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1.
Clin Chem ; 65(7): 871-881, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30996050

RESUMO

BACKGROUND: Cardiac troponins are associated with cardiovascular risk in the general population, but whether temporal changes in cardiac troponin I provide independent prognostic information remains uncertain. Using a large community-based cohort with follow-up close to the present day, we aimed to investigate the associations between temporal changes in cardiac troponin and cardiovascular events. METHODS: We measured cardiac troponin I with a high-sensitivity assay (hs-cTnI) in 4805 participants attending both the second (HUNT 2, 1995-97) and third wave (HUNT 3, 2006-2008) of the prospective observational Nord-Trøndelag Health (HUNT) Study. We constructed statistical models with both relative and absolute changes of hs-cTnI from HUNT 2 to HUNT 3. A composite end point of cardiovascular death or first admission for myocardial infarction or heart failure was generated. RESULTS: Participants with relative decrease in hs-cTnI were more frequently younger and female and had lower blood pressure and body mass index. Participants with relative increase in hs-cTnI more frequently were older and male, with higher systolic blood pressure. The adjusted hazard ratio (HR) for relative increase in hs-cTnI was 1.68 (95% CI, 1.16-2.42) and the adjusted HR for relative decrease was 1.19 (95% CI, 0.84-1.68). Absolute increases in hs-cTnI exhibited similar prognostic properties as relative increases in hs-cTnI. The most recent measurement of hs-cTnI outperformed the change variables in discrimination and reclassification models. CONCLUSIONS: Both relative and absolute increases in hs-cTnI are independently associated with cardiovascular risk. For refinement of risk prediction models, the most recent measurement of hs-cTnI should be preferred in clinical practice.

2.
J Rheumatol ; 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936278

RESUMO

OBJECTIVE: The genetic component of ankylosing spondylitis (AS) development is ~90%. Of the known heritability, ~20% is explained by HLA-B27, and 113 identified AS-associated single-nucleotide polymorphisms (SNP) account for ~7.4%. The objectives were to construct a weighted genetic risk score (wGRS) using currently known genome-wide susceptibility SNP, and to evaluate its predictive ability for AS in the Norwegian population-based Nord-Trøndelag Health Study (HUNT). METHODS: AS cases (n = 164) and controls (n = 49,032) were from the second (1995-1997) and third (2006-2008) waves of the HUNT study, to which the entire adult population of the northern region of Trøndelag was invited. A wGRS based on 110 SNP weighted by published OR for AS was constructed, representing each person's carriage of all risk variants. Logistic regression models including the wGRS alone or in combination with HLA-B27 carrier state and other adjustment variables (sex, age, smoking, body mass index, and hypertension) were developed. Discrimination among models was compared using area under the curve (AUC). RESULTS: The wGRS was associated with AS (OR 1.7, 95% CI 1.4-2.1), but showed low discrimination (AUC 0.62, 95% CI 0.58-0.67). HLA-B27 was significantly associated with AS (OR 50, 95% CI 32-81), showing high discrimination (AUC 0.88, 95% CI 0.85-0.90). Combining the wGRS and HLA-B27 improved prediction (AUC 0.90, 95% CI 0.87-0.92; p < 0.001 vs wGRS alone, p < 0.01 vs HLA-B27 alone). Further inclusion of adjustment variables gave a small improvement (AUC 0.91, 95% CI 0.89-0.94; p = 0.03). CONCLUSION: Prediction in a population-based setting based on all currently known AS susceptibility SNP was better than HLA-B27 carrier state alone, although the improvement was small and of uncertain clinical value.

3.
Commun Biol ; 1: 68, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271950

RESUMO

Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.

4.
Nat Genet ; 50(9): 1234-1239, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30061737

RESUMO

To identify genetic variation underlying atrial fibrillation, the most common cardiac arrhythmia, we performed a genome-wide association study of >1,000,000 people, including 60,620 atrial fibrillation cases and 970,216 controls. We identified 142 independent risk variants at 111 loci and prioritized 151 functional candidate genes likely to be involved in atrial fibrillation. Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5)1, or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN). Pathway and functional enrichment analyses also suggested that many of the putative atrial fibrillation genes act via cardiac structural remodeling, potentially in the form of an 'atrial cardiomyopathy'2, either during fetal heart development or as a response to stress in the adult heart.


