Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 73
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Clin Sleep Med ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31482803

RESUMO

STUDY OBJECTIVES: We hypothesized that sleep duration in the Amish would be longer than in non-Amish. METHODS: Sleep duration was obtained by questionnaire administered to Amish individuals (n = 3,418) and from the 2015-2016 National Health and Nutrition Examination Survey (NHANES; n = 1,912). Self-reported sleep duration was calculated as the difference in usual times that the participants went to bed at night and woke up in the morning. RESULTS: In Amish (43.7 ± 16.7 years) and NHANES (50.0 ± 20.6 years), women had a longer sleep duration than men (P < .0001 in both groups) and sleep was significantly longer in those aged 18-29 years and ≥ 70 years, compared to those aged 30-69 years. Seasonal-adjusted sleep duration was shorter in Amish than that in NHANES (7.8 minutes shorter, age- and sex-adjusted P < .0001). However, Amish were less likely to report sleeping fewer than 7 hours per night (15.4% in Amish versus 20.5% in NHANES, P < .0001). Amish went to bed 80.4 minutes earlier than NHANES and arose 87.6 minutes earlier (age-, sex-, and season-adjusted P < .0001 for both). In the Amish, sleep duration was longer in clerks than in farmers (P < .0001) and was significantly correlated among household members (.15 < r < .62, P < .001), although there was no evidence that this trait was heritable (h² approximately 0) after adjustment for household. CONCLUSIONS: The lower frequency of short sleepers in the Amish may contribute to the relatively lower risks of cardiometabolic diseases observed in this population.

2.
J Clin Sleep Med ; 15(9): 1321-1328, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31538603

RESUMO

STUDY OBJECTIVES: We hypothesized that sleep duration in the Amish would be longer than in non-Amish. METHODS: Sleep duration was obtained by questionnaire administered to Amish individuals (n = 3,418) and from the 2015-2016 National Health and Nutrition Examination Survey (NHANES; n = 1,912). Self-reported sleep duration was calculated as the difference in usual times that the participants went to bed at night and woke up in the morning. RESULTS: In Amish (43.7 ± 16.7 years) and NHANES (50.0 ± 20.6 years), women had a longer sleep duration than men (P < .0001 in both groups) and sleep was significantly longer in those aged 18-29 years and ≥ 70 years, compared to those aged 30-69 years. Seasonal-adjusted sleep duration was shorter in Amish than that in NHANES (7.8 minutes shorter, age- and sex-adjusted P < .0001). However, Amish were less likely to report sleeping fewer than 7 hours per night (15.4% in Amish versus 20.5% in NHANES, P < .0001). Amish went to bed 80.4 minutes earlier than NHANES and arose 87.6 minutes earlier (age-, sex-, and season-adjusted P < .0001 for both). In the Amish, sleep duration was longer in clerks than in farmers (P < .0001) and was significantly correlated among household members (.15 < r < .62, P < .001), although there was no evidence that this trait was heritable (h² approximately 0) after adjustment for household. CONCLUSIONS: The lower frequency of short sleepers in the Amish may contribute to the relatively lower risks of cardiometabolic diseases observed in this population. CITATION: Zhang M, Ryan KA, Wickwire E, Postolache TT, Xu H, Daue M, Snitker S, Pollin TI, Shuldiner AR, Mitchell BD. Self-reported sleep duration and pattern in old order amish and non-amish adults. J Clin Sleep Med. 2019;15(9):1321-1328.

