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1.
Artigo em Inglês | MEDLINE | ID: mdl-31680049

RESUMO

OBJECTIVE: A recently published genome wide association study of abdominal aortic aneurysms (AAA), based on pooled case control data of European ancestry, identified four new loci for AAA: SMYD2 (top single nucleotide polymorphism [SNP] rs1795061), LINC00540 (rs9316871), PCIF1/MMP9/ZNF335 (rs3827066), and ERG (rs2836411). Of the four, rs1795061 and rs2836411 showed significant heterogeneity across studies and the p value for rs9316871 did not reach the genome wide significance threshold until discovery and replication data were pooled together in that study. The objective of this study was to replicate these newly identified genetic associations for AAA in a US based prospective cohort study, the Atherosclerosis Risk in Communities (ARIC) Study, and a Greece based case control study. METHODS: ARIC identified 408 clinically diagnosed AAAs among 8 962 individuals of European ancestry during a median of 22 years of follow up. The Greek case control study included 341 AAAs of European ancestry recruited in a tertiary referral centre and 292 geographically and ethnically matched controls recruited from the same institution. A Cox proportional hazards model was used to analyse the ARIC data and logistic regression to analyse the Greek data. RESULTS: In ARIC, rs9316871 and rs3827066 were significantly associated with AAA risk (HR [p] was 0.77 [.004] and 1.22 [.03], respectively), rs2836411 was associated at borderline significance (1.13 [.08]), whereas rs1795061 was not associated (p = .55). In the Greek case control study, rs1795061 and rs2836411 were significantly associated with AAA (OR [p] was 1.66 [< .001] and 1.29 [.04], respectively), whereas rs9316871 was not (p = .81). Genotyping of rs3827066 did not succeed. In the meta-analysis of the two studies, the association for rs9316871and rs2836411 was statistically significant and consistent between the two studies: p = .02 and .007, respectively. CONCLUSIONS: Associations between rs9316871and rs2836411 and AAA risk were replicated in the meta-analysis of the two independent cohorts, providing further support for the importance of these loci in the aetiology of AAA.

2.
Diabetes Metab ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31706030

RESUMO

AIM: Determine whether plasma omega-7 vaccenic acid and palmitoleic acid levels are related to homeostasis model of insulin resistance scores and incident type II diabetes, and whether race/ethnicity modifies these associations. METHODS: Plasma phospholipid fatty acids were measured by gas chromatography with flame-ionization detection in Multi-Ethnic Study of Atherosclerosis participants. Linear regression determined associations of vaccenic acid and palmitoleic acid with log-transformed homeostasis model of insulin resistance scores (N=5689), and Cox regression determined associations with incident type II diabetes (N=5413, 660 cases). Race-interactions were tested. RESULTS: Adjusting for typical risk factors, higher levels of plasma vaccenic acid were found to be inversely associated with insulin resistance scores across all four race/ethnicities, and a significant race-interaction was observed between Hispanics and Caucasians (P for interaction = 0.03). Vaccenic acid was related to 17%, 32%, and 39% lower risks of incident type II diabetes in Black, Hispanic, and Chinese American participants, respectively. Differences in associations between races were detected (P for interactions < 0.05). By contrast, higher levels of plasma palmitoleic acid were related to greater insulin resistance scores in Blacks (P < 0.001) and Hispanics (P < 0.001); significant race-based differences between associations were detected (P for interactions < 0.05). Palmitoleic acid was correspondingly related to a 21% greater risk of incident type II diabetes in Black individuals. CONCLUSIONS: Results suggest that plasma vaccenic acid and palmitoleic acid are markers of metabolic health and dysfunction, respectively. Coupled with previous evidence and the significant race interactions, our findings have implications for future studies of the race-based differences in omega-7 fatty acids and their regulation in the context of deteriorating metabolic health.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31630168

RESUMO

Methylation levels measured at defined sites across the genome have recently been shown to be correlated with an individual's chronological age. Age acceleration, or the difference between age estimated from DNA methylation status and chronological age, has been proposed as a novel biomarker of aging. In this study, the cross-sectional association between two different measures of age acceleration and cognitive function was investigated using whole blood samples from 2,157 African-American participants 47-70 years of age in the population-based Atherosclerosis Risk in Communities (ARIC) Study. Cognition was evaluated using three domain-specific tests. A significant inverse association between a one-year increase in age acceleration calculated using a blood-based age predictor and scores on the Word Fluency Test was found using a general linear model adjusted for chronological age, gender, and years of education (ß = -0.140 words; p = 0.001) and after adding other potential confounding variables (ß = -0.104 words, p = 0.023). The results were replicated in 1,670 European participants in the Generation Scotland: Scottish Family Health Study (fully adjusted model: ß = -0.199 words; p = 0.034). A significant association was also identified in a trans-ethnic meta-analysis across cohorts that included an additional 708 European American ARIC study participants (fully adjusted model: ß = -0.110 words, p = 0.003). There were no associations found using an estimate of age acceleration derived from multiple tissues. These findings provide evidence that age acceleration is a correlate of performance on a test of verbal fluency in middle-aged adults.

