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1.
Artigo em Inglês | MEDLINE | ID: mdl-31478921

RESUMO

PURPOSE: There are limited data on cardiopulmonary exercise testing (CPX) and cardiorespiratory fitness (CRF), following open repair for a proximal thoracic aortic aneurysm or dissection. The aim was to evaluate serious adverse events, abnormal CPX event rate, CRF (peak oxygen uptake, Vo2peak), and blood pressure. METHODS: Patients were retrospectively identified from cardiac rehabilitation participation or prospectively enrolled in a research study and grouped by phenotype: (1) bicuspid aortic valve/thoracic aortic aneurysm, (2) tricuspid aortic valve/thoracic aortic aneurysm, and (3) acute type A aortic dissection. RESULTS: Patients (n = 128) completed a CPX a median of 2.9 mo (interquartile range: 1.8, 3.5) following repair. No serious adverse events were reported, although 3 abnormal exercise tests (2% event rate) were observed. Eighty-one percent of CPX studies were considered peak effort (defined as respiratory exchange ratio of ≥1.05). Median measured Vo2peak was <36% predicted normative values (19.2 mL·kgmin vs 29.3 mL·kg·min, P < .0001); the most marked impairment in Vo2peak was observed in the acute type A aortic dissection group (<40% normative values), which was significantly different from other groups (P < .05). Peak exercise systolic and diastolic blood pressures were 160 mm Hg (144, 172) and 70 mm Hg (62, 80), with no differences noted between groups. CONCLUSIONS: We observed no serious adverse events with an abnormal CPX event rate of only 2% 3 mo following repair for a proximal thoracic aortic aneurysm or dissection. Vo2peak was reduced among all patient groups, especially the acute type A aortic dissection group, which may be clinically significant, given the well-established prognostic importance of reduced cardiorespiratory fitness.

2.
Nat Commun ; 10(1): 3503, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409809

RESUMO

Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.

3.
Nat Commun ; 10(1): 1847, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015462

RESUMO

Chronic kidney disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.


Assuntos
Loci Gênicos , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular/genética , Insuficiência Renal Crônica/genética , Feminino , Carga Global da Doença , Humanos , Rim/fisiopatologia , Masculino , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Medição de Risco/métodos , Fatores de Risco , Fatores Sexuais
4.
Nat Genet ; 51(3): 387-393, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804566

RESUMO

Insomnia is a common disorder linked with adverse long-term medical and psychiatric outcomes. The underlying pathophysiological processes and causal relationships of insomnia with disease are poorly understood. Here we identified 57 loci for self-reported insomnia symptoms in the UK Biobank (n = 453,379) and confirmed their effects on self-reported insomnia symptoms in the HUNT Study (n = 14,923 cases and 47,610 controls), physician-diagnosed insomnia in the Partners Biobank (n = 2,217 cases and 14,240 controls), and accelerometer-derived measures of sleep efficiency and sleep duration in the UK Biobank (n = 83,726). Our results suggest enrichment of genes involved in ubiquitin-mediated proteolysis and of genes expressed in multiple brain regions, skeletal muscle, and adrenal glands. Evidence of shared genetic factors was found between frequent insomnia symptoms and restless legs syndrome, aging, and cardiometabolic, behavioral, psychiatric, and reproductive traits. Evidence was found for a possible causal link between insomnia symptoms and coronary artery disease, depressive symptoms, and subjective well-being.


Assuntos
Predisposição Genética para Doença/genética , Distúrbios do Início e da Manutenção do Sono/genética , Sono/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteólise , Autorrelato , Ubiquitina/genética
5.
Genet Epidemiol ; 43(5): 462-476, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30793809

RESUMO

With the availability of large-scale biobanks, genome-wide scale phenome-wide association studies are being instrumental in discovering novel genetic variants associated with clinical phenotypes. As increasing number of such association results from different biobanks become available, methods to meta-analyse those association results is of great interest. Because the binary phenotypes in biobank-based studies are mostly unbalanced in their case-control ratios, very few methods can provide well-calibrated tests for associations. For example, traditional Z-score-based meta-analysis often results in conservative or anticonservative Type I error rates in such unbalanced scenarios. We propose two meta-analysis strategies that can efficiently combine association results from biobank-based studies with such unbalanced phenotypes, using the saddlepoint approximation-based score test method. Our first method involves sharing the overall genotype counts from each study, and the second method involves sharing an approximation of the distribution of the score test statistic from each study using cubic Hermite splines. We compare our proposed methods with a traditional Z-score-based meta-analysis strategy using numerical simulations and real data applications, and demonstrate the superior performance of our proposed methods in terms of Type I error control.