3.
Pain ; 160(8): 1824-1834, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31335650

RESUMO

Genetics studies on the placebo hypoalgesic effect highlight a promising link between single nucleotide polymorphisms (SNPs) in the dopamine, opioid, and endocannabinoid genes and placebo hypoalgesia. However, epistasis and replication studies are missing. In this study, we expanded on previous findings related to the 3 SNPs in the opioid receptor mu subunit (OPRM1 rs1799971), catechol-O-methyltransferase (COMT rs4680), and fatty acid amide hydrolase (FAAH rs324420) genes associated with placebo hypoalgesia and tested the effect of a 3-way interaction on placebo hypoalgesia. Using 2 well-established placebo procedures (verbal suggestion and learning paradigm), we induced significant placebo hypoalgesic effects in 160 healthy participants. We found that individuals with OPRM1 AA combined with FAAH Pro/Pro and those carrying COMT met/met together with FAAH Pro/Pro showed significant placebo effects. Participants with COMT met/val alleles showed significant placebo effects independently of OPRM1 and FAAH allele combinations. Finally, the model that included the placebo procedure and genotypes predicted placebo responsiveness with a higher accuracy (area under the curve, AUC = 0.773) as compared to the SNPs alone indicating that genetic variants can only partially explain the placebo responder status. Our results suggest that the endogenous mu-opioid system with a larger activation in response to pain in the met/val allele carriers as well as the synergism between endogenous mu-opioid system and cannabinoids might play the most relevant role in driving hypoalgesic responses. Future epistasis studies with larger sample sizes will help us to fully understand the complexity of placebo effects and explain the mechanisms that underlie placebo responsiveness.

4.
Am J Hum Genet ; 104(1): 112-138, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595373

RESUMO

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.

5.
J Clin Lipidol ; 13(1): 109-114, 2019 Jan - Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30553757

RESUMO

BACKGROUND: Postprandial lipemia (PPL), defined as a prolonged or elevated rise in triglycerides that accompanies fat feeding, is a significant risk factor for coronary heart disease and associated comorbidities. The impact of PPL on coronary heart disease risk is underscored by the preponderance of each day spent in the postprandial state. OBJECTIVE: In this study, we evaluated cross-sectionally the association between usual (ie, noninterventional) physical activity and the 6-hour triglyceride response to a standardized high-fat meal. METHODS: The high-fat meal intervention was carried out in 671 apparently healthy individuals as part of the Heredity and Phenotype Intervention Heart Study. Triglyceride levels were measured in the fasting state and during 6 hours after administration of a standardized fat challenge. We defined PPL response as the triglyceride area under the fat load curve (AUC) and measured physical activity using accelerometers that were worn continuously over a 7-day period. RESULTS: Physical activity levels decreased with increasing age and were higher in men than women (both P < .001). The triglyceride AUC increased with increasing age in both men and women (both P < .001) and was also higher in men than in women (age-adjusted P = 9.2 × 10-12). Higher physical activity levels were associated with a lower triglyceride AUC (P = .003), adjusting for age, sex, body mass index, and fasting low-density lipoprotein. CONCLUSION: These results suggest that the protective benefits of physical activity on cardiovascular health may operate, at least in part, through reduction of the PPL triglyceride response.

7.
Nat Commun ; 9(1): 2606, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973585

RESUMO

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans.

8.
Sci Rep ; 8(1): 7141, 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739999

RESUMO

Wnt1-inducible signaling pathway protein-1 (WISP1) is a novel target of the Wnt pathway for modulating osteogenesis and improving bone strength. However, it is not clear if genetic variants in the WISP1 region are associated with bone mineral density (BMD) in human. The aim of this study is to investigate the role of genetic variation in WISP1 gene as a determinant of BMD in 1,510 Old Order Amish (OOA). We performed regional association analysis of 58 tag variants within 5 kb upstream and downstream to WISP1 with BMD and found 5 variants that were associated with BMD at multiple skeletal sites (P values from 2.89 × 10-6 to 1.62 × 10-2), with some significant associations even after adjustment for multiple comparisons. To replicate these results in an independent dataset, we performed a look-up of BMD associations with these variants in European ancestry subjects from the large GEFOS Consortium and observed the nominal associations of two of these variants with BMD (P values: 0.031 to 0.048). In conclusion, we have demonstrated that genetic variants surrounding WISP1 are associated with BMD at multiple skeletal sites in the OOA, thus influencing osteoporosis risk. These results support a role for the WISP1 gene on influencing variation in BMD.

