutação/genética , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Serina Endopeptidases/genética
11.
Circ Cardiovasc Genet ; 7(2): 144-50, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24563418

RESUMO

BACKGROUND: Secretory phospholipase A2 (sPLA2) enzymes are considered to play a role in atherosclerosis. sPLA2 activity encompasses several sPLA2 isoenzymes, including sPLA2-V. Although observational studies show a strong association between elevated sPLA2 activity and CHD, no assay to measure sPLA2-V levels exists, and the only evidence linking the sPLA2-V isoform to atherosclerosis progression comes from animal studies. In the absence of an assay that directly quantifies sPLA2-V levels, we used PLA2G5 mRNA levels in a novel, modified Mendelian randomization approach to investigate the hypothesized causal role of sPLA2-V in coronary heart disease (CHD) pathogenesis. METHODS AND RESULTS: Using data from the Advanced Study of Aortic Pathology, we identified the single-nucleotide polymorphism in PLA2G5 showing the strongest association with PLA2G5 mRNA expression levels as a proxy for sPLA2-V levels. We tested the association of this SNP with sPLA2 activity and CHD events in 4 prospective and 14 case-control studies with 27 230 events and 70 500 controls. rs525380C>A showed the strongest association with PLA2G5 mRNA expression (P=5.1×10(-6)). There was no association of rs525380C>A with plasma sPLA2 activity (difference in geometric mean of sPLA2 activity per rs525380 A-allele 0.4% (95% confidence intervals [-0.9%, 1.6%]; P=0.56). In meta-analyses, the odds ratio for CHD per A-allele was 1.02 (95% confidence intervals [0.99, 1.04]; P=0.20). CONCLUSIONS: This novel approach for single-nucleotide polymorphism selection for this modified Mendelian randomization analysis showed no association between rs525380 (the lead single-nucleotide polymorphism for PLA2G5 expression, a surrogate for sPLA2-V levels) and CHD events. The evidence does not support a causal role for sPLA2-V in CHD.


Assuntos
Doença das Coronárias/enzimologia , Doença das Coronárias/genética , Fosfolipases A2 do Grupo V/genética , Alelos , Estudos de Casos e Controles , Doença das Coronárias/sangue , Genótipo , Fosfolipases A2 do Grupo V/sangue , Humanos , Isoenzimas/sangue , Isoenzimas/genética , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único
12.
Lancet ; 381(9874): 1293-301, 2013 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-23433573

RESUMO

BACKGROUND: Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. METHODS: In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. FINDINGS: We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0.90 [SD 0.23]) was strongly associated with LDL-C concentration (p=1.4 x 10(-77); R(2)=0.11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0 [SD 0.21]) than did WHII controls (p=4.5 x 10(-16)), as did the mutation-negative Belgian patients (0.99 [0.19]; p=5.2 x 10(-20)). The score was also higher in UK (0.95 [0.20]; p=1.6 x 10(-5)) and Belgian (0.92 [0.20]; p=0.04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. INTERPRETATION: In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. FUNDING: British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.


Assuntos
LDL-Colesterol/genética , Testes Genéticos/métodos , Hiperlipoproteinemia Tipo II/genética , Alelos , Bélgica , Estudos de Casos e Controles , LDL-Colesterol/sangue , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Reino Unido
13.
Eur Heart J ; 33(7): 881-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21444365

RESUMO

AIMS: A sequence variant, rs7025486[A], in DAB2IP on chromosome 9q33 has recently been associated with coronary heart disease (CHD). We sought to replicate this finding and to investigate associations with a panel of inflammatory and haemostatic biomarkers. We also sought to examine whether this variant, in combination with a chromosome 9p21 CHD variant (rs10757278) and the Framingham risk score (FRS), could improve the prediction of events compared with the FRS alone. METHODS AND RESULTS: rs7025486 was genotyped in 1386 CHD cases and 3532 controls and was associated with CHD [odds ratio (OR) of 1.16, 95% confidence interval (CI) 1.05-1.29, P= 0.003]. Meta-analysis, using data from the original report and from genome-wide association studies in both the Wellcome Trust Case Control Consortium and the Cardiovascular Health Study, comprising 9968 cases and 20 048 controls, confirmed the association (OR of 1.10, 95% CI 1.06-1.14, P= 3.2 × 10(-6)). There was no association with a panel of CHD biomarkers, including any lipid, inflammation, or coagulation trait, nor with telomere length. Addition to the FRS of this variant plus rs10757278 on chromosome 9p21 improved the area under the receiver-operating characteristic curve (A(ROC)) from 0.61 to 0.64 (P= 0.03) as well as improving the reclassification (net reclassification index = 11.1%, P= 0.007). CONCLUSION: This study replicates a previous association of a variant in DAB2IP with CHD. Addition of multiple variants improves the performance of predictive models based upon classical cardiovascular risk factors.


