RESUMO
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency can present at various ages from the neonatal period to adulthood, and poses the greatest risk of complications during intercurrent illness or after prolonged fasting. Early diagnosis, treatment, and surveillance can reduce mortality; hence, the disorder is included in the newborn Recommended Uniform Screening Panel (RUSP) in the United States. The Inborn Errors of Metabolism Information System (IBEM-IS) was established in 2007 to collect longitudinal information on individuals with inborn errors of metabolism included in newborn screening (NBS) programs, including VLCAD deficiency. We retrospectively analyzed early outcomes for individuals who were diagnosed with VLCAD deficiency by NBS and describe initial presentations, diagnosis, clinical outcomes and treatment in a cohort of 52 individuals ages 1-18years. Maternal prenatal symptoms were not reported, and most newborns remained asymptomatic. Cardiomyopathy was uncommon in the cohort, diagnosed in 2/52 cases. Elevations in creatine kinase were a common finding, and usually first occurred during the toddler period (1-3years of age). Diagnostic evaluations required several testing modalities, most commonly plasma acylcarnitine profiles and molecular testing. Functional testing, including fibroblast acylcarnitine profiling and white blood cell or fibroblast enzyme assay, is a useful diagnostic adjunct if uncharacterized mutations are identified.
Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Acil-CoA Desidrogenase de Cadeia Longa/genética , Erros Inatos do Metabolismo Lipídico/genética , Doenças Mitocondriais/genética , Doenças Musculares/genética , Triagem Neonatal , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Adolescente , Carnitina/análogos & derivados , Carnitina/sangue , Criança , Pré-Escolar , Síndrome Congênita de Insuficiência da Medula Óssea , Creatina Quinase/genética , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/sangue , Erros Inatos do Metabolismo Lipídico/fisiopatologia , Masculino , Doenças Mitocondriais/sangue , Doenças Mitocondriais/fisiopatologia , Doenças Musculares/sangue , Doenças Musculares/fisiopatologia , Mutação , Estudos RetrospectivosRESUMO
BACKGROUND: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations. OBJECTIVE: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study. METHODS: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. RESULTS: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-µg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences. CONCLUSIONS: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans.
Assuntos
Negro ou Afro-Americano/genética , Deficiência de Vitamina D/genética , Vitamina D/análogos & derivados , Idoso , Índice de Massa Corporal , Estudos Transversais , Suplementos Nutricionais , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Modelos Lineares , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Estações do Ano , Vitamina D/administração & dosagem , Vitamina D/sangue , Deficiência de Vitamina D/sangue , Proteína de Ligação a Vitamina D/genética , Proteína de Ligação a Vitamina D/metabolismo , População Branca/genéticaRESUMO
BACKGROUND: Vitamin D is associated with lung health in epidemiologic studies, but mechanisms mediating observed associations are poorly understood. This study explores mechanisms for an effect of vitamin D in lung through an in vivo gene expression study, an expression quantitative trait loci (eQTL) analysis in lung tissue, and a population-based cohort study of sequence variants. METHODS: Microarray analysis investigated the association of gene expression in small airway epithelial cells with serum 25(OH)D in adult non-smokers. Sequence variants in candidate genes identified by the microarray were investigated in a lung tissue eQTL database, and also in relation to cross-sectional pulmonary function in the Health, Aging, and Body Composition (Health ABC) study, stratified by race, with replication in the Framingham Heart Study (FHS). RESULTS: 13 candidate genes had significant differences in expression by serum 25(OH)D (nominal p < 0.05), and a genome-wide significant eQTL association was detected for SGPP2. In Health ABC, SGPP2 SNPs were associated with FEV1 in both European- and African-Americans, and the gene-level association was replicated in European-American FHS participants. SNPs in 5 additional candidate genes (DAPK1, FSTL1, KAL1, KCNS3, and RSAD2) were associated with FEV1 in Health ABC participants. CONCLUSIONS: SGPP2, a sphingosine-1-phosphate phosphatase, is a novel vitamin D-responsive gene associated with lung function. The identified associations will need to be followed up in further studies.
Assuntos
Pulmão/metabolismo , Proteínas de Membrana/genética , Monoéster Fosfórico Hidrolases/genética , Negro ou Afro-Americano/genética , Idoso , Envelhecimento , Composição Corporal , Estudos de Coortes , Células Epiteliais/metabolismo , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Testes de Função Respiratória , Vitamina D/sangue , População Branca/genéticaRESUMO
Antioxidant nutritional status is hypothesized to influence chronic obstructive pulmonary disease (COPD) susceptibility and progression. Although past studies relate antioxidants to gene expression, there are no data in patients with COPD. This study investigated the hypothesis that antioxidant status is compromised in patients with COPD, and antioxidant-responsive genes differentially express in a similar pattern. Lung tissue samples from patients with COPD were assayed for vitamin E and gene expression. Selenium and vitamin E were assayed in corresponding plasma samples. Discovery based genome-wide expression analysis compared moderate, severe, and very severe COPD (GOLD II-IV) patients to mild and at-risk/normal (GOLD 0-I). Hypotheses-driven analyses assessed differential gene expression by disease severity for vitamin E-responsive and selenium-responsive genes. GOLD II-IV COPD patients had 30% lower lung tissue vitamin E levels compared to GOLD 0-I participants (p = 0.0082). No statistically significant genome-wide differences in expression by disease severity were identified. Hypothesis-driven analyses of 109 genes found 16 genes differentially expressed (padjusted < 0.05) by disease severity including 6 selenium-responsive genes (range in fold-change -1.39 to 2.25), 6 vitamin E-responsive genes (fold-change -2.30 to 1.51), and 4 COPD-associated genes. Lung tissue vitamin E in patients with COPD was associated with disease severity and vitamin E-responsive genes were differentially expressed by disease severity. Although nutritional status is hypothesized to contribute to COPD risk, and is of therapeutic interest, evidence to date is mainly observational. The findings reported herein are novel, and support a role of vitamin E in COPD progression.
