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1.
Nat Genet ; 53(1): 65-75, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398198

RESUMO

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.


Assuntos
Grupos de Populações Continentais/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias da Próstata/genética , Humanos , Masculino , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Invasividade Neoplásica , Razão de Chances , Neoplasias da Próstata/diagnóstico , Fatores de Risco
2.
Artigo em Inglês | MEDLINE | ID: mdl-33420416

RESUMO

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

4.
Clin Chem ; 67(1): 276-287, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33409531

RESUMO

BACKGROUND: Individuals with obesity have higher concentrations of very low-density lipoprotein (VLDL) cholesterol and increased risk of myocardial infarction. We hypothesized that VLDL cholesterol explains a fraction of the excess myocardial infarction risk in individuals with obesity. METHODS: We included 29 010 individuals free of myocardial infarction at baseline, nested within 109 751 individuals from the Copenhagen General Population Study. During 10 years of follow-up, 2306 individuals developed myocardial infarction. Cholesterol content in large and small VLDLs, in intermediate-density lipoprotein (IDL), and in LDL was measured directly with nuclear magnetic resonance spectroscopy. RESULTS: Median concentrations of cholesterol in large and small VLDLs were 0.12 mmol/L (interquartile range [IQR], 0.07-0.20 mmol/L; 4.5 mg/dL [IQR, 2.6-6.9 mg/dL]) and 0.6 mmol/L (IQR, 0.5-0.8 mmol/L; 25 mg/dL [IQR, 20-30 mg/dL]) in individuals with obesity vs 0.06 mmol/L (IQR, 0.03-0.1 mmol/L; 2.2 mg/dL [IQR, 1.1-3.8 mg/dL]), and 0.5 mmol/L (IQR, 0.4-0.6 mmol/L; 20 mg/dL (IQR, 16-25 mg/dL]) in individuals with normal weight; in contrast, concentrations of IDL and LDL cholesterol were similar across body mass index (BMI) categories. Cholesterol in large and small VLDLs combined explained 40% (95% CI, 27%-53%) of the excess risk of myocardial infarction associated with higher BMI. In contrast, IDL and LDL cholesterol did not explain excess risk of myocardial infarction, whereas systolic blood pressure explained 17% (11%-23%) and diabetes mellitus explained 8.6% (3.2%-14%). CONCLUSIONS: VLDL cholesterol explains a large fraction of excess myocardial infarction risk in individuals with obesity. These novel findings support a focus on cholesterol in VLDL for prevention of myocardial infarction and atherosclerotic cardiovascular disease in individuals with obesity.

5.
Cancers (Basel) ; 12(11)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33158149

RESUMO

The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case-control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1-3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families.

6.
Eur Respir J ; 2020 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-32817007

RESUMO

Complement C3 plays a role in asthma development and severity. We tested the hypothesis that high plasma complement C3 concentration was associated with high risk of asthma hospitalisations and exacerbations.We prospectively assessed the risk of asthma hospitalisations in 101 029 individuals from the Copenhagen General Population Study with baseline measurements of plasma complement C3, and genotyped for rs1065489, rs429608, and rs448260 determining levels of complement C3. Risk of asthma exacerbations was further assessed in 2248 individuals with allergic asthma.The multivariable adjusted hazard ratio of asthma hospitalisations was 1.23(95% confidence interval 1.04-1.45) for individuals in the highest tertile(>1.19 g·L-1) of plasma complement C3 compared with those in the lowest tertile(<1.03 g·L-1). The C3 rs448260 genotype was associated with risk of asthma hospitalisations with an observed hazard ratio of 1.17(1.06-1.28) for the CC genotype compared with the AA genotype. High plasma complement C3 was associated with high levels of blood eosinophils and IgE(p for trends ≤6·10-9), but only the SKIV2L rs429608 genotype was positively associated with blood eosinophil count(p=3·10-4) and level of IgE(p=3·10-4). In allergic asthma, the multivariable adjusted incidence rate ratio for risk of exacerbations was 1.69(1.06-2.72) for individuals in the highest plasma complement C3 tertile(>1.24 g·L-1) versus the lowest(<1.06 g·L-1).In conclusion, high concentration of plasma complement C3 was associated with high risk of asthma hospitalisations in the general population and with high risk of asthma exacerbations in individuals with allergic asthma. Our findings support a causal role of the complement system in asthma severity.