Assuntos
Cromossomos Humanos Par 9/genética , Doença das Coronárias/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Ativadoras de ras GTPase/genética , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Fatores de Risco
14.
Atherosclerosis ; 217(2): 447-51, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21592478

RESUMO

BACKGROUND: Both genome-wide association studies and candidate gene studies have reported that the major determinant of plasma levels of the Lipoprotein (a) [Lp(a)] reside within the LPA locus on chromosome 6. We have used data from the HumanCVD BeadChip to explore the contribution of other candidate genes determining Lp(a) levels. METHODS: 48,032 single nucleotide polymorphisms (SNPs) from the Illumina HumanCVD BeadChip were genotyped in 5059 participants of the Whitehall II study (WHII) of randomly ascertained healthy men and women. SNPs showing association with Lp(a) levels of p<10(-4) outside the LPA locus were selected for replication in a total of an additional 9463 participants of five European based studies (EAS, EPIC-Norfolk, NPHSII, PROCARDIS, and SAPHIR). RESULTS: In Whitehall II, apart from the LPA locus (where p values for several SNPs were <10(-30)) there was significant association at four loci GALNT2, FABP1, PPARGC1A and TNFRSFF11A. However, a meta-analysis of the six studies did not confirm any of these findings. CONCLUSION: Results from this meta analysis of 14,522 participants revealed no candidate genes from the HumanCVD BeadChip outside the LPA locus to have an effect on Lp(a) levels. Further studies with genome-wide and denser SNP coverage are required to confirm or refute this finding.


Assuntos
Cromossomos Humanos Par 6 , Loci Gênicos , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Adulto , Idoso , Estudos de Coortes , Europa (Continente) , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo
15.
Ann Clin Biochem ; 47(Pt 1): 44-55, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19837725

RESUMO

AIMS: Current screening methods, such as single strand conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (dHPLC) that are used for detecting mutations in familial hypercholesterolaemia (FH) subjects are time consuming, costly and only 80-90% sensitive. Here we have tested high-resolution melt (HRM) analysis for mutation detection using the Rotor-Gene(6000) realtime rotary analyser. Methods and subjects Polymerase chain reaction and melt conditions (HRM) for 23 fragments of the LDL-receptor gene, a region of exon 26 in the APOB gene (including p.R3527Q) and exon 7 of the PCSK9 gene (including p.D374Y) were optimized. Two double stranded DNA saturating dyes, LC-Green and Syto9, were compared for sensitivity. Eighty-two samples with known mutations were used as positive controls. Twenty-eight Greek FH heterozygous patients and two homozygous patients from the UK and Croatia were screened. RESULTS: HRM was able to identify all the positive control mutations tested, with similar results with either dye. Eight different variations were found in 17 of the 28 Greek FH patients for an overall detection rate of 61%: c.41delT (1), p.W165X (1), p.C173R (3), p.S286R (2), p.V429M (4), p.G549D (4), p.V613I (1), and a previously unreported mutation p.F694V (1) which is predicted to be FH-causing by functional algorithms. Mutations were found in both the homozygous patients; p.Q92X (Croatia) and p.Y489C (UK); both patients were homozygous for their respective mutations. CONCLUSIONS: HRM is a sensitive, robust technique that could significantly reduce the time and cost of screening for mutations in a clinical setting.


Assuntos
Análise Mutacional de DNA/métodos , Hiperlipoproteinemia Tipo II/genética , Desnaturação de Ácido Nucleico , Adolescente , Adulto , Idoso , Pré-Escolar , Feminino , Testes Genéticos/métodos , Heterozigoto , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único , Sensibilidade e Especificidade
16.
Am J Hum Genet ; 85(5): 628-42, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19913121

RESUMO

Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.


Assuntos
Apolipoproteínas/genética , Doenças Cardiovasculares/genética , Lipídeos/genética , Adulto , Alelos , Apolipoproteína A-I/sangue , Apolipoproteína A-I/genética , Apolipoproteína A-V , Apolipoproteínas/sangue , Apolipoproteínas A/sangue , Apolipoproteínas A/genética , Apolipoproteínas B/sangue , Apolipoproteínas B/genética , Apolipoproteínas E/genética , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Estudos de Coortes , Simulação por Computador , Feminino , Variação Genética , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Probabilidade , Fatores de Risco , Triglicerídeos/sangue , Triglicerídeos/genética , População Branca/genética
17.
Intensive Care Med ; 34(12): 2279-83, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18787808

RESUMO

OBJECTIVE: The D allele of the I/D polymorphism in the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of ARDS in critically ill adults and severity of bronchopulmonary dysplasia in pre-term infants. We hypothesised that the presence of the hypoxia-associated ACE D allele would increase susceptibility to acute hypoxic respiratory failure (AHRF) in a cohort of critically ill children. DESIGN AND SETTING: Single-centre prospective observational cohort study. PATIENTS: Children under 16 years of age requiring admission to a tertiary general PICU. MEASUREMENTS AND RESULTS: A total of 216 Caucasian patients were enrolled. Thirty (13.9%) children developed AHRF and 13 were diagnosed with ARDS (6.0%). There was no significant difference in ACE D allele frequency between patient groups with or without AHRF (0.53 vs. 0.54). CONCLUSIONS: Variation in ACE activity does not influence the development of paediatric AHRF. This may reflect a different pathogenesis from adult ARDS.