Assuntos
Perfilação da Expressão Gênica , Expressão Gênica , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/genética , Selênio/sangue , alfa-Tocoferol/sangue , Idoso , Idoso de 80 Anos ou mais , Antioxidantes/análise , Antioxidantes/metabolismo , Feminino , Humanos , Pulmão/química , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Análise de Sequência com Séries de Oligonucleotídeos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , RNA/análise , Índice de Gravidade de Doença , alfa-Tocoferol/análiseRESUMO
PURPOSE: The treatment of inherited metabolic disorders (IMDs) has traditionally relied on dietary interventions that are difficult to maintain, expensive, and socially isolating. The development of gene therapy for IMDs aims to provide sufficient gene activity to address the underlying causes of these conditions. This study surveyed health care providers (HCPs) to characterize their familiarity with gene therapy technologies and to identify educational needs across roles in a multidisciplinary care team. METHODS: The link to a Web-based, 26-question survey was distributed to HCPs in North America and Europe who were involved in IMD patient care. Results were analyzed using descriptive statistics. FINDINGS: Of the 590 survey link recipients, 64 completed the survey. Of these, 35 (55%) respondents were physicians, 23 (36%) were dietitians, 3 (5%) were nurse practitioners, 2 (3%) were genetic counselors, and 1 (2%) was a nurse. Most survey respondents (88% [n = 56 of 64]) reported the belief that gene therapy for IMDs would be available within 5 years of study conduct. Although nearly all physicians (97% [n = 34 of 35]) expressed awareness of gene therapy, rates of reported familiarity were lower among dietitians (57% [n = 13 of 23]); confidence in conversations with colleagues and patients/caregivers was also discordant. Nearly all HCPs wanted education on gene therapy advancements, and the most preferred informational sources were published literature and congress presentations. IMPLICATIONS: There is an urgent need for education on topics related to gene therapy modalities. Professional education on gene therapies is desired across all specialties and will be important for unified treatment practices in IMD care.
Assuntos
Doenças Metabólicas , Comunicação , Terapia Genética/efeitos adversos , Pessoal de Saúde , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/terapia , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Increased infant birth weight and adiposity are associated with an altered risk of adult chronic diseases. The objective was to investigate the association between maternal dietary fat intake during pregnancy and newborn adiposity. STUDY DESIGN: The study included 79 singleton pregnancies. Associations between maternal dietary fat intake during each trimester and infant adiposity at birth were assessed. RESULT: Average total grams of maternal total dietary fat and unsaturated fat intake during pregnancy correlated with infant percent body fat after adjusting for potential confounding variables (r = 0.23, p = 0.045; r = 0.24, p = 0.037). Maternal average daily intake of total fat, saturated fat, and unsaturated fat during the second trimester of pregnancy were each associated with infant percent body fat (r = 0.25, p = 0.029; r = 0.23, p = 0.046; r = 0.25, p = 0.031; respectively). CONCLUSIONS: The second trimester of pregnancy is a key time period for fetal adipose tissue metabolic programming and therefore a target for nutritional intervention.
Assuntos
Adiposidade , Composição Corporal , Adulto , Peso ao Nascer , Índice de Massa Corporal , Gorduras na Dieta , Feminino , Desenvolvimento Fetal , Humanos , Lactente , Recém-Nascido , Gravidez , Trimestres da GravidezRESUMO
BACKGROUND: Phenylketonuria (PKU) is an inherited metabolic disorder affecting the conversion of phenylalanine (Phe) to tyrosine. Medical nutrition therapy, consisting of a Phe-restricted diet with medical formula, is the primary treatment for PKU. The Simplified Diet is an approach to PKU nutrition management that allows certain fruits, vegetables, and low-protein foods to be eaten without measuring or tracking, referred to as free/uncounted foods. There is no consensus on how to implement this approach in metabolic centers in the United States (U.S.), and clinical practice varies. AIM: This study describes the clinical experience of metabolic dietitians in U.S.-based metabolic centers related to the use and implementation of the Simplified Diet. METHODS: A survey was developed and sent out to metabolic dietitians to query current clinical practices related to the Simplified Diet. Descriptive statistics were used to analyze responses. RESULTS: Sixty-three dietitians managing ≥5 patients with PKU in U.S.-based metabolic centers responded to the survey. Ninety-eight percent of survey respondents reported using some version of the Simplified Diet in clinical practice. The survey identified areas of strong agreement, including introduction of the Simplified Diet at 6 to 12 months of age. The survey also identified areas of widespread variability, including specific Phe or protein thresholds for free/uncounted foods, and whether or not to set daily quantity limits on these foods. CONCLUSIONS: Significant variability related to implementation of the Simplified Diet exists across U.S.-based metabolic centers. This practice variability may contribute to differences in the patient experience across centers and may indicate a need for development of clinical guidelines.
RESUMO
BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P â=â 5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P â=â 2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.