7.
JAMA Cardiol ; 3(7): 619-627, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29926099

RESUMO

Importance: Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk. Objective: To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design, Setting, and Participants: A mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018. Exposures: Genetic LPA score and plasma Lp(a) mass concentration. Main Outcomes and Measures: Coronary heart disease. Results: Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. Conclusions and Relevance: The clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).


Assuntos
Doença das Coronárias/genética , Hipolipemiantes/uso terapêutico , Lipoproteína(a)/sangue , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Biomarcadores/sangue , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Doença das Coronárias/sangue , Doença das Coronárias/prevenção & controle , Feminino , Seguimentos , Variação Genética , Humanos , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Fatores de Risco
8.
Eur Respir J ; 51(5)2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29650563

RESUMO

Blood eosinophil count in chronic obstructive pulmonary disease (COPD) is associated with higher exacerbation rate and favourable response to corticosteroids; however, frequent exacerbations and use of inhaled corticosteroids could elevate pneumonia risk. We tested the hypothesis that high blood eosinophil counts are associated with high risk of pneumonia in individuals with severe COPD from the general population.We included 7180 individuals with COPD from the Copenhagen General Population Study, including 643 with forced expiratory volume in 1 s (FEV1) <50% predicted between 2003 and 2011. All primary discharge diagnoses of pneumonia during follow-up were recorded.Among individuals with COPD and FEV1 <50% pred, the multivariable adjusted incidence rate ratio was 2.17 (95% CI 1.31-3.58) for pneumonia comparing individuals with blood eosinophil counts ≥0.34×109 cells·L-1versus <0.34×109 cells·L-1 In individuals with clinical COPD, defined by recent exacerbation, ≥10 pack-years of smoking and FEV1 <70% pred, the corresponding risk was 4.52 (2.11-9.72). Risk of pneumonia did not differ by blood eosinophil count in individuals with COPD and FEV1 ≥50% pred.In individuals with COPD and FEV1 <50% pred, blood eosinophil count ≥0.34×109 cells·L-1 was associated with high risk of hospitalisation due to pneumonia.


Assuntos
Eosinófilos/citologia , Hospitalização/estatística & dados numéricos , Pneumonia/etiologia , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/complicações , Corticosteroides/uso terapêutico , Idoso , Dinamarca/epidemiologia , Progressão da Doença , Feminino , Volume Expiratório Forçado , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pneumonia/epidemiologia , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Análise de Regressão , Fumar/efeitos adversos
10.
BMJ ; 360: j5757, 2018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29321194

RESUMO

OBJECTIVES: To develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age. DESIGN: Analysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa. SETTING: Multiple institutions that were members of international PRACTICAL consortium. PARTICIPANTS: All consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men. MAIN OUTCOME MEASURES: Prediction with hazard score of age of onset of aggressive cancer in validation set. RESULTS: In the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P<10-16). When men in the validation set with high scores (>98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score. CONCLUSIONS: Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.


Assuntos
Detecção Precoce de Câncer/métodos , Calicreínas/análise , Polimorfismo de Nucleotídeo Único/genética , Antígeno Prostático Específico/análise , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Idade de Início , Idoso , Estudos de Coortes , Intervalo Livre de Doença , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Neoplasias da Próstata/diagnóstico , Medição de Risco , Análise de Sobrevida
11.
Thorax ; 73(8): 748-757, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29187594