9.
Circulation ; 138(13): 1343-1355, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-29593015

RESUMO

BACKGROUND: Elevated levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for cardiovascular disease via its contribution to the development and progression of atherosclerotic lesions. Although the genetic basis of LDL-C has been studied extensively, currently known genetic variants account for only ≈20% of the variation in LDL-C levels. METHODS: Through an array-based association analysis in 1102 Amish subjects, we identified a variant strongly associated with LDL-C levels. Using a combination of genetic analyses, zebrafish models, and in vitro experiments, we sought to identify the causal gene driving this association. RESULTS: We identified a founder haplotype associated with a 15 mg/dL increase in LDL-C on chromosome 5. After recombination mapping, the associated region contained 8 candidate genes. Using a zebrafish model to evaluate the relevance of these genes to cholesterol metabolism, we found that expression of the transcribed pseudogene, APOOP1, increased LDL-C and vascular plaque formation. CONCLUSIONS: Based on these data, we propose that APOOP1 regulates levels of LDL-C in humans, thus identifying a novel mechanism of lipid homeostasis.

10.
Diabetes Technol Ther ; 20(1): 32-38, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29293367

RESUMO

BACKGROUND: Insulin pumps and continuous glucose monitoring (CGM) are commonly used by patients with diabetes mellitus in the outpatient setting. The efficacy and safety of initiating inpatient insulin pumps and CGM in the nonintensive care unit setting is unknown. MATERIALS AND METHODS: In a prospective pilot study, inpatients with type 2 diabetes were randomized to receive standard subcutaneous basal-bolus insulin and blinded CGM (group 1, n = 5), insulin pump and blinded CGM (group 2, n = 6), or insulin pump and nonblinded CGM (group 3, n = 5). Feasibility, glycemic control, and patient satisfaction were evaluated among groups. RESULTS: Group 1 had lower mean capillary glucose levels, 144.5 ± 19.5 mg/dL, compared with groups 2 and 3, 191.5 ± 52.3 and 182.7 ± 59.9 mg/dL (P1 vs. 2+3 = 0.05). CGM detected 19 hypoglycemic episodes (glucose <70 mg/dL) among all treatment groups, compared with 12 episodes detected by capillary testing, although not statistically significant. No significant differences were found for the total daily dose of insulin or percentage of time spent below target glucose range (<90 mg/dL), in target glucose range (90-180 mg/dL), or above target glucose range (>180 mg/dL). On the Diabetes Treatment Satisfaction Questionnaire-Change, group 3 reported increased hyperglycemia and decreased hypoglycemia frequency compared with the other two groups, although the differences did not reach statistical significance. CONCLUSIONS: Insulin pump and CGM initiation are feasible during hospitalization, although they are labor intensive. Although insulin pump initiation may not lead to improved glycemic control, there is a trend toward CGM detecting a greater number of hypoglycemic episodes. Larger studies are needed to determine whether use of this technology can lower inpatient morbidity and mortality.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Pacientes Internados/estatística & dados numéricos , Sistemas de Infusão de Insulina , Monitorização Ambulatorial/estatística & dados numéricos , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos
11.
JCI Insight ; 2(16)2017 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-28814665

RESUMO

Postnatal bone formation is influenced by nutritional status and compromised by disturbances in metabolism. The oxidation of dietary lipids represents a critical source of ATP for many cells but has been poorly studied in the skeleton, where the prevailing view is that glucose is the primary energy source. Here, we examined fatty acid uptake by bone and probed the requirement for fatty acid catabolism during bone formation by specifically disrupting the expression of carnitine palmitoyltransferase 2 (Cpt2), an obligate enzyme in fatty acid oxidation, in osteoblasts and osteocytes. Radiotracer studies demonstrated that the skeleton accumulates a significant fraction of postprandial fatty acids, which was equal to or in excess of that acquired by skeletal muscle or adipose tissue. Female, but not male, Cpt2 mutant mice exhibited significant impairments in postnatal bone acquisition, potentially due to an inability of osteoblasts to modify fuel selection. Intriguingly, suppression of fatty acid utilization by osteoblasts and osteocytes also resulted in the development of dyslipidemia and diet-dependent modifications in body composition. Taken together, these studies demonstrate a requirement for fatty acid oxidation during bone accrual and suggest a role for the skeleton in lipid homeostasis.

