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1.
Environ Res ; 212(Pt C): 113360, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35500859

RESUMO

Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (PCochran's Q > 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Ozônio , Adulto , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/análise , Metilação de DNA , Epigenoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dióxido de Nitrogênio/análise , Ozônio/análise , Ozônio/toxicidade , Material Particulado/análise
2.
Front Endocrinol (Lausanne) ; 13: 863893, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35592775

RESUMO

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, P obesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, P extremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, P obesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, P extremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.


Assuntos
Estudo de Associação Genômica Ampla , Obesidade , Frequência do Gene , Variação Genética , Humanos , Obesidade/epidemiologia , Obesidade/genética , Sequenciamento Completo do Genoma
3.
Am J Respir Crit Care Med ; 206(3): 321-336, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35536696

RESUMO

Rationale: Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. Measurements and Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.


Assuntos
Metilação de DNA , Epigenoma , Ilhas de CpG , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Pulmão
4.
Am J Epidemiol ; 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35467716

RESUMO

Growth in early infancy is hypothesized to affect chronic disease risk factors later in life. To date, most reports draw on European ancestry cohorts with few repeated observations in early infancy. We investigated the association between infant growth before six months and lipid levels in adolescents in a Hispanic/Latino cohort. We characterized infant growth from birth to five months in males (n=311) and females (n=285) from the Santiago Longitudinal Study (1991-1996) using three metrics: weight (kg), length (cm) and weight-for-length (WFL) (g/cm). SuperImposition by Translation and Rotation (SITAR) and latent growth mixture models (LGMM) were used to estimate the association between infant growth characteristics and lipid levels at 17 years. We found a positive relationship between the SITAR length velocity parameter before six months of age and high-density lipoprotein cholesterol levels in adolescence (11.5, standard error=4.1) indicating higher high-density lipoprotein cholesterol levels occurring with faster length growth. The strongest associations from the LGMM models were between higher low-density lipoprotein cholesterol and slower WFL growth, following a pattern of associations between slower growth and adverse lipid profiles. Further research in this window of time can confirm the association between early infant growth as an exposure and adolescent cardiovascular disease risk factors.

5.
HGG Adv ; 3(2): 100099, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35399580

RESUMO

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite their notable anthropometric variability, ancestry proportions, and high burden of growth stunting and overweight/obesity. To address this knowledge gap, we analyzed densely imputed genetic data in a sample of Hispanic/Latino adults to identify and fine-map genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (stage 1, n = 59,771) and generalized our findings in 9 additional studies (stage 2, n = 10,538). We conducted a trans-ancestral GWAS with summary statistics from HISLA stage 1 and existing consortia of European and African ancestries. In our HISLA stage 1 + 2 analyses, we discovered one BMI locus, as well as two BMI signals and another height signal each within established anthropometric loci. In our trans-ancestral meta-analysis, we discovered three BMI loci, one height locus, and one WHRadjBMI locus. We also identified 3 secondary signals for BMI, 28 for height, and 2 for WHRadjBMI in established loci. We show that 336 known BMI, 1,177 known height, and 143 known WHRadjBMI (combined) SNPs demonstrated suggestive transferability (nominal significance and effect estimate directional consistency) in Hispanic/Latino adults. Of these, 36 BMI, 124 height, and 11 WHRadjBMI SNPs were significant after trait-specific Bonferroni correction. Trans-ancestral meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our findings demonstrate that future studies may also benefit from leveraging diverse ancestries and differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

6.
Dis Esophagus ; 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35265973

RESUMO

Eosinophilic Esophagitis (EoE) is an esophageal allergic inflammatory disorder triggered by food proteins. Symptoms of EoE are variable within and between individuals. Presenting symptoms may include dysphagia, food bolus impaction, dyspepsia, or more subtle symptoms such as feeding disorders, regurgitation sensation, or nausea. The development and validation of a pediatric EoE patient self-reported and parent proxy-reported outcome symptom scoring tool was created by Franciosi et al. published in BMJ 2011, titled the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS™ v2.0). To date, its use is largely for research purposes. We propose to evaluate the implementation of the PEESS™ v2.0 in a prospective interventional controlled clinical practice. The study included 620 patients over an 18-month period. Surveys were delivered and administered digitally every month through the MyGeisinger.org Patient Portal. Our analysis demonstrated symptom severity and symptom frequency scores significantly improved over time. However, counter to our hypothesis, patients who completed the PEESS™v2.0 ultimately had higher EoE-related health care utilization of office visits and endoscopies compared with those who did not complete the PEESS™v2.0. This could be related to greater awareness of disease activity and/or increased willingness to seek care. Our study, in the context of mobile health tool and patient-reported outcome trends, represents an opportunity for improved disease monitoring at-home within the field of eosinophilic gastrointestinal diseases.