4.
ACS Sens ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31612705

RESUMO

While the solid-state nanopore sensors have shown exceptional promise with their single-molecule sensitivity and label-free operations, one of the most significant challenges in the nanopore sensor is the limited analyte translocation event rate that leads to prolonged sensor response time. This issue is more pronounced when the analyte concentration is below the nanomolar (nM) range, owing to the diffusion-limited mass transport. In this work, we systematically studied the experimental factors beyond the intrinsic analyte concentration and electrophoretic mobility that affect the event rate in glass nanopore sensors. We developed a quantitative model to capture the impact of nanopore surface charge density, ionic strength, nanopore geometry, and translocation direction on the event rate. The synergistic effects of these factors on the event rates were investigated with the aim to find the optimized experimental conditions for operating the glass nanopore sensor from the response time standpoint. The findings in the study would provide useful and practical insight to enhance the device response time and achieve a lower detection limit for various glass nanopore-sensing experiments.

5.
Nano Lett ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31657939

RESUMO

Solid-state nanopores have shown great promise and achieved tremendous success in label-free single-molecule analysis. However, there are three common challenges in solid-state nanopore sensors, including the nanopore size variations from batch to batch that makes the interpretation of the sensing results difficult, the incorporation of sensor specificity, and the impractical analysis time at low analyte concentration due to diffusion-limited mass transport. Here, we demonstrate a novel loop-mediated isothermal amplification (LAMP)-coupled glass nanopore counting strategy that could effectively address these challenges. By using the glass nanopore in the counting mode (versus the sizing mode), the device fabrication challenge is considerably eased since it allows a certain degree of pore size variations and no surface functionalization is needed. The specific molecule replication effectively breaks the diffusion-limited mass transport thanks to the exponential growth of the target molecules. We show the LAMP-coupled glass nanopore counting has the potential to be used in a qualitative test as well as in a quantitative nucleic acid test. This approach lends itself to most amplification strategies as long as the target template is specifically replicated in numbers. The highly sensitive and specific sensing strategy would open a new avenue for solid-state nanopore sensors toward a new form of compact, rapid, low-cost nucleic acid testing at the point of care.

6.
West J Nurs Res ; : 193945919871697, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470769

RESUMO

The purpose of this study was to examine psychosocial constructs targeted as potential mediators in a prior physical activity (PA) intervention study. This secondary analysis used data from 102 older adults randomized to one of four conditions-within a 2 (Interpersonal Strategies: yes, no) x 2 (Intrapersonal Strategies: yes, no) factorial design. We tested intervention effects on social support, self-efficacy, self-regulation, and goal attainment, and whether these constructs mediated intervention effects on PA. Participants who received interventions with interpersonal strategies, compared to those who did not, increased their readiness (post-intervention), the self-regulation subscale of self-assessment, and goal attainment (post-intervention, 6-months). Participants who received interventions with intrapersonal strategies, compared to those who did not, increased their social support from family (post-intervention). There was no statistically significant mediation. To understand mechanisms through which interventions increase older adults' PA and to improve intervention effectiveness, researchers should continue to examine potential psychosocial mediators. Clinical Trial Registry: NCT02433249.

7.
Epigenomics ; 11(13): 1487-1500, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31536415

RESUMO

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

8.
Nat Commun ; 10(1): 4267, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537805

RESUMO

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.

9.
ACS Sens ; 4(7): 1957-1963, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31264411

RESUMO

Due to its simplicity and robustness, pore-based resistive pulse sensors have been widely used to detect, measure, and analyze particles at length scales ranging from nanometers to micrometers. While multiple pore-based resistive pulse sensors are preferred to increase the analysis throughput and to overcome the clogging issues, the scalability is often limited. In response, by combining the time-division multiple access technique in the telecommunication field with the microfluidics, we reported a microfluidic time-division multiplexing accessing (TDMA) single-end resistive pulse sensor, in which particles can be analyzed through a scalable number of microfluidic channels. With an eight-channel microfluidic device and polystyrene particles as proof-of-principle, we successfully demonstrated this multiplexed technology is effective in measuring the particle size and concentration, in analyzing the particle arriving dynamics, and in discriminating mixed populations. Importantly, the availability of multiple sensing pores provides a robust mechanism to overcome the clogging issue, allowing the analysis to continue even when some of the pores are clogged. We anticipate this TDMA approach could find wide applications and facilitate future development of multiplexed resistive pulse sensing from the microscale to nanoscale.