Assuntos
Fibrilação Atrial/genética , Mutação/genética , Bancos de Espécimes Biológicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Cardiopatias Congênitas/genética , Humanos , Risco
5.
Am J Cardiol ; 121(8): 949-955, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29496193

RESUMO

C-reactive protein and cardiac troponin I measured with high-sensitivity assays (high-sensitivity C-reactive protein [hs-CRP] and high-sensitivity troponin I [hs-TnI]) have been associated with risk of fatal and nonfatal cardiovascular events in the general population. The relative prognostic merits of hs-CRP and hs-TnI, and whether these markers of inflammation and subclinical myocardial injury provide incremental information to established cardiovascular risk prediction models, remain unclear. hs-CRP and hs-TnI were measured in 9,005 participants from the prospective observational Nord-Trøndelag Health (HUNT) study. All study subjects were free from known cardiovascular disease at baseline. During a median follow-up period of 13.9 years, 733 participants reached the composite end point of hospitalization for acute myocardial infarction or heart failure, or cardiovascular death. In adjusted models, increased hs-TnI concentrations (>10 ng/L for women and >12 ng/L for men) were associated with the incidence of the composite end point (hazard ratio 3.61, 95% confidence interval [CI] 2.89 to 4.51]), whereas the risk associated with increased hs-CRP concentrations (>3 mg/L for both genders) appeared to be weaker (HR 1.71, 95% CI 1.40 to 2.10). The addition of hs-TnI to established cardiovascular risk prediction models led to a net reclassification improvement of 0.35 (95% CI 0.27 to 0.42), superior to that of hs-CRP (0.21, 95% CI 0.13 to 0.28). The prognostic accuracy of hs-TnI, assessed by C-statistics, was significantly greater than that of hs-CRP (0.753, 95% CI 0.735 to 0.772, vs 0.644, 95% CI 0.625 to 0.663). In conclusion, in subjects from the general population without a history of cardiovascular disease, hs-TnI provides prognostic information superior to that provided by hs-CRP and may therefore be a preferred marker for targeted prevention.


Assuntos
Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/metabolismo , Insuficiência Cardíaca/metabolismo , Infarto do Miocárdio/metabolismo , Troponina I/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Feminino , Insuficiência Cardíaca/epidemiologia , Hospitalização , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Noruega/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco
6.
Am J Hum Genet ; 102(1): 103-115, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29290336

RESUMO

Atrial fibrillation (AF) is a common cardiac arrhythmia and a major risk factor for stroke, heart failure, and premature death. The pathogenesis of AF remains poorly understood, which contributes to the current lack of highly effective treatments. To understand the genetic variation and biology underlying AF, we undertook a genome-wide association study (GWAS) of 6,337 AF individuals and 61,607 AF-free individuals from Norway, including replication in an additional 30,679 AF individuals and 278,895 AF-free individuals. Through genotyping and dense imputation mapping from whole-genome sequencing, we tested almost nine million genetic variants across the genome and identified seven risk loci, including two novel loci. One novel locus (lead single-nucleotide variant [SNV] rs12614435; p = 6.76 × 10-18) comprised intronic and several highly correlated missense variants situated in the I-, A-, and M-bands of titin, which is the largest protein in humans and responsible for the passive elasticity of heart and skeletal muscle. The other novel locus (lead SNV rs56202902; p = 1.54 × 10-11) covered a large, gene-dense chromosome 1 region that has previously been linked to cardiac conduction. Pathway and functional enrichment analyses suggested that many AF-associated genetic variants act through a mechanism of impaired muscle cell differentiation and tissue formation during fetal heart development.


Assuntos
Fibrilação Atrial/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Coração/embriologia , Sequências Reguladoras de Ácido Nucleico/genética , Humanos , Padrões de Herança/genética , Herança Multifatorial/genética , Especificidade de Órgãos/genética , Mapeamento Físico do Cromossomo , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Fatores de Risco
7.
Nat Genet ; 49(12): 1752-1757, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083406

RESUMO

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.