7.
Nat Genet ; 54(4): 382-392, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35241825

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human host cells via angiotensin-converting enzyme 2 (ACE2) and causes coronavirus disease 2019 (COVID-19). Here, through a genome-wide association study, we identify a variant (rs190509934, minor allele frequency 0.2-2%) that downregulates ACE2 expression by 37% (P = 2.7 × 10-8) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P = 4.5 × 10-13), providing human genetic evidence that ACE2 expression levels influence COVID-19 risk. We also replicate the associations of six previously reported risk variants, of which four were further associated with worse outcomes in individuals infected with the virus (in/near LZTFL1, MHC, DPP9 and IFNAR2). Lastly, we show that common variants define a risk score that is strongly associated with severe disease among cases and modestly improves the prediction of disease severity relative to demographic and clinical factors alone.


Assuntos
COVID-19 , Enzima de Conversão de Angiotensina 2/genética , COVID-19/genética , Estudo de Associação Genômica Ampla , Humanos , Fatores de Risco , SARS-CoV-2/genética
8.
Am J Hum Genet ; 109(4): 669-679, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-35263625

RESUMO

One mechanism by which genetic factors influence complex traits and diseases is altering gene expression. Direct measurement of gene expression in relevant tissues is rarely tenable; however, genetically regulated gene expression (GReX) can be estimated using prediction models derived from large multi-omic datasets. These approaches have led to the discovery of many gene-trait associations, but whether models derived from predominantly European ancestry (EA) reference panels can map novel associations in ancestrally diverse populations remains unclear. We applied PrediXcan to impute GReX in 51,520 ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) participants (35% African American, 45% Hispanic/Latino, 10% Asian, and 7% Hawaiian) across 25 key cardiometabolic traits and relevant tissues to identify 102 novel associations. We then compared associations in PAGE to those in a random subset of 50,000 White British participants from UK Biobank (UKBB50k) for height and body mass index (BMI). We identified 517 associations across 47 tissues in PAGE but not UKBB50k, demonstrating the importance of diverse samples in identifying trait-associated GReX. We observed that variants used in PrediXcan models were either more or less differentiated across continental-level populations than matched-control variants depending on the specific population reflecting sampling bias. Additionally, variants from identified genes specific to either PAGE or UKBB50k analyses were more ancestrally differentiated than those in genes detected in both analyses, underlining the value of population-specific discoveries. This suggests that while EA-derived transcriptome imputation models can identify new associations in non-EA populations, models derived from closely matched reference panels may yield further insights. Our findings call for more diversity in reference datasets of tissue-specific gene expression.


Assuntos
Doenças Cardiovasculares , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença , Humanos , Estilo de Vida , Polimorfismo de Nucleotídeo Único , Transcriptoma
9.
Nutr Metab Cardiovasc Dis ; 32(4): 1055-1063, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35181188

RESUMO

BACKGROUND AND AIMS: Adipose tissue secretes adipokines such as adiponectin and leptin, playing important roles in energy metabolism. The longitudinal associations between such adipokines and body fat accumulation have not been established, especially during adolescence and young adulthood and in diverse populations. The study aims to assess the longitudinal association between body fat measured with dual X-ray absorptiometry and plasma adipokines from adolescence to young adulthood. METHODS AND RESULTS: Among Hispanic/Latino participants (N = 537) aged 16.8 (SD: 0.3) years of the Santiago Longitudinal Study, we implemented structural equation modeling to estimate the sex-specific associations between adiposity (body fat percent (BF%) and proportion of trunk fat (PTF)) and adipokines (adiponectin and leptin levels) during adolescence (16 y) and these values after 6 years of follow-up (22 y). In addition, we further investigated whether the associations differed by baseline insulin resistance (IR) status. We found evidence for associations between 16 y BF% and 22 y leptin levels (ß (SE): 0.58 (0.06) for females; 0.53 (0.05) for males), between 16 y PTF and 22 y adiponectin levels (ß (SE): -0.31 (0.06) for females; -0.18 (0.06) for males) and between 16 y adiponectin levels and 22 y BF% (ß (SE): 0.12 (0.04) for both females and males). CONCLUSION: We observed dynamic relationships between adiposity and adipokines levels from late adolescence to young adulthood in a Hispanic/Latino population further demonstrating the importance of this period of the life course in the development of obesity.