Assuntos
Bancos de Espécimes Biológicos , Estudo de Associação Genômica Ampla , Simulação por Computador , Genótipo , Humanos , Modelos Genéticos , Análise Numérica Assistida por Computador , Reino Unido
6.
Int J Cardiol ; 2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30482443

RESUMO

BACKGROUND: Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. METHODS: We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. RESULTS: In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24-1.52, p = 6.9 × 10-10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31-1.79) compared to those with CAD (OR 1.27; 95%CI 1.12-1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88-0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27-1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95-1.02). CONCLUSIONS: Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.

7.
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.

8.
J Card Fail ; 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-30219550

RESUMO

BACKGROUND: Frailty reflects decreased resilience to physiological stressors; its prevalence and prognosis are not fully defined in heart failure with preserved ejection fraction (HFpEF). METHODS: The Short Physical Performance Battery (SPPB) was prospectively obtained in 114 outpatients with HFpEF. The SPPB tests gait speed, tandem balance, and timed chair rises, each scored from 0 to 4 points. Severe and mild frailty were respectively defined as an SPPB score ≤6 and 7-9 points. We used risk-adjusted logistic, Poisson, and negative binominal regression, respectively, to assess the relationship between SPPB score and risk of death or all-cause hospitalization, number of hospitalizations, and days hospitalized or dead longer than 6 months. RESULTS: Patients were similar to other HFpEF cohorts (age 68 ± 13 years, 58% female, body mass index 36 ± 8 kg/m2, multiple comorbidities). Mean SPPB score was 6.9 ± 3.2, and 80% of patients were at least mildly frail. Over a 6-month period, the SPPB score independently predicted death or all-cause hospitalization (odds ratio 0.81 per point, 95% confidence interval [CI] 0.69-0.94, P = .006), number of hospitalizations (incidence rate ratio 0.92 per point, 95% CI 0.86-0.97, P = .006), and days hospitalized or dead (incidence rate ratio 0.85 per point, 95% CI 0.73-0.99, P = .04). CONCLUSIONS: Lower extremity function, as measured by the SPPB, independently predicts hospitalization burden in outpatients with HFpEF. Additional studies are warranted to explore shared mechanisms and treatment implications of frailty in HFpEF.

9.
Nat Genet ; 50(9): 1234-1239, 2018 Sep.
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.

10.
Nat Commun ; 9(1): 3391, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30140000

RESUMO

Large-scale deep-coverage whole-genome sequencing (WGS) is now feasible and offers potential advantages for locus discovery. We perform WGS in 16,324 participants from four ancestries at mean depth >29X and analyze genotypes with four quantitative traits-plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides. Common variant association yields known loci except for few variants previously poorly imputed. Rare coding variant association yields known Mendelian dyslipidemia genes but rare non-coding variant association detects no signals. A high 2M-SNP LDL-C polygenic score (top 5th percentile) confers similar effect size to a monogenic mutation (~30 mg/dl higher for each); however, among those with severe hypercholesterolemia, 23% have a high polygenic score and only 2% carry a monogenic mutation. At these sample sizes and for these phenotypes, the incremental value of WGS for discovery is limited but WGS permits simultaneous assessment of monogenic and polygenic models to severe hypercholesterolemia.

11.
Nat Genet ; 50(9): 1335-1341, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30104761

RESUMO

In genome-wide association studies (GWAS) for thousands of phenotypes in large biobanks, most binary traits have substantially fewer cases than controls. Both of the widely used approaches, the linear mixed model and the recently proposed logistic mixed model, perform poorly; they produce large type I error rates when used to analyze unbalanced case-control phenotypes. Here we propose a scalable and accurate generalized mixed model association test that uses the saddlepoint approximation to calibrate the distribution of score test statistics. This method, SAIGE (Scalable and Accurate Implementation of GEneralized mixed model), provides accurate P values even when case-control ratios are extremely unbalanced. SAIGE uses state-of-art optimization strategies to reduce computational costs; hence, it is applicable to GWAS for thousands of phenotypes by large biobanks. Through the analysis of UK Biobank data of 408,961 samples from white British participants with European ancestry for > 1,400 binary phenotypes, we show that SAIGE can efficiently analyze large sample data, controlling for unbalanced case-control ratios and sample relatedness.