Assuntos
Asma/genética , Eczema/genética , Predisposição Genética para Doença/genética , Hipersensibilidade/genética , Rinite Alérgica Sazonal/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
8.
Genet Epidemiol ; 41(8): 744-755, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28861891

RESUMO

The accuracy of genotype imputation depends upon two factors: the sample size of the reference panel and the genetic similarity between the reference panel and the target samples. When multiple reference panels are not consented to combine together, it is unclear how to combine the imputation results to optimize the power of genetic association studies. We compared the accuracy of 9,265 Norwegian genomes imputed from three reference panels-1000 Genomes phase 3 (1000G), Haplotype Reference Consortium (HRC), and a reference panel containing 2,201 Norwegian participants from the population-based Nord Trøndelag Health Study (HUNT) from low-pass genome sequencing. We observed that the population-matched reference panel allowed for imputation of more population-specific variants with lower frequency (minor allele frequency (MAF) between 0.05% and 0.5%). The overall imputation accuracy from the population-specific panel was substantially higher than 1000G and was comparable with HRC, despite HRC being 15-fold larger. These results recapitulate the value of population-specific reference panels for genotype imputation. We also evaluated different strategies to utilize multiple sets of imputed genotypes to increase the power of association studies. We observed that testing association for all variants imputed from any panel results in higher power to detect association than the alternative strategy of including only one version of each genetic variant, selected for having the highest imputation quality metric. This was particularly true for lower frequency variants (MAF < 1%), even after adjusting for the additional multiple testing burden.


Assuntos
Estudo de Associação Genômica Ampla , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Variação Genética , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Noruega , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
9.
J Am Coll Cardiol ; 69(7): 823-836, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28209224

RESUMO

BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10-4 with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.


Assuntos
Doença da Artéria Coronariana/genética , Loci Gênicos , Pleiotropia Genética , Estudos de Casos e Controles , Doença da Artéria Coronariana/epidemiologia , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único
10.
Am J Cardiol ; 118(6): 816-821, 2016 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-27453509

RESUMO

Gender is an important determinant of cardiovascular risk, and men generally develop cardiovascular disease earlier than women. Increased levels of high-sensitivity cardiac troponin I (hs-TnI) have been shown to be predictive of cardiovascular death, with stronger effects in women. However, it remains unclear whether the stronger association between hs-TnI and cardiovascular death in women is based on the ability of hs-TnI to predict myocardial infarction (MI) or heart failure (HF). Accordingly, we aimed to assess the influence of gender on the association between levels of hs-TnI and incident MI and HF. hs-TnI was measured in 5,060 women and 4,054 men participating in the prospective observational Nord-Trøndelag Health Study using the Architect STAT High-Sensitive Troponin assay. All subjects were free from known coronary heart disease at baseline. After a median follow-up of 5,105 and 6,169 days, 292 MIs and 209 admissions for HF were registered, respectively. In our total cohort, hs-TnI was associated with the incidence of both end points, with adjusted hazard ratio per 1 SD in log hs-TnI 1.19 (95% CI 1.02 to 1.39) for MI and 1.58 (1.38 to 1.82) for HF. The corresponding values for women and men were 1.35 (1.02 to 1.78) versus 1.13 (0.93 to 1.38) for MI and 1.55 (1.26 to 1.91) versus 1.61 (1.36 to 1.90) for HF. The C-index for hs-TnI was stronger for women than men for MI (p <0.001), and no such difference was observed for HF (p = 0.06). In conclusion, in the general population, the association between hs-TnI concentrations and MI is stronger in women than in men. For HF, the impact of gender on the prognostic value of hs-TnI is less pronounced. Increased levels of troponin I in women may thus reflect an adverse phenotype more prone to the development of cardiovascular disease.


Assuntos
Insuficiência Cardíaca/sangue , Infarto do Miocárdio/sangue , Troponina I/sangue , Adulto , Biomarcadores/sangue , Estudos de Coortes , Feminino , Insuficiência Cardíaca/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Noruega/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores Sexuais
11.
N Engl J Med ; 374(12): 1134-44, 2016 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-26934567

RESUMO

BACKGROUND: The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS: Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS: We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)). CONCLUSIONS: We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).