Assuntos
Suscetibilidade a Doenças , Peptidil Dipeptidase A/genética , Polimorfismo Genético/genética , Insuficiência Respiratória/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Frequência do Gene/genética , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva , Síndrome do Desconforto Respiratório/genética
18.
Surg Laparosc Endosc Percutan Tech ; 18(1): 106-8, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18287999

RESUMO

Recurrent abdominal pain due to spigelian hernia (SH) is rare and notoriously difficult to diagnose. This is particularly true when patient present with pain only without visible or palpable mass. Ultrasonic scanning and computed tomography is valuable in diagnosing this rare condition. However, for a small hernia with its content reduced spontaneously during examination, even computed tomography will miss the diagnosis. In the era of laparoscopic surgery, the role of laparoscopy in the management of recurrent abdominal pain of unknown origin has become more and more important. It is especially true in the management of SH as it is both diagnostic and therapeutic. We report a case of SH presented as recurrent lower abdominal pain of unknown origin and its successful diagnosis and treatment by laparoscopic approach.


Assuntos
Dor Abdominal/etiologia , Hérnia Ventral/diagnóstico , Laparoscopia , Dor Abdominal/cirurgia , Idoso , Hérnia Ventral/complicações , Hérnia Ventral/prevenção & controle , Hérnia Ventral/cirurgia , Humanos , Masculino , Prevenção Secundária
19.
Gastrointest Endosc ; 67(1): 35-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17945225

RESUMO

BACKGROUND: The feasibility, efficacy, and safety of the TriClip in the management of peptic ulcer hemorrhage in human beings are scarcely reported in the literature. OBJECTIVE: A pilot study was conducted to assess the feasibility, efficacy, and safety of the TriClip endoscopic clipping device in the control of peptic ulcer hemorrhage. DESIGN: Prospective evaluation. SETTING: Regional government hospital. PATIENTS: From July 2004 to January 2005, patients older than 16 years and with Forrest type I and IIa peptic ulcer hemorrhages were included in the study. INTERVENTIONS: TriClips were used for initial hemostasis. Salvage procedures, including adrenalin injection, heat probe application, argon plasma coagulation, or surgery will be carried out appropriately if TriClip failed to control bleeding alone. An endoscopy was repeated 24 hours later for the security of the TriClip and for any endoscopic evidence of recurrent bleeding. A follow-up endoscopy was performed 8 weeks later to assess ulcer healing. MAIN OUTCOME MEASUREMENTS: Procedure time, successful hemostatic rate, number of clips used, ulcer recurrent bleeding rate, complications, and ulcer healing rate were measured. LIMITATIONS: No comparative arm; pilot study only. RESULT: A total of 27 cases (11 women, 16 men) were included in the study, with a median age of 70 years (range 18-88 years). There were 19 cases of duodenal ulcer and 8 cases of gastric ulcer, with median size of 8 mm (range 2-20 mm). The rate of successful hemostasis in the first endoscopy by TriClips alone was 81.5% (22/27), with a median procedure time of 10 minutes (range 3-30 minutes). In the second endoscopy, the endoscopic recurrent bleeding rate was 14.8% (4/27) and the TriClips were found dislodged in 11 patients (40.7%). The permanent hemostasis rate was 67% (18/27). The overall failure rate was 33% (9/27). Three patients required blood transfusion before the first endoscopy. There was no morbidity or mortality observed in all cases. All ulcers healed after 8 weeks. CONCLUSIONS: The use of the TriClip is feasible in the initial control of peptic ulcer hemorrhage. However, we could not detect any obvious advantages in arresting bleeding vessels by using this new clipping device.


Assuntos
Hemostase Endoscópica/instrumentação , Úlcera Péptica Hemorrágica/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Desenho de Equipamento , Estudos de Viabilidade , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Recidiva
20.
J Laparoendosc Adv Surg Tech A ; 17(6): 759-62, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18158805

RESUMO

Incarcerated femoral hernia is a common surgical emergency condition. Diagnosis is always obvious and straightforward by clinical examination, and open surgical repair is the mainstay of treatment. In the era of minimally invasive surgery, laparoscopic repair of femoral hernia has been shown to be feasible and safe. However, laparoscopic repair of acutely incarcerated femoral hernia has gained little discussion in the past. In this paper, we report the results of 8 consecutive cases of strangulated femoral hernia that was successfully managed by the laparoscopic approach.


Assuntos
Hérnia Femoral/cirurgia , Laparoscopia/métodos , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Complicações Pós-Operatórias , Resultado do Tratamento
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