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1.
Prev Med ; 147: 106483, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33640399

RESUMO

The objective of this study is to provide an assessment of allostatic load (AL) burden among US adults across race/ethnicity, gender, and age groups over a 30-year time period. We analyzed data from 50,671 participants of the National Health and Nutrition Examination Survey (NHANES) years 1988 through 2018. AL score was defined as the sum total for abnormal measures of the following components: serum albumin, body mass index, serum C - reactive protein, serum creatinine, diastolic blood pressure, glycated hemoglobin, systolic blood pressure, total cholesterol, and serum triglycerides. We performed modified Poisson regression to estimate the adjusted Relative Risks (aRRs) of allostatic load, and generalized linear models to determine adjusted mean differences accounting for NHANES sampling weights. Among US adults aged 18 or older, the prevalence of high AL increased by more than 45% from 1988 to 1991 to 2015-2018, from 33.5% to 48.6%. By the latest period, 2015-2018, Non-Hispanic Black women (aRR: 1.292; 95% CI: 1.290-1.293) and Latina women (aRR: 1.266; 95% CI: 1.265-1.267) had higher risks of AL than non-Hispanic White women. Similar trends were observed among men. Age-adjusted mean AL score among NH-Black and Latinx adults was higher than for NH-Whites of up to a decade older regardless of gender. From 1988 through 2018, Adults aged 40 years old and older had over 2-fold increased risks of high AL when compared to adults 18-29 years old. After 30-years of collective data, racial disparities in allostatic load persist for NH-Black and Latinx adults.

2.
Nature ; 590(7845): 290-299, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33568819

RESUMO

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Genômica , National Heart, Lung, and Blood Institute (U.S.) , Medicina de Precisão , Citocromo P-450 CYP2D6/genética , Haplótipos/genética , Heterozigoto , Humanos , Mutação INDEL , Mutação com Perda de Função , Mutagênese , Fenótipo , Polimorfismo de Nucleotídeo Único , Densidade Demográfica , Medicina de Precisão/normas , Controle de Qualidade , Tamanho da Amostra , Estados Unidos , Sequenciamento Completo do Genoma/normas
3.
Nat Commun ; 12(1): 900, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568662

RESUMO

Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference.


Assuntos
Miócitos Cardíacos/metabolismo , Sono , Adulto , Idoso , Pressão Sanguínea , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Cátion TRPC6/genética , Reino Unido , Circunferência da Cintura
4.
Hum Mol Genet ; 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33517400

RESUMO

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

5.
Sex Transm Infect ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436506

RESUMO

ObjectivesThe southeastern US is a domestic epicentre for incident HIV with high prevalence of herpes simplex virus (HSV) coinfection. We estimated the incidence rates (IR) of symptomatic herpetic anogenital ulcer disease (HAUD) and assessed its associations with demographic and clinical characteristics, specifically with immunological markers using median, nadir and trajectory CD4 counts. METHODS: Electronic medical records (EMR) of over 7000 people living with HIV (PLWH) attending one of the leading HIV clinics in the southeastern US between 2006 and 2018 were reviewed and analysed. IR of HSV-related HAUD were estimated per 10 000 person years. Joinpoint regressions were performed to examine temporal changes in the trends of IR. All IR and trends were stratified by gender and race. Six CD4 trajectory groups were constructed using the group-based trajectory modelling. Multivariable logistic models were conducted to assess the associations of CD4 counts (nadir, median CD4 and newly defined CD4 trajectory), separately with HAUD. RESULTS: Of the 4484 PLWH eligible individuals (3429 men, 1031 women and 24 transgender), we observed 425 patients with HSV-related HAUD. The mean log10viral load was higher in HAUD than HAUD-free groups, whereas the median nadir CD4 count (cells/uL) was higher in the non-cases than the case groups (p<0.05). HAUD were more frequent in women than men. Median CD4 (<200 cell/uL) was associated with HAUD (OR=2.1), but there were no significant associations with nadir CD4. Significant associations with declining and sustained low CD4 counts trajectory patterns were observed with HAUD. CONCLUSIONS: There were significant differences between men and women with incident HAUD among PLWH. EMR-based studies can provide innovative trajectory models that can potentially be helpful in guiding screening and clinical care of HAUD among high-risk PLWH.

6.
Nat Commun ; 11(1): 6417, 2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33339817

RESUMO

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10-8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD.