Assuntos
Adipocinas , Leptina , Adiponectina , Tecido Adiposo/diagnóstico por imagem , Tecido Adiposo/metabolismo , Adiposidade , Adolescente , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino , Obesidade/epidemiologia , Adulto Jovem
10.
Clin Epigenetics ; 13(1): 230, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34937574

RESUMO

BACKGROUND: Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health. RESULTS: The discovery study population was derived from three Women's Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation ß values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm ß value, the risk of incident CHD increased by 9% in one site and decreased by 6-10% in two sites over 25 years. CONCLUSIONS: Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.


Assuntos
Índice de Massa Corporal , Doenças Cardiovasculares/genética , Doenças Metabólicas/complicações , Idoso , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Metilação de DNA/genética , Metilação de DNA/fisiologia , Feminino , Humanos , Masculino , Doenças Metabólicas/genética , Pessoa de Meia-Idade
11.
Pediatr Res ; 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645953

RESUMO

BACKGROUND: Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). This study aims to investigate the genetic determinants of metabolic biomarkers-adiponectin, leptin, ghrelin, and orexin-and their associations with CMD risk factors. METHODS: We characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling. RESULTS: We identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels. CONCLUSIONS: The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers. IMPACT: This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents. Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts. Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.

12.
Circ Genom Precis Med ; 14(4): e003354, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34282949

RESUMO

BACKGROUND: Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry. METHODS: We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization-phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants. RESULTS: In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA-odds ratio and 95% CI for coronary heart disease 1.28 (1.16-1.41); cerebrovascular disease 1.14 (1.07-1.21); peripheral artery disease 1.22 (1.11-1.34); abdominal aortic aneurysm 1.28 (1.17-1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99-1.24) and cerebrovascular disease 1.06 (0.99-1.14) but similar for peripheral artery disease 1.16 (1.01-1.33) and abdominal aortic aneurysm 1.34 (1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10-1.62), mitral valve disorders 1.18 (1.09-1.27), congestive heart failure 1.12 (1.05-1.19), and chronic kidney disease 1.07 (1.01-1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94-1.25), mitral valve disorders 1.02 (0.89-1.16), congestive heart failure 1.02 (0.95-1.10), or chronic kidney disease 1.05 (0.99-1.12). Mendelian randomization-phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. CONCLUSIONS: Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.


Assuntos
Negros/genética , Doenças Cardiovasculares/genética , Predisposição Genética para Doença , Lipoproteína(a)/genética , Característica Quantitativa Herdável , Brancos/genética , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Reino Unido
13.
Am J Hum Genet ; 108(7): 1350-1355, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34115965

RESUMO

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome wide or when specifically focusing on (1) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19, (2) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative, or (3) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, and results are publicly available through the Regeneron Genetics Center COVID-19 Results Browser.


Assuntos
COVID-19/diagnóstico , COVID-19/genética , Exoma/genética , Predisposição Genética para Doença , Hospitalização/estatística & dados numéricos , Sequenciamento Completo do Exoma , COVID-19/imunologia , COVID-19/terapia , Feminino , Humanos , Interferons/genética , Masculino , Prognóstico , SARS-CoV-2 , Tamanho da Amostra
14.
Hum Mol Genet ; 30(22): 2190-2204, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34165540

RESUMO

Central obesity is a leading health concern with a great burden carried by ethnic minority populations, especially Hispanics/Latinos. Genetic factors contribute to the obesity burden overall and to inter-population differences. We aimed to identify the loci associated with central adiposity measured as waist-to-hip ratio (WHR), waist circumference (WC) and hip circumference (HIP) adjusted for body mass index (adjBMI) by using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL); determine if differences in associations differ by background group within HCHS/SOL and determine whether previously reported associations generalize to HCHS/SOL. Our analyses included 7472 women and 5200 men of mainland (Mexican, Central and South American) and Caribbean (Puerto Rican, Cuban and Dominican) background residing in the USA. We performed genome-wide association analyses stratified and combined across sexes using linear mixed-model regression. We identified 16 variants for waist-to-hip ratio adjusted for body mass index (WHRadjBMI), 22 for waist circumference adjusted for body mass index (WCadjBMI) and 28 for hip circumference adjusted for body mass index (HIPadjBMI), which reached suggestive significance (P < 1 × 10-6). Many loci exhibited differences in strength of associations by ethnic background and sex. We brought a total of 66 variants forward for validation in cohorts (N = 34 161) with participants of Hispanic/Latino, African and European descent. We confirmed four novel loci (P < 0.05 and consistent direction of effect, and P < 5 × 10-8 after meta-analysis), including two for WHRadjBMI (rs13301996, rs79478137); one for WCadjBMI (rs3168072) and one for HIPadjBMI (rs28692724). Also, we generalized previously reported associations to HCHS/SOL, (8 for WHRadjBMI, 10 for WCadjBMI and 12 for HIPadjBMI). Our study highlights the importance of large-scale genomic studies in ancestrally diverse Hispanic/Latino populations for identifying and characterizing central obesity susceptibility that may be ancestry-specific.