10.
Anal Chem ; 91(17): 11178-11184, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31322338

RESUMO

Nanopore sensor conceptually represents an ideal single molecule counting device due to its unique partitioning-free, label-free electronic sensing. Existing theories and experiments have shown that sample concentration is proportional to the molecule translocation rate. However, a detailed nanopore geometry and size characterization or a calibration curve of concentration standards are often required for quantifying the unknown sample. In this work, we proposed and validated a calibration-free nanopore single molecule digital counting method for isolated molecule quantification. With the background ions as the in situ references, the molecule translocation rates can be normalized to the ion translocation rates (i.e., baseline current). This in situ reference alleviates the requirement for knowing the nanopore geometry and size or generating a calibration curve. In recognition of this effect, we developed a quantitative model for nanopore quantification without the need for prior knowledge of experimental conditions such as nanopore geometry, size, and applied voltage. This model was experimentally validated for different nanopores and DNA molecules with different sizes. We anticipate this calibration-free digital counting approach would provide a new avenue for nanopore-based molecule sensing.

11.
Environ Int ; 132: 104723, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31208937

RESUMO

BACKGROUND: DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5-10 µm in diameter (PM2.5; PM10; PM2.5-10). METHODS: We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10-7; PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study. RESULTS: Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10-8). One-month mean PM10 and PM2.5-10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10-8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10-8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA. CONCLUSIONS: Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.

12.
Am J Transplant ; 19(10): 2795-2804, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30953600

RESUMO

Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10-5 -8.8 × 10-6 ) and one suggestive variant in Asian Americans (P = 5.6 × 10-6 ). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants.

13.
Am J Transplant ; 19(8): 2262-2273, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30920136

RESUMO

Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables.

14.
Transplantation ; 103(8): 1591-1602, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30801535

RESUMO

BACKGROUND: Identifying kidney allograft recipients who are predisposed to acute rejection (AR) could allow for optimization of clinical treatment to avoid rejection and prolong graft survival. It has been hypothesized that a part of this predisposition is caused by the inheritance of specific genetic variants. There are many publications reporting a statistically significant association between a genetic variant, usually in the form of a single-nucleotide polymorphism (SNP), and AR. However, there are additional publications reporting a lack of this association when a different cohort of recipients is analyzed for the same single-nucleotide polymorphism. METHODS: In this report, we attempted to validate 75 common genetic variants, which have been previously reported to be associated with AR, using a large kidney allograft recipient cohort of 2390 European Americans and 482 African Americans. RESULTS: Of those variants tested, only 1 variant, rs2910164, which alters the expression of the microRNA MIR146A, was found to exhibit a significant association within the African American cohort. Suggestive variants were found in the genes CTLA and TLR4. CONCLUSIONS: Our results show that most variants previously reported to be associated with AR were not validated in our cohort. This shows the importance of validation when reporting the associations with complex clinical outcomes such as AR. Additional work will need to be done to understand the role of MIR146A in the risk of AR in kidney allograft recipients.

15.
Transplantation ; 103(6): 1131-1139, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30801552

RESUMO

BACKGROUND: The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes. METHODS: We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes. RESULTS: Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified. CONCLUSIONS: These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.

16.
J Genet Couns ; 28(2): 355-366, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30710467

RESUMO

Rationales for returning results from whole genome sequencing (WGS) and genetic testing have historically focused on medical utility. Understanding the wide array of actions individuals might take following genetic testing results could have important implications for clinical care. We aimed to survey the public regarding their perceptions of the importance of a wide variety of different actions one might take upon receiving hypothetical results from a WGS test where the results indicate a high risk of developing a genetic condition. We assessed whether demographic characteristics, type of condition, and perceived severity of the condition differentially affected importance ratings of actions they would take. In a survey administered at the 2015 Minnesota State Fair, 909 participants imagined that they had a blood test that looked at their genes and indicated that they were at high risk of developing one of three randomized conditions (Alzheimer's disease, macular degeneration, or colon cancer). Participants rated the importance of 35 actions. Principal component analysis, used to categorize actions, yielded eight categories: (1) medical management and communication; (2) partner support; (3) support and life fulfillment; (4) diet and exercise; (5) distal planning; (6) religion/spiritual support; (7) reproductive actions; and (8) proximal planning. Participants rated a wide range of actions as important, with medical management and communication, and partner support receiving the highest mean ratings. Linear regression yielded significant associations between importance ratings and demographics variables (age and gender), genetic condition, and perceived severity of the condition for different action categories. Genetic counselors and other healthcare professionals should consider a variety of possible patient actions beyond medical actionability when discussing genetic testing results.