RESUMO

BACKGROUND: Urate is a strong antioxidant in plasma and may protect against lung function impairment. We tested the hypothesis that high plasma urate is causally associated with better lung function and low risk of respiratory symptoms and COPD. METHODS: We measured lung function and plasma urate in 114 979 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study and genotyped for SLC2A9 rs7442295 and ABCG2 rs2231142 variants, previously associated with high plasma urate, in 110 152 individuals. RESULTS: In the two studies combined, multivariable-adjusted 100 µmol/L higher plasma urate was associated with -1.54% (95% CI -1.67 to -1.40) lower FEV1 % predicted and -1.57% (95% CI -1.69 to -1.44) lower FVC % predicted observationally; the corresponding estimates for genetically determined 100 µmol/L higher plasma urate were -0.46% (95% CI -1.17 to 0.25) and -0.40% (95% CI -1.03 to 0.23). High plasma urate was also associated with higher risk of respiratory symptoms; however, genetically determined high plasma urate was not associated with respiratory symptoms. Finally, we identified 14 151 individuals with COPD and found ORs of 1.08 (95% CI 1.06 to 1.11) for COPD observationally and 1.01 (95% CI 0.88 to 1.15) genetically per 100 µmol/L higher plasma urate. CONCLUSION: High plasma urate was associated with worse lung function and higher risk of respiratory symptoms and COPD in observational analyses; however, genetically high plasma urate was not associated with any of these outcomes. Thus, our data do not support a direct causal relationship.


Assuntos
Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ácido Úrico/sangue , Idoso , Biomarcadores/sangue , Dinamarca , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Testes de Função Respiratória , Fatores de Risco
12.
Clin Chem ; 63(12): 1866-1876, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28971985

RESUMO

BACKGROUND: Low plasma lipoprotein(a) concentrations are associated with type 2 diabetes. Whether this is due to low lipoprotein(a) concentrations per se or to a large number of kringle IV type 2 (KIV-2) repeats remains unclear. We therefore aimed to identify genetic variants associated selectively with lipoprotein(a) concentrations or with the number of KIV-2 repeats, to investigate which of these traits confer risk of diabetes. METHODS: We genotyped 8411 individuals from the Copenhagen City Heart Study for 778 single-nucleotide polymorphisms (SNPs) in the proximity of the LPA gene, and examined the association of these SNPs with plasma concentrations of lipoprotein(a) and with KIV-2 number of repeats. SNPs that were selectively associated with lipoprotein(a) concentrations but not with KIV-2 number of repeats, or vice versa, were included in a Mendelian randomization study. RESULTS: We identified 3 SNPs (rs12209517, rs12194138, and rs641990) that were associated selectively with lipoprotein(a) concentrations and 3 SNPs (rs1084651, rs9458009, and rs9365166) that were associated selectively with KIV-2 number of repeats. For SNPs selectively associated with lipoprotein(a) concentrations, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.03 (95% CI, 0.86-1.23). In contrast, for SNPs selectively associated with KIV-2 number of repeats, an allele score of 4-6 vs 0-2 had an odds ratio for type 2 diabetes of 1.42 (95% CI, 1.17-1.69). CONCLUSIONS: Using a novel genetic approach, our results indicate that it is a high number of KIV-2 repeats that are associated causally with increased risk of type 2 diabetes, and not low lipoprotein(a) concentrations per se. This is a reassuring finding for lipoprotein(a)-lowering therapies that do not increase the KIV-2 number of repeats.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Kringles , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Polimorfismo de Nucleotídeo Único , Diabetes Mellitus Tipo 2/etiologia , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Lipoproteína(a)/química , Masculino , Fatores de Risco
13.
Sci Rep ; 7(1): 4394, 2017 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-28663568

RESUMO

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10-3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Obesidade Mórbida/genética , Obesidade Pediátrica/genética , Animais , Estudos de Casos e Controles , Cromograninas/química , Cromograninas/genética , Cromograninas/metabolismo , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/química , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Humanos , Masculino , Camundongos , Modelos Moleculares , Mutação , Obesidade Mórbida/diagnóstico , Razão de Chances , Obesidade Pediátrica/diagnóstico , Linhagem , Conformação Proteica , Roedores
14.
Nat Genet ; 49(7): 1113-1119, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530674

RESUMO

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.