Assuntos
Adiposidade/genética , Distribuição da Gordura Corporal , Estudo de Associação Genômica Ampla , Característica Quantitativa Herdável , Alelos , Humanos , Polimorfismo de Nucleotídeo Único
15.
Environ Res ; 198: 111211, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33895111

RESUMO

BACKGROUND: Short-duration exposure to ambient particulate matter (PM) air pollution is associated with cardiac autonomic dysfunction and prolonged ventricular repolarization. However, associations with sub-chronic exposures to coarser particulates are relatively poorly characterized as are molecular mechanisms underlying their potential relationships with cardiovascular disease. MATERIALS AND METHODS: We estimated associations between monthly mean concentrations of PM < 10 µm and 2.5-10 µm in diameter (PM10; PM2.5-10) with time-domain measures of heart rate variability (HRV) and QT interval duration (QT) among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities Study (nHRV = 82,107; nQT = 76,711). Then we examined mediation of the PM-HRV and PM-QT associations by DNA methylation (DNAm) at three Cytosine-phosphate-Guanine (CpG) sites (cg19004594, cg24102420, cg12124767) with known sensitivity to monthly mean PM concentrations in a subset of the participants (nHRV = 7,169; nQT = 6,895). After multiply imputing missing PM, electrocardiographic and covariable data, we estimated associations using attrition-weighted, linear, mixed, longitudinal models adjusting for sociodemographic, behavioral, meteorological, and clinical characteristics. We assessed mediation by estimating the proportions of PM-HRV and PM-QT associations mediated by DNAm. RESULTS: We found little evidence of PM-HRV association, PM-QT association, or mediation by DNAm. CONCLUSIONS: The findings suggest that among racially/ethnically and environmentally diverse U.S. populations, sub-chronic exposures to coarser particulates may not exert appreciable, epigenetically mediated effects on cardiac autonomic function or ventricular repolarization. Further investigation in better-powered studies is warranted, with additional focus on shorter duration exposures to finer particulates and non-electrocardiographic outcomes among relatively susceptible populations.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Aterosclerose , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Aterosclerose/induzido quimicamente , Aterosclerose/epidemiologia , Aterosclerose/genética , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Feminino , Humanos , Masculino , Material Particulado/análise , Material Particulado/toxicidade , Saúde da Mulher
16.
Am J Hum Genet ; 108(4): 564-582, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33713608

RESUMO

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.


Assuntos
/genética , Estatura/genética , Estudo de Associação Genômica Ampla , África/etnologia , Afro-Americanos/genética , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
17.
Nat Med ; 27(1): 66-72, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33432171

RESUMO

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10-6), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.


Assuntos
Registros Eletrônicos de Saúde , Exoma , Genótipo , Fenótipo , Idoso , Biologia Computacional , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
18.
Pediatr Obes ; 16(7): e12765, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33381925

RESUMO

BACKGROUND: The genetic underpinnings of glycemic traits have been understudied in adolescent and Hispanic/Latino (H/L) populations in comparison to adults and populations of European ancestry. OBJECTIVE: To identify genetic factors underlying glycemic traits in an adolescent H/L population. METHODS: We conducted a genome-wide association study (GWAS) of fasting glucose (FG) and fasting insulin (FI) in H/L adolescents from the Santiago Longitudinal Study. RESULTS: We identified one novel variant positioned in the CSMD1 gene on chromosome 8 (rs77465890, effect allele frequency = 0.10) that was associated with FI (ß = -0.299, SE = 0.054, p = 2.72×10-8 ) and was only slightly attenuated after adjusting for body mass index z-scores (ß = -0.252, SE = 0.047, p = 1.03×10-7 ). We demonstrated directionally consistent, but not statistically significant results in African and Hispanic adults of the Population Architecture Using Genomics and Epidemiology Consortium. We also identified secondary signals for two FG loci after conditioning on known variants, which demonstrate allelic heterogeneity in well-known glucose loci. CONCLUSION: Our results exemplify the importance of including populations with diverse ancestral origin and adolescent participants in GWAS of glycemic traits to uncover novel risk loci and expand our understanding of disease aetiology.


Assuntos
Estudo de Associação Genômica Ampla , Insulina , Adolescente , Glicemia , Chile , Jejum , Frequência do Gene , Humanos , Insulina/sangue , Estudos Longitudinais , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas Supressoras de Tumor/genética
19.
PLoS One ; 15(11): e0242182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33180868

RESUMO

BACKGROUND: Empirical data on conditions that increase risk of coronavirus disease 2019 (COVID-19) progression are needed to identify high risk individuals. We performed a comprehensive quantitative assessment of pre-existing clinical phenotypes associated with COVID-19-related hospitalization. METHODS: Phenome-wide association study (PheWAS) of SARS-CoV-2-positive patients from an integrated health system (Geisinger) with system-level outpatient/inpatient COVID-19 testing capacity and retrospective electronic health record (EHR) data to assess pre-COVID-19 pandemic clinical phenotypes associated with hospital admission (hospitalization). RESULTS: Of 12,971 individuals tested for SARS-CoV-2 with sufficient pre-COVID-19 pandemic EHR data at Geisinger, 1604 were SARS-CoV-2 positive and 354 required hospitalization. We identified 21 clinical phenotypes in 5 disease categories meeting phenome-wide significance (P<1.60x10-4), including: six kidney phenotypes, e.g. end stage renal disease or stage 5 CKD (OR = 11.07, p = 1.96x10-8), six cardiovascular phenotypes, e.g. congestive heart failure (OR = 3.8, p = 3.24x10-5), five respiratory phenotypes, e.g. chronic airway obstruction (OR = 2.54, p = 3.71x10-5), and three metabolic phenotypes, e.g. type 2 diabetes (OR = 1.80, p = 7.51x10-5). Additional analyses defining CKD based on estimated glomerular filtration rate, confirmed high risk of hospitalization associated with pre-existing stage 4 CKD (OR 2.90, 95% CI: 1.47, 5.74), stage 5 CKD/dialysis (OR 8.83, 95% CI: 2.76, 28.27), and kidney transplant (OR 14.98, 95% CI: 2.77, 80.8) but not stage 3 CKD (OR 1.03, 95% CI: 0.71, 1.48). CONCLUSIONS: This study provides quantitative estimates of the contribution of pre-existing clinical phenotypes to COVID-19 hospitalization and highlights kidney disorders as the strongest factors associated with hospitalization in an integrated US healthcare system.


Assuntos
Infecções por Coronavirus/epidemiologia , Hospitalização/estatística & dados numéricos , Nefropatias/epidemiologia , Pneumonia Viral/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Registros Eletrônicos de Saúde , Feminino , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pennsylvania/epidemiologia , Diálise Renal , Insuficiência Renal Crônica/epidemiologia , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2
20.
Epigenomics ; 12(17): 1483-1499, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32901515

RESUMO

Aim: We conducted a methylome-wide association study to examine associations between DNA methylation in whole blood and central adiposity and body fat distribution, measured as waist circumference, waist-to-hip ratio and waist-to-height ratio adjusted for body mass index, in 2684 African-American adults in the Atherosclerosis Risk in Communities study. Materials & methods: We validated significantly associated cytosine-phosphate-guanine methylation sites (CpGs) among adults using the Women's Health Initiative and Framingham Heart Study participants (combined n = 5743) and generalized associations in adolescents from The Raine Study (n = 820). Results & conclusion: We identified 11 CpGs that were robustly associated with one or more central adiposity trait in adults and two in adolescents, including CpG site associations near TXNIP, ADCY7, SREBF1 and RAP1GAP2 that had not previously been associated with obesity-related traits.


Assuntos
Adiposidade/genética , Metilação de DNA , Sistema Endócrino/metabolismo , Epigênese Genética , Epigenômica , Sistema Imunitário/metabolismo , Estudos de Coortes , Ilhas de CpG , Suscetibilidade a Doenças , Epigenômica/métodos , Estudo de Associação Genômica Ampla , Humanos , Obesidade/genética , Obesidade/metabolismo
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