12.
Hum Genet ; 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30008065

RESUMO

The evolutionary and biological bases of the Central African "pygmy" phenotype, a characteristic of rainforest hunter-gatherers defined by reduced body size compared with neighboring farmers, remain largely unknown. Here, we perform a joint investigation in Central African hunter-gatherers and farmers of adult standing height, sitting height, leg length, and body mass index (BMI), considering 358 hunter-gatherers and 169 farmers with genotypes for 153,798 SNPs. In addition to reduced standing heights, hunter-gatherers have shorter sitting heights and leg lengths and higher sitting/standing height ratios than farmers and lower BMI for males. Standing height, sitting height, and leg length are strongly correlated with inferred levels of farmer genetic ancestry, whereas BMI is only weakly correlated, perhaps reflecting greater contributions of non-genetic factors to body weight than to height. Single- and multi-marker association tests identify one region and eight genes associated with hunter-gatherer/farmer status, and 24 genes associated with the height-related traits. Many of these genes have putative functions consistent with roles in determining their associated traits and the pygmy phenotype, and they include three associated with standing height in non-Africans (PRKG1, DSCAM, MAGI2). We find evidence that European height-associated SNPs or variants in linkage disequilibrium with them contribute to standing- and sitting-height determination in Central Africans, but not to the differential status of hunter-gatherers and farmers. These findings provide new insights into the biological basis of the pygmy phenotype, and they highlight the potential of cross-population studies for exploring the genetic basis of phenotypes that vary naturally across populations.

13.
Nat Commun ; 9(1): 2252, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899519

RESUMO

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

14.
J Clin Lipidol ; 12(4): 878-882, 2018 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29773422

RESUMO

Low high-density lipoprotein cholesterol (HDL-C) can be caused by several acquired secondary causes as well as primary genetic disorders. However, only a few conditions are associated with profoundly reduced levels below 10 mg/dL. We present an unusual case of a healthy man with severely decreased HDL-C because of a novel homozygous variant causing a Proline > Arginine amino acid change at position 1412 in the ATP-binding cassette transporter A1 gene. Homozygous variations in ATP-binding cassette transporter A1 typically cause Tangier disease, a rare autosomal recessive condition linked with several other abnormalities (eg, enlarged discolored tonsils). Despite having an HDL-C below 10 mg/dL, our patient presented without any other clinical symptoms or physical signs suggestive of Tangier disease. This case of presumptive Tangier disease adds support to the growing body of evidence that this genetic disorder may have greater phenotypic heterogeneity along with a more varied presentation than traditionally considered.

15.
Hum Mol Genet ; 27(R1): R14-R21, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29547983

RESUMO

The combination of electronic health records (EHRs) with genetic data has ushered in the next wave of complex disease genetics. Population-based biobanks and other large cohorts provide sufficient sample sizes to identify novel genetic associations across the hundreds to thousands of phenotypes gleaned from EHRs. In this review, we summarize the current state of these EHR-linked biobanks, explore ongoing methods development in the field and highlight recent discoveries of genetic associations. We enumerate the many existing biobanks with EHRs linked to genetic data, many of which are available to researchers via application and contain sample sizes >50 000. We also discuss the computational and statistical considerations for analysis of such large datasets including mixed models, phenotype curation and cloud computing. Finally, we demonstrate how genome-wide association studies and phenome-wide association studies have identified novel genetic findings for complex diseases, specifically cardiometabolic traits. As more researchers employ innovative hypotheses and analysis approaches to study EHR-linked biobanks, we anticipate a richer understanding of the genetic etiology of complex diseases.

16.
Nat Commun ; 9(1): 987, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29511194

RESUMO

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10-22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10-13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10-10) and aortic root diameter (P = 1.30 × 10-8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10-3) and coronary artery disease (OR = 1.05, P = 9.3 × 10-5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases.

17.
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.

18.
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
19.
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
20.
Sci Rep ; 7(1): 10252, 2017 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-28860667

RESUMO

Cyclooxygenase-2 inhibitors (coxibs) are characterized by multiple molecular off-target effects and increased coronary artery disease (CAD) risk. Here, we systematically explored common variants of genes representing molecular targets of coxibs for association with CAD. Given a broad spectrum of pleiotropic effects of coxibs, our intention was to narrow potential mechanisms affecting CAD risk as we hypothesized that the affected genes may also display genomic signals of coronary disease risk. A Drug Gene Interaction Database search identified 47 gene products to be affected by coxibs. We traced association signals in 200-kb regions surrounding these genes in 84,813 CAD cases and 202,543 controls. Based on a threshold of 1 × 10-5 (Bonferroni correction for 3131 haplotype blocks), four gene loci yielded significant associations. The lead SNPs were rs7270354 (MMP9), rs4888383 (BCAR1), rs6905288 (VEGFA1), and rs556321 (CACNA1E). By additional genotyping, rs7270354 at MMP9 and rs4888383 at BCAR1 also reached the established GWAS threshold for genome-wide significance. The findings demonstrate overlap of genes affected by coxibs and those mediating CAD risk and points to further mechanisms, which are potentially responsible for coxib-associated CAD risk. The novel approach furthermore suggests that genetic studies may be useful to explore the clinical relevance of off-target drug effects.

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