Assuntos
Artérias/patologia , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla , Aterosclerose/genética , Adesão Celular/genética , Quimiotaxia de Leucócito/genética , Doença da Artéria Coronariana/patologia , Doença da Artéria Coronariana/fisiopatologia , Metabolismo Energético/genética , Feminino , Predisposição Genética para Doença , Genótipo , Código das Histonas , Humanos , Masculino , Músculo Liso Vascular/patologia , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco
15.
Eur J Prev Cardiol ; 24(5): 492-504, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27940953

RESUMO

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2 enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA2. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. Results Lp-PLA2 activity was decreased by 64% ( p = 2.4 × 10-25) with carriage of any of the four loss-of-function variants, by 45% ( p < 10-300) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 × 10-12) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA2 activity by 65% ( p < 10-300). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2 activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2 is unlikely to be a causal risk factor.


Assuntos
Benzaldeídos/uso terapêutico , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/genética , Terapia de Alvo Molecular , Oximas/uso terapêutico , Inibidores de Fosfolipase A2/uso terapêutico , 1-Alquil-2-acetilglicerofosfocolina Esterase/efeitos dos fármacos , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Doença das Coronárias/diagnóstico , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ensaios Clínicos Controlados Aleatórios como Assunto , Valores de Referência , Reprodutibilidade dos Testes , Medição de Risco , Resultado do Tratamento
16.
J Allergy Clin Immunol ; 138(5): 1404-1413.e13, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27464961

RESUMO

BACKGROUND: High alcohol consumption is associated with high IgE levels in observational studies; however, whether high alcohol consumption leads to high IgE levels and allergic disease is unclear. OBJECTIVE: We tested the hypothesis that high alcohol consumption is associated with high IgE levels and allergic disease both observationally and genetically using a Mendelian randomization design free of reverse causation and largely free of confounding. METHODS: Among 111,408 subjects aged 20 to 100 years from the general population, 50,019 had plasma IgE measurements, and 102,270 were genotyped for the alcohol-metabolizing enzymes alcohol dehydrogenase 1B (ADH-1B; rs1229984) and alcohol dehydrogenase 1c (ADH-1C; rs698). Observationally, we investigated associations between IgE levels and allergic disease (allergic asthma, rhinitis, and eczema) and between alcohol consumption and IgE levels and allergic disease. Genetically, we explored potential causal relationships between alcohol consumption and IgE levels and allergic disease. RESULTS: The multivariable adjusted odds ratio for IgE levels greater than versus less than 150 kU/L and compared with subjects without allergic disease was 2.3 (95% CI, 2.2-2.5) for 1 allergic disease, 3.9 (95% CI, 3.5-4.4) for 2 allergic diseases, and 7.5 (95% CI, 6.2-9.0) for 3 allergic diseases. High alcohol consumption was associated with high IgE levels but not with high risk of allergic disease. The odds ratio for high versus low IgE levels per 1 alcoholic drink per week higher consumption was 1.12 (95% CI, 1.02-1.23) genetically and 1.01 (95% CI, 1.01-1.02) observationally; for allergic disease, the corresponding odds ratios were 0.96 (95% CI, 0.92-1.00) genetically and 1.00 (95% CI, 1.00-1.00) observationally. CONCLUSION: High alcohol consumption is associated observationally and genetically with high IgE levels but not with high risk of allergic disease.


Assuntos
Consumo de Bebidas Alcoólicas , Hipersensibilidade , Imunoglobulina E/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/imunologia , Feminino , Genótipo , Humanos , Hipersensibilidade/sangue , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Adulto Jovem
17.
PLoS One ; 11(3): e0151636, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26986063

RESUMO

BACKGROUND: Permanent hair dye contains aromatic amines which are carcinogenic, and can cause allergic skin reactions. In the long term personal use of hair dye might therefore influence both morbidity and mortality. OBJECTIVES: We tested the hypothesis that personal use of hair dye in women is associated with increased morbidity and mortality in the general population. METHODS: We included 7,684 women from the Copenhagen City Heart Study with information on the use of personal hair dye. We assessed the risk of cancer, skin diseases, other morbidities, and mortality during a median follow-up of 27 years (range 0-37). RESULTS: The multivariable adjusted hazard ratio for malignant melanoma in women with versus without personal use of hair dye was 2.07 (95% confidence interval 1.25-3.42). There was no increased risk of other cancer types. For other skin diseases and other major causes of morbidity we found no differences between the two groups, except for a minor excess of digestive diseases and increased risk of Parkinson's disease among women using hair dye. Finally, we found no difference in all-cause mortality comparing women using personal hair dye or not. After correction for multiple comparisons, none of the results remained significant. However, in sensitivity analysis the excess risk of malignant melanoma remained increased with a hazard ratio of 2.58 (95%CI 1.33-5.03) among users of personal hair dye. CONCLUSIONS: Personal use of hair dye does not have major influences on morbidity and mortality. Our finding of a 2-fold risk of malignant melanoma in women using hair dye is hypothesis generating.


Assuntos
Tinturas para Cabelo/efeitos adversos , Melanoma/epidemiologia , Adulto , Estudos de Casos e Controles , Dinamarca , Feminino , Seguimentos , Humanos , Incidência , Melanoma/etiologia , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida
18.
Science ; 351(6278): 1166-71, 2016 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-26965621

RESUMO

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).


Assuntos
HDL-Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/genética , Receptores Depuradores Classe B/genética , Idoso , Substituição de Aminoácidos , Animais , Análise Mutacional de DNA , Feminino , Variação Genética , Heterozigoto , Homozigoto , Humanos , Leucina/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Prolina/genética , Processamento de Proteína Pós-Traducional , Risco , Receptores Depuradores Classe B/metabolismo
19.
Clin Chem ; 62(3): 525-34, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26797686

RESUMO

BACKGROUND: Complement activation may contribute to venous thromboembolism, including deep venous thrombosis and pulmonary embolism. We tested the hypothesis that high complement C3 concentrations are associated with high risk of venous thromboembolism in the general population. METHODS: We included 80 517 individuals without venous thromboembolism from the Copenhagen General Population Study recruited in 2003-2012. Plasma complement C3 concentrations were measured at baseline, and venous thromboembolism (n = 1176) was ascertained through April 2013 in nationwide registries. No individuals were lost to follow-up. RESULTS: Complement C3 concentrations were approximately normally distributed, with a mean value of 1.13 g/L (interquartile range 0.98-1.26; SD 0.21). The cumulative incidence of venous thromboembolism was higher with progressively higher tertiles of complement C3 (log-rank trend: P = 3 × 10(-8)): at age 80, 7%, 9%, and 11% of individuals in the first, second, and third tertiles, respectively, had developed venous thromboembolism. Multivariable-adjusted hazard ratios for venous thromboembolism compared with individuals in the first tertile were 1.36 (95% CI, 1.16-1.59) for those in the second tertile and 1.58 (1.33-1.88) for those in the third tertile. Corresponding values were 1.36 (1.16-1.60) and 1.57 (1.33-1.87) after additional adjustment for C-reactive protein and 1.27 (1.09-1.49) and 1.31(1.10-1.57) after additional adjustment for body mass index. These results were similar for deep venous thrombosis and pulmonary embolism separately. The multivariable-adjusted hazard ratio for venous thromboembolism for a 1-g/L increase in complement C3 was 2.43 (1.74-3.40). CONCLUSIONS: High concentrations of complement C3 were associated with high risk of venous thromboembolism in the general population.


Assuntos
Complemento C3/metabolismo , Tromboembolia Venosa/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Tipagem e Reações Cruzadas Sanguíneas , Complemento C3/análise , Dinamarca , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Tromboembolia Venosa/fisiopatologia
20.
Hum Genet ; 135(1): 137-54, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26621531

RESUMO

Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Tolerância Imunológica/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Feminino , Humanos
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