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Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses was used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 × 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 × 10-8) and mtDNA replication (p = 1.2 × 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell-related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 × 10-4).
Assuntos
Variações do Número de Cópias de DNA , DNA Mitocondrial , Megacariócitos/fisiologia , Mitocôndrias/genética , Ativação Plaquetária , Polimorfismo de Nucleotídeo Único , Idoso , Proliferação de Células , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Nucleotídeos/metabolismo , FenótipoRESUMO
PURPOSE: Obstructive sleep apnea (OSA) is common in people with intellectual disabilities (ID), but in practice continuous positive airway pressure (CPAP) is often deemed unfeasible. We investigated adherence to and effect of CPAP in patients with ID and OSA. METHODS: Patients with ID were started on CPAP using an intensive training program. Acceptable adherence was defined as use of ≥ 4 h/night during ≥ 70% of the nights. Treatment effect was measured with a patient global impression scale and customized questionnaires. Reasons for not starting CPAP, factors influencing treatment, and reasons for terminating CPAP were explored. RESULTS: Of 39 patients with ID, 87% after 8-10 weeks and 70% at 8 months still used CPAP, of whom 74% and 77% showed acceptable adherence. Baseline apnea-hypopnea (AHI) index decreased from 41.2/h to 5.3/h after 8-10 weeks (p < 0.001), and 4.3/h after 8 months (p < 0.001). At 8-10 weeks and after 8 months, there was an improvement in the most restrictive reported complaint (both p < 0.0005), difficulty waking up (p < 0.01; p < 0.0005), handling behavior (p < 0.03; p < 0.02), presence of irritability (p < 0.01), and sleepiness (p < 0.05). The expectation that CPAP would not be tolerated was the main reason for not starting. CPAP use in the first 2 weeks predicted adherence at 8-10 weeks and 8 months (r = 0.51, p < 0.01; r = 0.69, p < 0.01). Of 13 patients who terminated CPAP, the reasons for termination included behavioral problems, comorbid insomnia, anxiety, discomfort, or other side effects. CONCLUSIONS: With adequate guidance, CPAP is both feasible and effective in people with ID and OSA.
Assuntos
Pressão Positiva Contínua nas Vias Aéreas/estatística & dados numéricos , Deficiência Intelectual/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/terapia , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.
Assuntos
Envelhecimento/genética , Etnicidade/genética , Genômica/tendências , Frequência Cardíaca/genética , Farmacogenética/tendências , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/efeitos dos fármacos , Envelhecimento/etnologia , Estudos de Coortes , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/tendências , Feminino , Genômica/métodos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.
Assuntos
Eletrocardiografia/efeitos dos fármacos , Etnicidade/genética , Compostos de Sulfonilureia/efeitos adversos , Idoso , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/genética , Citocromo P-450 CYP2C9/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Feminino , Variação Genética/efeitos dos fármacos , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Testes Farmacogenômicos/métodos , Compostos de Sulfonilureia/uso terapêuticoRESUMO
Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).
Assuntos
Moléculas de Adesão Celular/genética , Café/genética , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Ingestão de Líquidos/genética , Estudo de Associação Genômica Ampla/métodos , Antígenos de Neoplasias/genética , Proteínas Reguladoras de Apoptose/genética , Cafeína/farmacologia , Linhagem Celular , Feminino , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Predisposição Genética para Doença/genética , Humanos , Masculino , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , População Branca/genéticaRESUMO
In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.
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INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (nâ¯=â¯6); BMD (nâ¯=â¯6); gonadal impairment (nâ¯=â¯2); hearing impairment (nâ¯=â¯12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (nâ¯<â¯200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26â¯=â¯15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.
Assuntos
Sobreviventes de Câncer , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Variação Genética/fisiologia , Transtornos de Início Tardio/genética , Neoplasias/genética , Lesões por Radiação/genética , Densidade Óssea/genética , Sobreviventes de Câncer/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Transtornos de Início Tardio/epidemiologia , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/genética , Neoplasias/epidemiologia , Neoplasias/terapia , Lesões por Radiação/epidemiologia , Fatores de TempoRESUMO
The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (ß=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (ß=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (ß=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE É4 non-carriers (ß=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (ß=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (ß=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in É4-carriers (ß=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE É4-carriers might be at differential risk.
Assuntos
Disfunção Cognitiva/genética , Análise da Randomização Mendeliana , Telômero/genética , População Branca/genética , Adulto , Idoso , Apolipoproteína E4/genética , Disfunção Cognitiva/diagnóstico , Estudos de Coortes , Feminino , Triagem de Portadores Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Psicometria , Estatística como AssuntoRESUMO
Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.