17.
Arterioscler Thromb Vasc Biol ; 39(3): 523-529, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30727753

RESUMO

Objective- Lp(a) [lipoprotein(a)] is a well-described risk factor for atherosclerosis, but Lp(a)-associated risk may vary by race/ethnicity. We aimed to determine whether race/ethnicity modifies Lp(a)-related risk of carotid atherosclerotic plaque outcomes among black, white, Chinese, and Hispanic individuals. Approach and Results- Carotid plaque presence and score were assessed by ultrasonography at baseline (n=5155) and following a median 9.4 year period (n=3380) in MESA (Multi-Ethnic Study of Atherosclerosis) participants. Lp(a) concentrations were measured by immunoassay and examined as a continuous and categorical variable using clinically-based cutoffs, 30 and 50 mg/dL. Lp(a) was related to greater risk of prevalent carotid plaque at baseline in whites alone (all P<0.001): per log unit (relative risk, 1.05); Lp(a)≥30 mg/dL (relative risk, 1.16); and Lp(a)≥50 mg/dL (relative risk, 1.20). Lp(a) levels over 50 mg/dL were associated with a higher plaque score at baseline in whites (all P<0.001) and Hispanics ( P=0.04). In prospective analyses, whites with Lp(a) ≥50 mg/dL were found to have greater risk of plaque progression (relative risk, 1.12; P=0.03) and higher plaque scores (all P<0.001) over the 9.4-year follow-up. Race-based differences between whites and black participants were significant for cross-sectional associations and for carotid plaque score following the 9.4 year study period. Conclusions- Race was found to be a modifying variable in Lp(a)-related risk of carotid plaque, and Lp(a) levels may have greater influence on plaque burden in whites than in black individuals. Borderline results in Hispanics suggest that elevated Lp(a) may increase the risk of carotid plaque, but follow-up studies are needed.

18.
Genet Epidemiol ; 43(4): 449-457, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30659681

RESUMO

Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.


Assuntos
Exoma/genética , Estudo de Associação Genômica Ampla/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Análise em Microsséries/métodos , Tromboembolia Venosa/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Masculino , Análise em Microsséries/estatística & dados numéricos , Razão de Chances , Polimorfismo de Nucleotídeo Único , Tamanho da Amostra , Tromboembolia Venosa/etnologia
19.
Epigenomics ; 11(2): 187-198, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30618290

RESUMO

AIM: We examined maternal prepregnancy anthropometry and cord blood DNA methylation. METHODS: Associations between maternal measures (i.e., weight, height, waist circumference, hip circumference, skinfolds, leptin) and methylation ß-values at each CpG (measured by the Infinium MethylationEPIC BeadChip) were estimated among 391 singletons. RESULTS:  Total of 18% of mothers were obese (body mass index ≥ 30) and 27% centrally obese (waist-to-hip ratio ≥ 0.85). One Bonferroni significant CpG with respect to obesity (cg02975187) and two with central obesity (cg12053563, cg12549355) were identified (p < 6 × 10-8). A suggestive association (p < 10-6) was observed at SFRS8 with increasing body mass index. SFRS8 was previously identified with propensity for weight gain in adults. CONCLUSION: While associations identified with multiple measures related to maternal adiposity suggest different pathways, methylation differences were small in magnitude.

20.
Nanotechnology ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30523901

RESUMO

We investigate the current transport characteristics in the electrolyte-dielectric-electrolyte structure commonly used in the in-situ controlled breakdown (CBD) fabrication of solid-state nanopores. It is found that the stochastic breakdown process could lead to fidelity issues of false positives (an incorrect indication of a true nanopore formation) and false negatives (inability to detect initial nanopore formation). Robust and deterministic detection of initial physical breakdown to alleviate false positives and false negatives is critical for precise nanopore size control. To this end, we report a high fidelity moving Z-Score method based CBD fabrication of solid-state nanopore. We demonstrate 100% success rate of realizing the initial nanopore conductance of 3±1 nS (corresponds to size of 1.7±0.6 nm) regardless of the dielectric membrane characteristics. Our study also elucidates the Joule heating is the dominant mechanism for electric field-based nanopore enlargement. Single DNA molecule sensing using nanopores fabricated by this method was successfully demonstrated. We anticipate the moving Z-Score based CBD method could enable broader access to the solid state nanopore-based single molecule analysis.

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