Assuntos
Angiopoietinas/genética , Moléculas de Adesão Celular/genética , Doença da Artéria Coronariana/genética , Lipase Lipoproteica/genética , Mutação , Triglicerídeos/sangue , Idoso , Proteína 4 Semelhante a Angiopoietina , Feminino , Técnicas de Genotipagem , Humanos , Lipase Lipoproteica/antagonistas & inibidores , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fatores de Risco , Análise de Sequência de DNA , Triglicerídeos/genética
12.
Genet Epidemiol ; 39(4): 227-38, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25740221

RESUMO

Advances in exome sequencing and the development of exome genotyping arrays are enabling explorations of association between rare coding variants and complex traits. To ensure power for these rare variant analyses, a variety of association tests that group variants by gene or functional unit have been proposed. Here, we extend these tests to family-based studies. We develop family-based burden tests, variable frequency threshold tests and sequence kernel association tests. Through simulations, we compare the performance of different tests. We describe situations where family-based studies provide greater power than studies of unrelated individuals to detect rare variants associated with moderate to large changes in trait values. Broadly speaking, we find that when sample sizes are limited and only a modest fraction of all trait-associated variants can be identified, family samples are more powerful. Finally, we illustrate our approach by analyzing the relationship between coding variants and levels of high-density lipoprotein (HDL) cholesterol in 11,556 individuals from the HUNT and SardiNIA studies, demonstrating association for coding variants in the APOC3, CETP, LIPC, LIPG, and LPL genes and illustrating the value of family samples, meta-analysis, and gene-level tests. Our methods are implemented in freely available C++ code.


Assuntos
Estudos de Associação Genética/métodos , Variação Genética/genética , Modelos Genéticos , Software , Apolipoproteína C-III/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/genética , Simulação por Computador , Exoma/genética , Família , Genótipo , Humanos , Lipase/genética , Lipase Lipoproteica/genética , Fenótipo
13.
Clin Chem ; 61(4): 646-56, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25695851

RESUMO

BACKGROUND: A new, high-sensitivity assay for cardiac troponin I (hs-cTnI) permits evaluation of the prognostic value of cardiac troponins within the reference interval. Men have higher hs-cTnI concentrations than women, but the underlying pathophysiological mechanisms and prognostic implications are unclear. The aim of this study was to assess the potential impact of sex on the association between hs-cTnI and cardiovascular death. METHODS: By use of the Architect STAT High-Sensitive Troponin assay, we measured hs-cTnI in 4431 men and 5281 women aged ≥20 years participating in the prospective observational Nord-Trøndelag Health Study (HUNT). RESULTS: hs-cTnI was detectable in 98.5% of men and 94.7% of women. During a mean follow-up period of 13.9 years, 708 cardiovascular deaths were registered. hs-cTnI was associated with the incidence of cardiovascular death [adjusted hazard ratio (HR) per 1 SD in log hs-cTnI 1.23 (95% CI 1.15-1.31)], with higher relative risk in women than men [HR 1.44 (1.31-1.58) vs 1.10 (1.00-1.20); Pinteraction < 0.001]. This finding was mediated by both lower risk associated with low hs-cTnI concentrations in women than in men and higher risk associated with high concentrations of hs-cTnI in women than in men. Male sex was associated with a higher risk of cardiovascular death [HR 1.28 (1.11-1.49)], but after adjustment for hs-cTnI, this association disappeared [HR 0.87 (0.75-1.02)]. CONCLUSIONS: The prognostic value of hs-cTnI concentrations in the general population is stronger in women than in men. Subtle impairment of cardiovascular status may contribute to higher hs-cTnI concentrations in men, reflecting sex-dependent differences in cardiovascular risk.


Assuntos
Doenças Cardiovasculares/mortalidade , Troponina I/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Curva ROC , Fatores Sexuais , Adulto Jovem
14.
N Engl J Med ; 371(1): 22-31, 2014 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-24941081

RESUMO

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).