12.
J Neuroimmunol ; 307: 37-41, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28495136

RESUMO

BACKGROUND: We examined the heritability of neopterin, a biomarker for cell-mediated immunity and oxidative stress, and potentially for psychiatric disorders, in the Old Order Amish. METHODS: Plasma neopterin levels were determined in 2015 Old Order Amish adults. Quantitative genetic procedures were used to estimate heritability of neopterin. RESULTS: Heritability of log-neopterin was estimated at 0.07 after adjusting for age, gender, and household (p=0.03). The shared household effect was 0.06 (p<0.02). CONCLUSIONS: We found a low heritability of neopterin and small household effect, suggesting that non-household environmental factors are more important determinants of variance of neopterin levels in the Amish.


Assuntos
Envelhecimento/sangue , Amish/estatística & dados numéricos , Neopterina/sangue , Adulto , Envelhecimento/imunologia , Meio Ambiente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neopterina/genética , Estudos Retrospectivos
13.
Diabetes ; 66(7): 2054-2058, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28428224

RESUMO

Alleles associated with lower levels of LDL cholesterol (LDL-C) have recently been associated with an increased risk of type 2 diabetes (T2D), highlighting the complex relationship between LDL-C and diabetes. This observation begs the question of whether LDL-C-raising alleles are associated with a decreased risk of T2D. This issue was recently addressed in a large familial hypercholesterolemia (FH) screening study, which reported a lower prevalence of self-reported diabetes in FH subjects than in age-matched relatives without FH. To extend this observation, we tested the association of FH with diabetes status and glycemia in a large Amish population enriched for the FH-associated APOB R3527Q variant that included 640 APOB R3527Q carriers and 4,683 noncarriers. Each copy of the R3527Q T allele was associated with a 74.9 mg/dL increase in LDL-C. There was little difference in T2D prevalence between subjects with (5.2%) and without (4.5%) the R3527Q allele (P = 0.23), and there was no association between R3527Q variant and impaired fasting glucose, fasting glucose or insulin, or oral glucose tolerance test-derived measures. Our data provide no evidence supporting an association between the APOB R3527Q variant and T2D or glycemia and highlight the asymmetry of the LDL-C-T2D relationship and/or the gene/variant-dependent specificity of the LDL-C-T2D association.


Assuntos
Amish/genética , Apolipoproteínas B/genética , Diabetes Mellitus Tipo 2/genética , Hiperlipoproteinemia Tipo II/genética , Glicemia/metabolismo , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Predisposição Genética para Doença , Genótipo , Hemoglobina A Glicada/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Insulina/metabolismo , Modelos Logísticos
14.
J Am Soc Nephrol ; 28(5): 1553-1565, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27927781

RESUMO

Parathyroid hormone (PTH) is a primary calcium regulatory hormone. Elevated serum PTH concentrations in primary and secondary hyperparathyroidism have been associated with bone disease, hypertension, and in some studies, cardiovascular mortality. Genetic causes of variation in circulating PTH concentrations are incompletely understood. We performed a genome-wide association study of serum PTH concentrations among 29,155 participants of European ancestry from 13 cohort studies (n=22,653 and n=6502 in discovery and replication analyses, respectively). We evaluated the association of single nucleotide polymorphisms (SNPs) with natural log-transformed PTH concentration adjusted for age, sex, season, study site, and principal components of ancestry. We discovered associations of SNPs from five independent regions with serum PTH concentration, including the strongest association with rs6127099 upstream of CYP24A1 (P=4.2 × 10-53), a gene that encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-dihydroxyvitamin D. Each additional copy of the minor allele at this SNP associated with 7% higher serum PTH concentration. The other SNPs associated with serum PTH concentration included rs4074995 within RGS14 (P=6.6 × 10-17), rs219779 adjacent to CLDN14 (P=3.5 × 10-16), rs4443100 near RTDR1 (P=8.7 × 10-9), and rs73186030 near CASR (P=4.8 × 10-8). Of these five SNPs, rs6127099, rs4074995, and rs219779 replicated. Thus, common genetic variants located near genes involved in vitamin D metabolism and calcium and renal phosphate transport associated with differences in circulating PTH concentrations. Future studies could identify the causal variants at these loci, and the clinical and functional relevance of these variants should be pursued.