Assuntos
Doenças Cardiovasculares/genética , Genoma Humano , Mutação com Perda de Função/genética , Terapia de Alvo Molecular , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/sangue , Inativação Gênica , Marcação de Genes , Estudo de Associação Genômica Ampla , Humanos , Lipídeos/sangue , Fígado/metabolismo , Fenômica , Receptores de LDL/genética , Reino Unido
7.
Am J Clin Nutr ; 112(5): 1200-1211, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-32930325

RESUMO

BACKGROUND: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown. OBJECTIVES: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases. METHODS: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator. RESULTS: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with ß = 58.4 ± 7.27, P = 8.98 x 10-16 for CHO intake; ß = -36.4 ± 5.95, P = 9.96 x 10-10 for FAT intake; and ß = 3.30 ± 0.49, P = 1.48 x 10-11 for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases. CONCLUSIONS: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)-NCT01023750; and the Framingham Heart Study (FHS)-NCT00005121.

8.
Nat Genet ; 52(9): 969-983, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32839606

RESUMO

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce 'annotation principal components', multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Genoma/genética , LDL-Colesterol/genética , Simulação por Computador , Estudo de Associação Genômica Ampla/métodos , Humanos , Modelos Genéticos , Anotação de Sequência Molecular/métodos , Fenótipo , Sequenciamento Completo do Genoma/métodos
9.
Metabolites ; 10(7)2020 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-32664690

RESUMO

Advancements in high-throughput technologies have made it feasible to study thousands of biological pathways simultaneously for a holistic assessment of health and disease risk via 'omics platforms. A major challenge in 'omics research revolves around the reproducibility of findings-a feat that hinges upon balancing false-positive associations with generalizability. Given the foundational role of reproducibility in scientific inference, replication and validation of 'omics findings are cornerstones of this effort. In this narrative review, we define key terms relevant to replication and validation, present issues surrounding each concept with historical and contemporary examples from genomics (the most well-established and upstream 'omics), discuss special issues and unique considerations for replication and validation in metabolomics (an emerging field and most downstream 'omics for which best practices remain yet to be established), and make suggestions for future research leveraging multiple 'omics datasets.

10.
Cancers (Basel) ; 12(6)2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32604717

RESUMO

Among 29,701 Black and White participants aged 45 years and older in the Reasons forGeographic and Racial Difference in Stroke (REGARDS) study, allostatic load (AL) was defined asthe sum score of established baseline risk-associated biomarkers for which participants exceeded aset cutoff point. Cox proportional hazard regression was utilized to determine the association of ALscore with all-cause and cancer-specific mortality, with analyses stratified by body-mass index, agegroup, and race. At baseline, Blacks had a higher AL score compared with Whites (Black mean ALscore: 2.42, SD: 1.50; White mean AL score: 1.99, SD: 1.39; p < 0.001). Over the follow-up period,there were 4622 all-cause and 1237 cancer-specific deaths observed. Every unit increase in baselineAL score was associated with a 24% higher risk of all-cause (HR: 1.24, 95% CI: 1.22, 1.27) and a 7%higher risk of cancer-specific mortality (HR: 1.07, 95% CI: 1.03, 1.12). The association of AL withoverall- and cancer-specific mortality was similar among Blacks and Whites and across age-groups,however the risk of cancer-specific mortality was higher among normal BMI than overweight orobese participants. In conclusion, a higher baseline AL score was associated with increased risk ofall-cause and cancer-specific mortality among both Black and White participants. Targetedinterventions to patient groups with higher AL scores, regardless of race, may be beneficial as astrategy to reduce all-cause and cancer-specific mortality.