Assuntos
Apolipoproteína C-III/genética , Doença das Coronárias/genética , Mutação , Triglicerídeos/sangue , Grupo com Ancestrais do Continente Africano/genética , Apolipoproteína C-III/sangue , Doença das Coronárias/sangue , Grupo com Ancestrais do Continente Europeu/genética , Exoma , Genótipo , Heterozigoto , Humanos , Fígado/patologia , Fatores de Risco , Análise de Sequência de DNA
15.
Hum Mol Genet ; 23(17): 4721-8, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-24728188

RESUMO

Genome-wide association studies have identified variants, primarily common, that are associated with coronary artery disease or myocardial infarction (MI), but have not tested the majority of the low frequency and rare variation in the genome. We explored the hypothesis that previously untested low frequency (1-5% minor allele frequency) and rare (<1% minor allele frequency) coding variants are associated with MI. We genotyped 2906 MI cases and 6738 non-MI controls from Norway using the Illumina HumanExome Beadchip, allowing for direct genotyping of 85 972 polymorphic coding variants as well as 48 known GWAS SNPs. We followed-up 34 coding variants in an additional 2350 MI cases and 2318 controls from Norway. We evaluated exome array coverage in a subset of these samples using whole exome sequencing (N = 151). The exome array provided successful genotyping for an estimated 72.5% of Norwegian loss-of-function or missense variants with frequency >1% and 66.2% of variants <1% frequency observed more than once. Despite 80% power in the two-stage study (N = 14 312) to detect association with low-frequency variants with high effect sizes [odds ratio (OR) >1.86 and >1.36 for 1 and 5% frequency, respectively], we did not identify any novel genes or single variants that reached significance. This suggests that low-frequency coding variants with large effect sizes (OR >2) may not exist for MI. Larger sample sizes may identify coding variants with more moderate effects.


Assuntos
Predisposição Genética para Doença , Variação Genética , Infarto do Miocárdio/genética , Fases de Leitura Aberta/genética , Exoma/genética , Feminino , Genoma Humano/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco
16.
BMC Med Genet ; 15: 28, 2014 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-24593135

RESUMO

BACKGROUND: Preeclampsia is associated with an increased risk of hypertension later in life. The regulator of G protein signaling 2 negatively regulates several vasoconstrictors. We recently demonstrated an association between preeclampsia and the CG or GG genotype of the C1114G polymorphism (rs4606) of the regulator of G protein signaling 2 gene. Here, we examined the polymorphism with respect to the development of hypertension after pregnancy. METHODS: We genotyped 934 women on average 15.1 years after preeclampsia and 2011 age matched women with previous normotensive pregnancy. All women in this study were retrospectively recruited from the Nord-Trøndelag Health Study (HUNT2). Information from HUNT2 was linked to the Medical Birth Registry of Norway to identify women with a history of preeclampsia and women without a history of preeclampsia. RESULTS: No significant association was found between hypertension (blood pressure ≥140/90 mmHg and/or taking antihypertensive drugs) and the polymorphism in crude analysis (OR (95% CI): CG genotype: 1.07 (0.90-1.27); GG genotype: 1.23 (0.90-1.67)). However, in a minimally adjusted model (age and BMI adjusted), a significant association between the GG genotype and hypertension was found (OR (95% CI): 1.49 (1.05-2.11)). This association remained significant also after adjustment for a history of preeclampsia (OR (95% CI): 1.46 (1.02-2.09)), but not in a model adjusted for multiple other variables (OR (95% CI): 1.26 (0.82-1.94)). In multivariate, but not in crude, analysis, the GG genotype of rs4606 (OR (95% CI): 1.93 (1.05-3.53)) was significantly and independently associated with severe hypertension later in life, defined as systolic blood pressure ≥160 mmHg (stage 2 hypertension) and/or taking antihypertensive drugs. A significant association was also found for the merged CG and GG genotypes (OR (95% CI): 1.43 (1.02-2.00)). Moreover, an interaction with physical activity was found. A history of preeclampsia was a significant and independent predictor of either definition of hypertension, both in crude and adjusted analyses. CONCLUSION: Women carrying the rs4606 CG or GG genotype are at elevated risk for developing hypertension after delivery. Physical activity may interact with the association. Preeclampsia remains an independent risk factor for subsequent hypertension after adjusting for this polymorphism and classical CVD risk factors.


Assuntos
Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Proteínas RGS/genética , Adulto , Estudos de Casos e Controles , Exercício , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/epidemiologia , Noruega , Pré-Eclâmpsia/epidemiologia , Gravidez , Prevalência , Fatores de Risco
17.
Nat Genet ; 46(4): 345-51, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24633158

RESUMO

Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify new genes influencing lipid traits, fine map known lipid loci and evaluate whether low-frequency variants with large effects exist for these traits. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians and identified ten loci with coding variants associated with a lipid trait (P < 5 × 10(-8)). One variant in TM6SF2 (encoding p.Glu167Lys), residing in a known genome-wide association study locus for lipid traits, influences total cholesterol levels and is associated with myocardial infarction. Transient TM6SF2 overexpression or knockdown of Tm6sf2 in mice alters serum lipid profiles, consistent with the association observed in humans, identifying TM6SF2 as a functional gene within a locus previously known as NCAN-CILP2-PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.


Assuntos
Variação Genética , Lipídeos/sangue , Proteínas de Membrana/genética , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Animais , LDL-Colesterol/sangue , LDL-Colesterol/genética , Exoma/genética , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto/genética , Noruega/epidemiologia , Fatores de Risco
18.
Am J Hum Genet ; 94(2): 233-45, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24507775

RESUMO

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.


Assuntos
LDL-Colesterol/genética , Exoma , Frequência do Gene , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Apolipoproteínas E/sangue , Apolipoproteínas E/genética , Estudos de Coortes , Dislipidemias/sangue , Dislipidemias/genética , Feminino , Seguimentos , Código Genético , Genótipo , Humanos , Lipase/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Análise de Sequência de DNA , Serina Endopeptidases/genética
19.
Nat Genet ; 46(2): 200-4, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24336170

RESUMO

The majority of reported complex disease associations for common genetic variants have been identified through meta-analysis, a powerful approach that enables the use of large sample sizes while protecting against common artifacts due to population structure and repeated small-sample analyses sharing individual-level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the focus of analysis. Here we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable-threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features from single-variant meta-analysis approaches and demonstrate its use in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.


Assuntos
Estudos de Associação Genética/métodos , Variação Genética , Lipídeos/genética , Metanálise como Assunto , Projetos de Pesquisa , Interpretação Estatística de Dados , Exoma/genética , Genética Populacional , Genótipo , Humanos , Lipídeos/sangue , Modelos Genéticos , Método de Monte Carlo
20.
PLoS Genet ; 7(12): e1002439, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22242009

RESUMO

Common genetic variants have been shown to explain a fraction of the inherited variation for many common diseases and quantitative traits, including height, a classic polygenic trait. The extent to which common variation determines the phenotype of highly heritable traits such as height is uncertain, as is the extent to which common variation is relevant to individuals with more extreme phenotypes. To address these questions, we studied 1,214 individuals from the top and bottom extremes of the height distribution (tallest and shortest ∼1.5%), drawn from ∼78,000 individuals from the HUNT and FINRISK cohorts. We found that common variants still influence height at the extremes of the distribution: common variants (49/141) were nominally associated with height in the expected direction more often than is expected by chance (p<5×10⁻²8), and the odds ratios in the extreme samples were consistent with the effects estimated previously in population-based data. To examine more closely whether the common variants have the expected effects, we calculated a weighted allele score (WAS), which is a weighted prediction of height for each individual based on the previously estimated effect sizes of the common variants in the overall population. The average WAS is consistent with expectation in the tall individuals, but was not as extreme as expected in the shortest individuals (p<0.006), indicating that some of the short stature is explained by factors other than common genetic variation. The discrepancy was more pronounced (p<10⁻6) in the most extreme individuals (height<0.25 percentile). The results at the extreme short tails are consistent with a large number of models incorporating either rare genetic non-additive or rare non-genetic factors that decrease height. We conclude that common genetic variants are associated with height at the extremes as well as across the population, but that additional factors become more prominent at the shorter extreme.


Assuntos
Alelos , Estatura/genética , Herança Multifatorial/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , Irmãos
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