Assuntos
Variação Genética , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
15.
J Nutrigenet Nutrigenomics ; 9(5-6): 254-264, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28002826

RESUMO

BACKGROUND/AIMS: Alpha-carotene is a provitamin A carotenoid present in fruits and vegetables. Higher serum concentrations of α-carotene have been associated with lower risk of cancer and all-cause mortality. Previous studies have suggested that genetic variants influence serum concentrations of provitamin A carotenoids, but to date no variants have been robustly associated with serum α-carotene concentrations. The aim of this study was to identify genetic associations with serum α-carotene concentrations using the genome-wide association study (GWAS) approach. METHODS: A GWAS of serum α-carotene concentrations was conducted in 433 Old Order Amish adults who had consumed a 6-day controlled diet. Linear regression models adjusting for age, gender, and family structure were utilized to evaluate associations between genetic variants and serum α-carotene concentrations. RESULTS: Genome-wide significant associations with α-carotene concentrations were observed for loci on chromosome 1q41 between the genes CAPN2 and CAPN8 (rs12137025, p = 3.55 × 10-8), chromosome 2p21 in PRKCE (rs2594495, p = 1.01 × 10-8), and chromosome 4q34 (rs17830069, p = 2.89 × 10-8). CONCLUSIONS: We identified 3 novel loci associated with serum α-carotene concentrations among a population that consumed a controlled diet. While replication is necessary, the CAPN2/CAPN8 locus provides compelling evidence for an association with serum α-carotene concentrations and may suggest a relationship with the development and progression of cancers.


Assuntos
Calpaína/genética , Carotenoides/sangue , Cromossomos Humanos Par 1 , Loci Gênicos , Adulto , Amish/genética , Dieta , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
16.
J Am Heart Assoc ; 5(11)2016 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-27799230

RESUMO

BACKGROUND: Platelet activation can lead to enhanced oxidative stress, inflammatory response, and endothelial dysfunction. To quantify the effects of platelet inhibition on endothelial function, we assessed platelet activity of healthy persons before and after clopidogrel administration and evaluated its effects on endothelial function. We hypothesized that clopidogrel, by attenuating platelet activity, would result in enhanced endothelial function. METHODS AND RESULTS: Microcirculatory endothelial function was quantified by laser Doppler flowmetry (LDF) mediated by thermal hyperemia (TH) and postocclusive reactive hyperemia, respectively, in 287 and 241 relatively healthy and homogenous Old Order Amish persons. LDF and platelet aggregation measures were obtained at baseline and after 7 days of clopidogrel administration. Our primary outcome was percentage change in post- versus preclopidogrel LDF measures. Preclopidogrel TH-LDF and platelet aggregation were higher in women than in men (P<0.001). Clopidogrel administration was associated with ≈2-fold higher percentage change in TH-LDF in participants with high versus low baseline platelet aggregation (39.4±10.1% versus 17.4±5.6%, P=0.03). Clopidogrel also increased absolute TH-LDF measures in persons with high platelet aggregation (1757±766 to 2154±1055, P=0.03), with a more prominent effect in women (1909±846 to 2518±1048, P=0.001). There was no evidence that clopidogrel influenced postocclusive reactive hyperemia LDF measures. CONCLUSIONS: The administration of clopidogrel in healthy persons with high baseline platelet aggregation results in improved TH-induced microcirculatory endothelial function. These data suggest that clopidogrel may have a beneficial effect on microcirculatory endothelial function, presumably through antiplatelet activity, and may confer additional vascular benefits. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799396.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Pele/irrigação sanguínea , Ticlopidina/análogos & derivados , Adulto , Idoso , Clopidogrel , Citocromo P-450 CYP2C19/genética , Feminino , Genótipo , Voluntários Saudáveis , Humanos , Hiperemia/genética , Hiperemia/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/genética , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/genética , Agregação Plaquetária/genética , Ticlopidina/farmacologia , Adulto Jovem
17.
G3 (Bethesda) ; 6(9): 2909-18, 2016 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-27412988