11.
Public Health Nutr ; : 1-12, 2020 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-32597744

RESUMO

OBJECTIVE: To characterise dietary habits, their temporal and spatial patterns and associations with BMI in the 23andMe study population. DESIGN: We present a large-scale cross-sectional analysis of self-reported dietary intake data derived from the web-based National Health and Nutrition Examination Survey 2009-2010 dietary screener. Survey-weighted estimates for each food item were characterised by age, sex, race/ethnicity, education and BMI. Temporal patterns were plotted over a 2-year time period, and average consumption for select food items was mapped by state. Finally, dietary intake variables were tested for association with BMI. SETTING: US-based adults 20-85 years of age participating in the 23andMe research programme. PARTICIPANTS: Participants were 23andMe customers who consented to participate in research (n 526 774) and completed web-based surveys on demographic and dietary habits. RESULTS: Survey-weighted estimates show very few participants met federal recommendations for fruit: 2·6 %, vegetables: 5·9 % and dairy intake: 2·8 %. Between 2017 and 2019, fruit, vegetables and milk intake frequency declined, while total dairy remained stable and added sugars increased. Seasonal patterns in reporting were most pronounced for ice cream, chocolate, fruits and vegetables. Dietary habits varied across the USA, with higher intake of sugar and energy dense foods characterising areas with higher average BMI. In multivariate-adjusted models, BMI was directly associated with the intake of processed meat, red meat, dairy and inversely associated with consumption of fruit, vegetables and whole grains. CONCLUSIONS: 23andMe research participants have created an opportunity for rapid, large-scale, real-time nutritional data collection, informing demographic, seasonal and spatial patterns with broad geographical coverage across the USA.

12.
Lipids Health Dis ; 19(1): 153, 2020 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-32586392

RESUMO

BACKGROUND: The lipoprotein insulin resistance (LPIR) score was shown to predict insulin resistance (IR) and type 2 diabetes (T2D) in healthy adults. However, the molecular basis underlying the LPIR utility for classification remains unclear. OBJECTIVE: To identify small molecule lipids associated with variation in the LPIR score, a weighted index of lipoproteins measured by nuclear magnetic resonance, in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 980). METHODS: Linear mixed effects models were used to test the association between the LPIR score and 413 lipid species and their principal component analysis-derived groups. Significant associations were tested for replication with homeostatic model assessment-IR (HOMA-IR), a phenotype correlated with the LPIR score (r = 0.48, p <  0.001), in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 590). RESULTS: In GOLDN, 319 lipids were associated with the LPIR score (false discovery rate-adjusted p-values ranging from 4.59 × 10- 161 to 49.50 × 10- 3). Factors 1 (triglycerides and diglycerides/storage lipids) and 3 (mixed lipids) were positively (ß = 0.025, p = 4.52 × 10- 71 and ß = 0.021, p = 5.84 × 10- 41, respectively) and factor 2 (phospholipids/non-storage lipids) was inversely (ß = - 0.013, p = 2.28 × 10- 18) associated with the LPIR score. These findings were replicated for HOMA-IR in the HAPI Heart Study (ß = 0.10, p = 1.21 × 10- 02 for storage, ß = - 0.13, p = 3.14 × 10- 04 for non-storage, and ß = 0.19, p = 8.40 × 10- 07 for mixed lipids). CONCLUSIONS: Non-storage lipidomics species show a significant inverse association with the LPIR metabolic dysfunction score and present a promising focus for future therapeutic and prevention studies.

13.
Sex Transm Dis ; 47(9): 628-633, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32530855

RESUMO

BACKGROUND: It is unclear how the characteristics of CD4 counts predict non-AIDS-defining human papillomavirus-related anogenital warts (AGWs) and anal high-grade squamous intraepithelial lesions/cancer (HSIL) in people living with HIV infection-1 (PLWH). We compared the associations between 3 CD4 counts measures and these disease outcomes in the study. METHODS: Retrospective sociobehavioral and clinical data from electronic health records of 4803 PLWH from 2006 to 2018 were included. Three different measurements of CD4 counts-(a) nadir, (b) median, and (c) trajectory-were estimated. Six CD4 trajectory groups were constructed using the group-based trajectory modeling from all patients older than 18 years with ≥3 clinical visits. Univariate and multivariable logistic regression models were used to assess the associations with AGW and HSIL, separately. RESULTS: A total of 408 AGW, 102 anal HSIL (43 HSIL, 59 cancer), 4 penile cancer, and 15 vaginal cancer cases were observed. Median CD4 (<200 cell/µL) was associated with AGW (odds ratio [OR], 2.2 [95% confidence interval {CI}, 1.6-3.0]), and anal HSIL (OR, 2.7 [95% CI, 1.5-5.0]; each, P < 0.001). Low nadir CD4 (<200 cell/µL) was associated with AGW (OR, 1.8 [95% CI, 1.3-2.6]) and anal HSIL (OR, 2.4 [95% CI, 1.2-4.7]; each, P ≤ 0.001). Different patterns (declining and sustained low CD4 counts) of CD4 trajectories showed the strongest associations with onset of both AGW (OR, 1.8-3.1) and HSIL (OR, 2.7-6.7). CONCLUSIONS: People living with HIV infection-1 with the same median CD4 could have very different CD4 trajectories, implying different dynamics of immune status. CD4 trajectory could be a better predictor of incident AGW and HSIL among PLWH.

14.
Circ Genom Precis Med ; 13(4): e002766, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32525743

RESUMO

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied. METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P<1.6×10-3). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (P=5.7×10-15). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (P<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR P<4.5×10-4). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR, P=1.5×10-14).and hypermethylation of cg02079413 (SNORA54; NAP1L4) was associated with body mass index (corrected MR, P=1×10-6). CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.

15.
BMC Infect Dis ; 20(1): 144, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059635

RESUMO

BACKGROUND: The southeastern US is an epicenter for incident HIV in the US with high prevalence of human papillomavirus (HPV) co-infections. However, epidemiologies of HPV-associated clinical conditions (CC) among people living with HIV-1 infection (PLWH) are not fully known. METHODS: Electronic medical records (EMR) of PLWH attending one of the leading HIV clinics in the southeastern US between 2006 and 2018 were reviewed and analyzed. The retrospective study was nested within the University of Alabama at Birmingham HIV clinical cohort, which has electronically collected over 7000 PLWH's clinical and sociobehavioral data since 1999. Incidence rates of HPV-related CC including anogenital warts, penile, anal, cervical, and vaginal/vulvar low- and high-grade squamous intraepithelial lesions (LSIL and HSIL) were estimated per 10,000 person years. Joinpoint regressions were performed to examine temporal changes in the trends of incident CC. All rates and trends were stratified by gender and race. RESULTS: Of the 4484 PLWH included in the study (3429 men, 1031 women, and 24 transgender), we observed 1038 patients with HPV-related CC. The median nadir CD4 count (cells/uL) was higher in the HPV-condition free group than the case groups (P < 0.0001). Anogenital warts, anal LSIL, HSIL, and cancer were more likely to be diagnosed among HIV-infected men than women. White men presented more frequently with anal LSIL and anal and penile cancers than black men (P < 0.03). White women were also more likely to be diagnosed with cervical HSIL (P = 0.023) and cancer (P = 0.037) than black women. CONCLUSIONS: There were significant differences between gender and race with incidence of HPV-related CC among HIV patients. EMR-based studies provide insights on understudied HPV-related anogenital conditions in PLWH; however, large-scale studies in other regions are needed to generalize current findings and draw public health attention to co-infection induced non-AIDS defining comorbidities among PLWH.


Assuntos
Infecções por HIV/epidemiologia , Infecções por Papillomavirus/epidemiologia , Adulto , Afro-Americanos/estatística & dados numéricos , Canal Anal/virologia , Contagem de Linfócito CD4 , Estudos de Coortes , Comorbidade , Condiloma Acuminado/epidemiologia , Condiloma Acuminado/virologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Infecções por HIV/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/patologia , Prevalência , Estudos Retrospectivos , Sudeste dos Estados Unidos/epidemiologia
16.
Pediatr Diabetes ; 21(1): 40-47, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31591761

RESUMO

OBJECTIVE: The incidence of type 1 diabetes has increased in the United States and worldwide. We hypothesized that trends in the annual incidence rates of childhood-onset type 1 diabetes in the state of Alabama would be different by race and sex. METHODS: We performed a retrospective observational cohort study, analyzing children with type 1 diabetes (n = 3770) managed at the Children's Hospital of Alabama between 2000 and 2017. We compared crude incidence rates using negative binomial regression models and analyzed differences in annual trends of age-adjusted incidence by race and sex using joinpoint regression. RESULTS: The crude type 1 diabetes incidence rate was estimated at 16.7 per 100 000 children <19 years of age in Alabama. Between 2000 and 2007, there was an increase in age-adjusted incidence of type 1 diabetes with an annual percent change (APC) of 10% from 2000 to 2007 and a 1.7% APC decrease from 2007 to 2017. The age-adjusted incidence for Whites and Blacks increased with an average annual percentage change (AAPC) of 4.4% and 2.8%, respectively. A nearly 11% increasing trend in age-adjusted incidence was observed for both races, though the increase plateaued in 2006 for Whites and 2010 for Blacks. CONCLUSIONS: Following significantly increasing annual trends for both races, the age-adjusted rate remained statistically stable for Whites and decreased significantly for Blacks. Longer-sustained trend increases for Blacks resulted in type 1 diabetes incidence tripling compared to the doubling of the rate for Whites.

17.
Med Sci Sports Exerc ; 52(3): 589-597, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31652233

RESUMO

INTRODUCTION: DNA methylation may be one of the biological mechanisms underlying the health benefits of physical activity (PA). Our objective was to determine the association between PA and genome-wide DNA methylation at CpG level. METHODS: We designed a two-stage epigenome wide association study. In the discovery stage, we used 619 individuals from the REgistre GIroní del COR cohort. Next, we validated the CpG suggestively associated with PA (P < 10) in two independent populations (n = 1735 and 190, respectively). Physical activity was assessed with validated questionnaires and classified as light PA (LPA), moderate PA, vigorous PA, moderate-vigorous PA (MVPA) and total PA. We examined linear and nonlinear associations and meta-analyzed the results in the three populations. The linear associations were meta-analyzed with a fixed-effects model and the P values of the nonlinear associations with the Stouffer and Fisher methods. We established a P value threshold that fulfilled Bonferroni criteria over the number of CpG analyzed (0.05/421,940 = 1.185 × 10). RESULTS: In the meta-analyses, two CpG sites had a statistically significant nonlinear association with MVPA. cg24155427 (P = 1.19 × 10), located in an intergenic region in chromosome 1, has been previously associated with smoking, lupus, and aging. cg09565397 (P = 1.59 × 10), located within DGAT1 in chromosome 8, which encodes an enzyme involved in triacylglycerol synthesis. CONCLUSIONS: This population-based study identified two new, differentially methylated CpG sites with a nonlinear dose-response relationship to MVPA. These associations must be additionally validated and may be considered for further research on the biological mechanisms underlying health benefits of PA.


Assuntos
Ilhas de CpG/fisiologia , Metilação de DNA/fisiologia , Exercício Físico/fisiologia , Estudo de Associação Genômica Ampla , Humanos
18.
Nat Commun ; 10(1): 5121, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719535

RESUMO

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.


Assuntos
Loci Gênicos , Lipídeos/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Sono/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Epigenomics ; 11(13): 1487-1500, 2019 10.
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.


Assuntos
Metilação de DNA , Epigenômica/métodos , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar Tabaco/genética , Adulto , Estudos de Coortes , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Exposição Materna/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fumar Tabaco/epidemiologia
20.
Mol Genet Genomic Med ; 7(10): e00788, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31407531

RESUMO

BACKGROUND: Left ventricular (LV) hypertrophy affects up to 43% of African Americans (AAs). Antihypertensive treatment reduces LV mass (LVM). However, interindividual variation in LV traits in response to antihypertensive treatments exists. We hypothesized that genetic variants may modify the association of antihypertensive treatment class with LV traits measured by echocardiography. METHODS: We evaluated the main effects of the three most common antihypertensive treatments for AAs as well as the single nucleotide polymorphism (SNP)-by-drug interaction on LVM and relative wall thickness (RWT) in 2,068 participants across five community-based cohorts. Treatments included thiazide diuretics (TDs), angiotensin converting enzyme inhibitors (ACE-Is), and dihydropyridine calcium channel blockers (dCCBs) and were compared in a pairwise manner. We performed fixed effects inverse variance weighted meta-analyses of main effects of drugs and 2.5 million SNP-by-drug interaction estimates. RESULTS: We observed that dCCBs versus TDs were associated with higher LVM after adjusting for covariates (p = 0.001). We report three SNPs at a single locus on chromosome 20 that modified the association between RWT and treatment when comparing dCCBs to ACE-Is with consistent effects across cohorts (smallest p = 4.7 × 10-8 , minor allele frequency range 0.09-0.12). This locus has been linked to LV hypertrophy in a previous study. A marginally significant locus in BICD1 (rs326641) was validated in an external population. CONCLUSIONS: Our study identified one locus having genome-wide significant SNP-by-drug interaction effect on RWT among dCCB users in comparison to ACE-I users. Upon additional validation in future studies, our findings can enhance the precision of medical approaches in hypertension treatment.


Assuntos
Anti-Hipertensivos/uso terapêutico , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Disfunção Ventricular Esquerda/genética , Afro-Americanos/genética , Afro-Americanos/estatística & dados numéricos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Humanos , Estudos Observacionais como Assunto , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/epidemiologia
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