RESUMO

Using genomic applications to glean insights into human biology, we systematically searched for nonsense single nucleotide variants (SNVs) that are rare in the general population but enriched in the Old Order Amish (Amish) due to founder effect. We identified two nonlinked, nonsense SNVs (R12X and W48X) in SLC13A1 (allele frequencies 0.29% and 0.74% in the Amish; enriched 1.2-fold and 3.7-fold, compared to the outbred Caucasian population, respectively). SLC13A1 encodes the apical sodium-sulfate cotransporter (NaS1) responsible for sulfate (re)absorption in the kidneys and intestine. SLC13A1 R12X and W48X were independently associated with a 27.6% (P = 2.7 × 10(-8)) and 27.3% (P = 6.9 × 10(-14)) decrease in serum sulfate, respectively (P = 8.8 × 10(-20) for carriers of either SLC13A1 nonsense SNV). We further performed the first exome- and genome-wide association study (ExWAS/GWAS) of serum sulfate and identified a missense variant (L348P) in SLC26A1, which encodes the basolateral sulfate-anion transporter (Sat1), that was associated with decreased serum sulfate (P = 4.4 × 10(-12)). Consistent with sulfate's role in xenobiotic detoxification and protection against acetaminophen-induced hepatotoxicity, SLC13A1 nonsense SNV carriers had higher aminotransferase levels compared to noncarriers. Furthermore, SLC26A1 L348P was associated with lower whole-body bone mineral density (BMD) and higher serum calcium, consistent with the osteochondrodysplasia exhibited by dogs and sheep with naturally occurring, homozygous, loss-of-function mutations in Slc13a1 This study demonstrates the power and translational potential of systematic identification and characterization of rare, loss-of-function variants and warrants additional studies to better understand the importance of sulfate in human physiology, disease, and drug toxicity.


Assuntos
Proteínas de Transporte de Cátions/genética , Códon sem Sentido/genética , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único/genética , Simportadores/genética , Acetaminofen/efeitos adversos , Adulto , Idoso , Amish/genética , Animais , Densidade Óssea/genética , Cálcio/sangue , Proteínas de Transporte de Cátions/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cães , Feminino , Heterozigoto , Humanos , Mucosa Intestinal/metabolismo , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Proteínas de Membrana Transportadoras/sangue , Pessoa de Meia-Idade , Ovinos , Cotransportador de Sódio-Sulfato , Transportadores de Sulfato , Sulfatos/sangue , Simportadores/sangue , Transaminases/sangue
18.
Vaccine ; 34(24): 2737-44, 2016 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-27126875

RESUMO

BACKGROUND: School-located influenza vaccination (SLIV) programs are a promising strategy for increasing vaccination coverage among schoolchildren. However, questions of economic sustainability have dampened enthusiasm for this approach in the United States. We evaluated SLIV sustainability of a health department led, county-wide SLIV program in Alachua County, Florida. Based on Alachua's outcome data, we modeled the sustainability of SLIV programs statewide using two different implementation costs and at different vaccination rates, reimbursement amount, and Vaccines for Children (VFC) coverage. METHODS: Mass vaccination clinics were conducted at 69 Alachua County schools in 2013 using VFC (for Medicaid and uninsured children) and non-VFC vaccines. Claims were processed after each clinic and submitted to insurance providers for reimbursement ($5 Medicaid and $47.04 from private insurers). We collected programmatic expenditures and volunteer hours to calculate fixed and variable costs for two different implementation costs (with or without in-kind costs included). We project program sustainability for Florida using publicly available county-specific student populations and health insurance enrollment data. RESULTS: Approximately 42% (n=12,853) of pre-kindergarten - 12th grade students participated in the SLIV program in Alachua. Of the 13,815 doses provided, 58% (8042) were non-VFC vaccine. Total implementation cost was $14.95/dose or $7.93/dose if "in-kind" costs were not included. The program generated a net surplus of $24,221, despite losing $4.68 on every VFC dose provided to Medicaid and uninsured children. With volunteers, 99% of Florida counties would be sustainable at a 50% vaccination rate and average reimbursement amount of $3.25 VFC and $37 non-VFC. Without volunteers, 69% of counties would be sustainable at 50% vaccination rate if all VFC recipients were on Medicaid and its reimbursement increased from $5 to $10 (amount private practices receive). CONCLUSIONS AND RELEVANCE: Key factors that contributed to the sustainability and success of an SLIV program are: targeting privately insured children and reducing administration cost through volunteers. Counties with a high proportion of VFC eligible children may not be sustainable without subsidies at $5 Medicaid reimbursement.


Assuntos
Programas de Imunização/economia , Vacinas contra Influenza/uso terapêutico , Instituições Acadêmicas , Vacinação/economia , Adolescente , Criança , Pré-Escolar , Florida , Custos de Cuidados de Saúde , Gastos em Saúde , Humanos , Vacinas contra Influenza/economia , Influenza Humana/prevenção & controle , Seguro Saúde , Medicaid , Estados Unidos , Vacinação/estatística & dados numéricos
19.
Stroke ; 47(4): 918-22, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26965853

RESUMO

BACKGROUND AND PURPOSE: Although case reports have long identified a temporal association between cocaine use and ischemic stroke (IS), few epidemiological studies have examined the association of cocaine use with IS in young adults, by timing, route, and frequency of use. METHODS: A population-based case-control study design with 1090 cases and 1154 controls was used to investigate the relationship of cocaine use and young-onset IS. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between cocaine use and IS with and without adjustment for potential confounders. RESULTS: Ever use of cocaine was not associated with stroke with 28% of cases and 26% of controls reporting ever use. In contrast, acute cocaine use in the previous 24 hours was strongly associated with increased risk of stroke (age-sex-race adjusted odds ratio, 6.4; 95% confidence interval, 2.2-18.6). Among acute users, the smoking route had an adjusted odds ratio of 7.9 (95% confidence interval, 1.8-35.0), whereas the inhalation route had an adjusted odds ratio of 3.5 (95% confidence interval, 0.7-16.9). After additional adjustment for current alcohol, smoking use, and hypertension, the odds ratio for acute cocaine use by any route was 5.7 (95% confidence interval, 1.7-19.7). Of the 26 patients with cocaine use within 24 hours of their stroke, 14 reported use within 6 hours of their event. CONCLUSIONS: Our data are consistent with a causal association between acute cocaine use and risk of early-onset IS.


Assuntos
Isquemia Encefálica/etiologia , Transtornos Relacionados ao Uso de Cocaína/complicações , Cocaína/efeitos adversos , Acidente Vascular Cerebral/etiologia , Adolescente , Adulto , Isquemia Encefálica/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Risco , Fatores Sexuais , Acidente Vascular Cerebral/epidemiologia , Adulto Jovem
20.
Nutrients ; 8(2): 82, 2016 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-26861389

RESUMO

Dietary intake and higher serum concentrations of lycopene have been associated with lower incidence of prostate cancer and other chronic diseases. Identifying determinants of serum lycopene concentrations may thus have important public health implications. Prior studies have suggested that serum lycopene concentrations are under partial genetic control. The goal of this research was to identify genetic predictors of serum lycopene concentrations using the genome-wide association study (GWAS) approach among a sample of 441 Old Order Amish adults that consumed a controlled diet. Linear regression models were utilized to evaluate associations between genetic variants and serum concentrations of lycopene. Variant rs7680948 on chromosome 4, located in the intron region of the SETD7 gene, was significantly associated with serum lycopene concentrations (p = 3.41 × 10(-9)). Our findings also provided nominal support for the association previously noted between SCARB1 and serum lycopene concentrations, although with a different SNP (rs11057841) in the region. This study identified a novel locus associated with serum lycopene concentrations and our results raise a number of intriguing possibilities regarding the nature of the relationship between SETD7 and lycopene, both of which have been independently associated with prostate cancer. Further investigation into this relationship might help provide greater mechanistic understanding of these associations.


Assuntos
Antioxidantes/metabolismo , Carotenoides/sangue , Genótipo , Histona-Lisina N-Metiltransferase/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Adulto , Amish , Dieta , Feminino , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Licopeno , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA