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1.
Artigo em Inglês | MEDLINE | ID: mdl-36087113

RESUMO

BACKGROUND: In response to the COVID-19 pandemic, public health measures, including stay-at-home orders, were widely instituted in the United States (US) by March 2020. However, few studies have evaluated the impact of these measures on continuity of care among older adults living with chronic diseases. METHODS: Beginning in June 2020, participants of the national Women's Health Initiative (WHI) (N=64,061) were surveyed on the impact of the pandemic on various aspects of their health and well-being since March 2020, including access to care appointments, medications, and caregivers. Responses received by November 2020 (response rate=77.6%) were tabulated and stratified by prevalent chronic diseases, including hypertension, type 2 diabetes, and cardiovascular disease (CVD). RESULTS: Among 49,695 respondents (mean age=83.6 years), 70.2% had a history of hypertension, 21.8% had diabetes, and 18.9% had CVD. Half of respondents reported being very concerned about the pandemic and 24.5% decided against seeking medical care to avoid COVID-19 exposure. A quarter reported difficulties with getting routine care and 45.5% had in-person appointments converted to telemedicine formats; many reported cancelled (27.8%) or rescheduled (37.7%) appointments. Among those taking prescribed medication (88.0%), 9.7% reported changing their method of obtaining medications. Those living with and without chronic diseases generally reported similar changes in care and medication access. CONCLUSIONS: Early in the pandemic, many older women avoided medical care or adapted to new ways of receiving care and medications. Therefore, optimizing alternative services, like telemedicine, should be prioritized to ensure that older women continue to receive quality care during public health emergencies.

3.
Kidney Int ; 2022 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-35853479

RESUMO

Dyslipidemia associates with and usually precedes the onset of chronic kidney disease (CKD), but a comprehensive assessment of molecular lipid species associated with risk of CKD is lacking. Here, we sought to identify fasting plasma lipids associated with risk of CKD among American Indians in the Strong Heart Family Study, a large-scale community-dwelling of individuals, followed by replication in Mexican Americans from the San Antonio Family Heart Study and Caucasians from the Australian Diabetes, Obesity and Lifestyle Study. We also performed repeated measurement analysis to examine the temporal relationship between the change in the lipidome and change in kidney function between baseline and follow-up of about five years apart. Network analysis was conducted to identify differential lipid classes associated with risk of CKD. In the discovery cohort, we found that higher baseline level of multiple lipid species, including glycerophospholipids, glycerolipids and sphingolipids, was significantly associated with increased risk of CKD, independent of age, sex, body mass index, diabetes and hypertension. Many lipid species were replicated in at least one external cohort at the individual lipid species and/or the class level. Longitudinal change in the plasma lipidome was significantly associated with change in the estimated glomerular filtration rate after adjusting for covariates, baseline lipids and the baseline rate. Network analysis identified distinct lipidomic signatures differentiating high from low-risk groups. Thus, our results demonstrated that disturbed lipid metabolism precedes the onset of CKD. These findings shed light on the mechanisms linking dyslipidemia to CKD and provide potential novel biomarkers for identifying individuals with early impaired kidney function at preclinical stages.

4.
Genome Med ; 14(1): 71, 2022 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794667

RESUMO

Here, we report a lack of diversity in epigenome-wide association studies (EWAS) and DNA methylation (DNAm) data, discuss current challenges, and propose solutions for EWAS and DNAm research in diverse populations. The strategies we propose include fostering community involvement, new data generation, and cost-effective approaches such as locus-specific analysis and ancestry variable region analysis.


Assuntos
Epigênese Genética , Epigenoma , Metilação de DNA , Humanos
5.
Blood Press ; 31(1): 155-163, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35762607

RESUMO

PURPOSE: The current study examined the effects of chronic stress and a genetic risk score on the presence of hypertension and elevated systolic blood pressure and diastolic blood pressure among Hispanics/Latinos in the target population of Hispanic Community Health Study/Study of Latinos. MATERIALS AND METHODS: Of the participants (N = 11,623) assessed during two clinic visits (Visit 1 2008-2013 & Visit 2 2014-2018), we analysed data from 7,429 adults (50.4% female), aged 18-74, who were genotyped and responded to chronic stress questionnaires. We calculated an unweighted genetic risk score using blood pressure increasing single nucleotide polymorphisms (SNPs) found to be generalisable to Hispanics/Latinos (10 SNPs). Linear and logistic regression models were used to estimate associations between chronic stress and genetic risk score and their interaction, with prevalent Visit 2 SBP or DBP, and hypertension, respectively. Models accounted for sampling weights, stratification, and cluster design. RESULTS: Chronic stress (adjusted OR = 1.18, 95%CI:1.15,1.22) and hypertension genetic risk score (adjusted OR = 1.04, 95%CI:1.01,1.07) were significantly associated with prevalent hypertension, but there was no significant interaction between the chronic stress and genetic risk score on hypertension (p = .49). genetic risk score (b = .32, 95%CI:.08, .55, R2 = .02) and chronic stress (b = .45, 95%CI:.19, .72, R2 = .11) were related to DBP, with no significant interaction (p = .62). Genetic risk score (b = .42, 95%CI:.08, .76, R2 = .01) and chronic stress (b = .80, 95%CI:.34,1.26, R2 = .11) were also related to SBP, with no significant interaction (p = .51). CONCLUSION: Results demonstrate the utility of a genetic risk score for blood pressure and are consistent with literature suggesting chronic stress has a strong, direct association with elevated blood pressure among U.S. Hispanics/Latinos.


Assuntos
Hipertensão , Saúde Pública , Adulto , Feminino , Hispânico ou Latino/genética , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Masculino , Prevalência , Fatores de Risco
6.
Hypertension ; 79(8): 1656-1667, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35652341

RESUMO

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5×10-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P=4.99×10-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P=4.18×10-7) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P=7.28×10-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1×10-6 and P<1×10-4, respectively). DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.


Assuntos
Hipertensão , Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Medicina de Precisão
7.
Kidney Int ; 102(3): 492-505, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35690124

RESUMO

Hypertension is a major cardiovascular disease risk factor and contributor to premature death globally. Family-based investigations confirmed a significant heritable component of blood pressure (BP), whereas genome-wide association studies revealed >1000 common and rare genetic variants associated with BP and/or hypertension. The kidney is not only an organ of key relevance to BP regulation and the development of hypertension, but it also acts as the tissue mediator of genetic predisposition to hypertension. The identity of kidney genes, pathways, and related mechanisms underlying the genetic associations with BP has started to emerge through integration of genomics with kidney transcriptomics, epigenomics, and other omics as well as through applications of causal inference, such as Mendelian randomization. Single-cell methods further enabled mapping of BP-associated kidney genes to cell types, and in conjunction with other omics, started to illuminate the biological mechanisms underpinning associations of BP-associated genetic variants and kidney genes. Polygenic risk scores derived from genome-wide association studies and refined on kidney omics hold the promise of enhanced diagnostic prediction, whereas kidney omics-informed drug discovery is likely to contribute new therapeutic opportunities for hypertension and hypertension-mediated kidney damage.


Assuntos
Estudo de Associação Genômica Ampla , Hipertensão , Pressão Sanguínea/genética , Predisposição Genética para Doença , Humanos , Hipertensão/genética , Rim , Polimorfismo de Nucleotídeo Único
8.
Nat Commun ; 13(1): 3549, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35729114

RESUMO

In a multi-stage analysis of 52,436 individuals aged 17-90 across diverse cohorts and biobanks, we train, test, and evaluate a polygenic risk score (PRS) for hypertension risk and progression. The PRS is trained using genome-wide association studies (GWAS) for systolic, diastolic blood pressure, and hypertension, respectively. For each trait, PRS is selected by optimizing the coefficient of variation (CV) across estimated effect sizes from multiple potential PRS using the same GWAS, after which the 3 trait-specific PRSs are combined via an unweighted sum called "PRSsum", forming the HTN-PRS. The HTN-PRS is associated with both prevalent and incident hypertension at 4-6 years of follow up. This association is further confirmed in age-stratified analysis. In an independent biobank of 40,201 individuals, the HTN-PRS is confirmed to be predictive of increased risk for coronary artery disease, ischemic stroke, type 2 diabetes, and chronic kidney disease.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Adulto , Diabetes Mellitus Tipo 2/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Herança Multifatorial/genética , Prevalência , Fatores de Risco
10.
Sci Rep ; 12(1): 9317, 2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35665752

RESUMO

Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 × 10-9) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p = 2.1 × 10-6; TRPM3, rs760461668, p = 5 × 10-8; SPTY2D1, rs756851199, p = 1.6 × 10-8; and TSPO, rs566547284, p = 2.4 × 10-6). PHIL encoded protein is involved in pancreatic ß-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic ß-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/metabolismo , Jejum , Predisposição Genética para Doença , Glucose/metabolismo , Humanos , Insulina/genética , Polimorfismo de Nucleotídeo Único , Receptores de GABA/genética
11.
Int J STD AIDS ; 33(5): 462-466, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35306931

RESUMO

OBJECTIVE: This study aimed to compare COVID-19 positivity by HIV status and race/ethnicity using data from the U.S. National COVID Cohort Collaborative (N3C). METHODS: The N3C cohort (≥ 18 years) includes patients with any encounter after 1/1/2020 with SARS-CoV-2 laboratory tests. Detailed electronic medical records are centralized and harmonized across health-care organizations (34 sites). COVID-19 diagnosis was defined by RT-PCR or antibody testing. HIV infection was defined by standard diagnostic codes within 2 years prior to COVID-19 testing. Descriptive statistics and multivariable logistic regression were utilized to compare COVID-19 positivity and HIV status by patient's race/ethnicity. RESULTS: Over 2.1 million patients were captured in the N3C as of 01/29/2021, of whom 372,716 (15%) were positive for COVID-19; 17,820 (0.7%) were PLWH of whom 2428 (13.6%) tested positive for COVID-19. COVID-19 positive PLWH were more likely to be 30+ years of age (90% vs. 70%; χ2p < 0.001), male (67% vs. 46%, χ2p < 0.001), and Black (44% vs. 15%, χ2p < 0.001) compared to HIV-negative patients. Compared to non-Hispanic/Latinx (NH)-White PLWH, NH-Black (aOR: 1.59, 95% CI: 1.37-1.86), Latinx (aOR: 2.17, 95% CI: 1.68-2.83), and NH-Asian (aOR: 2.18, 95% CI: 1.30-3.63) PLWH were more likely to have COVID-19 after adjustment for age, sex, and CharlsonDeyo comorbidity score. CONCLUSION: PLWH and minoritized communities, including NH-Black and Latinx or Hispanic adults, appear to be disproportionately impacted by the COVID-19 pandemic.


Assuntos
COVID-19 , Infecções por HIV , Adulto , COVID-19/diagnóstico , COVID-19/epidemiologia , Teste para COVID-19 , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Humanos , Masculino , Pandemias , SARS-CoV-2 , Estados Unidos/epidemiologia
13.
BMC Genomics ; 23(1): 148, 2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35183128

RESUMO

BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10- 7). CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.


Assuntos
Estudo de Associação Genômica Ampla , Medicina de Precisão , Pressão Sanguínea/genética , Ligação Genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma
15.
Int J Epidemiol ; 50(6): 1995-2010, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34999880

RESUMO

BACKGROUND: This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization. METHODS: A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included. RESULTS: Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted body mass index (BMI), hypertension, systolic blood pressure, high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein(a), type 2 diabetes (T2D) and nephrolithiasis. In East Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2. CONCLUSIONS: Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Distribuição Aleatória , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética
16.
J Hum Genet ; 67(2): 87-93, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34376796

RESUMO

Despite the dramatic underrepresentation of non-European populations in human genetics studies, researchers continue to exclude participants of non-European ancestry, as well as variants rare in European populations, even when these data are available. This practice perpetuates existing research disparities and can lead to important and large effect size associations being missed. Here, we conducted genome-wide association studies (GWAS) of 31 serum and urine biomarker quantitative traits in African (n = 9354), East Asian (n = 2559), and South Asian (n = 9823) ancestry UK Biobank (UKBB) participants. We adjusted for all known GWAS catalog variants for each trait, as well as novel signals identified in a recent European ancestry-focused analysis of UKBB participants. We identify 7 novel signals in African ancestry and 2 novel signals in South Asian ancestry participants (p < 1.61E-10). Many of these signals are highly plausible, including a cis pQTL for the gene encoding gamma-glutamyl transferase and PIEZO1 and G6PD variants with impacts on HbA1c through likely erythrocytic mechanisms. This work illustrates the importance of using the genetic data we already have in diverse populations, with novel discoveries possible in even modest sample sizes.


Assuntos
Bancos de Espécimes Biológicos/estatística & dados numéricos , Biomarcadores/metabolismo , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Alelos , Asiáticos/genética , Biomarcadores/sangue , Biomarcadores/urina , Negros/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genótipo , Humanos , Masculino , Fenótipo , Reino Unido , Brancos/genética
17.
Kidney Int ; 101(1): 144-151, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34774559

RESUMO

Circulating metabolites are by-products of endogenous metabolism or exogenous sources and may inform disease states. Our study aimed to identify the source of variability in the association of metabolites with estimated glomerular filtration rate (eGFR) in Hispanics/Latinos with low chronic kidney disease prevalence by testing the association of 640 metabolites in 3,906 participants of the Hispanic Community Health Study/Study of Latinos. Metabolites were quantified in fasting serum through non-targeted mass spectrometry analysis. eGFR was regressed on inverse normally transformed metabolites in models accounting for study design and covariates. To identify the source of variation on eGFR associations, we tested the interaction of metabolites with lifestyle and clinical risk factors, and results were integrated with genotypes to identify metabolite genetic regulation. The mean age was 46 years, 43% were men, 22% were current smokers, 47% had a Caribbean Hispanic background, 19% had diabetes and the mean cohort eGFR was 96.4 ml/min/1.73 m2. We identified 404 eGFR-metabolite associations (False Discovery Rate under 0.05). Of these, 69 were previously reported, and 79 were novel associations with eGFR replicated in one or more published studies. There were significant interactions with lifestyle and clinical risk factors, with larger differences in eGFR-metabolite associations within strata of age, urine albumin to creatinine ratio, diabetes and Hispanic/Latino background. Several newly identified metabolites were genetically regulated, and variants were located at genomic regions previously associated with eGFR. Thus, our results suggest complex mechanisms contribute to the association of eGFR with metabolites and provide new insights into these associations.


Assuntos
Insuficiência Renal Crônica , Taxa de Filtração Glomerular/fisiologia , Humanos , Testes de Função Renal , Masculino , Metaboloma , Pessoa de Meia-Idade , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/genética
18.
J Am Soc Nephrol ; 33(1): 77-87, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34670813

RESUMO

BACKGROUND: Admixture mapping is a powerful approach for gene mapping of complex traits that leverages the diverse genetic ancestry in populations with recent admixture, such as Hispanic or Latino individuals in the United States. These individuals have an increased risk of CKD. METHODS: We performed genome-wide admixture mapping for both CKD and eGFR in a sample of 12,601 participants from the Hispanic Community Health Study/Study of Latinos, with validation in a sample of 8191 Black participants from the Women's Health Initiative (WHI). We also compared the findings with those from a conventional genome-wide association study. RESULTS: Three novel ancestry-of-origin loci were identified on chromosomes 2, 14, and 15 for CKD and eGFR. The chromosome 2 locus comprises two European ancestry regions encompassing the FSHR and NRXN1 genes, with European ancestry at this locus associated with increased CKD risk. The chromosome 14 locus, found within the DLK1-DIO3 imprinted domain, was associated with lower eGFR and driven by European ancestry. The eGFR-associated locus on chromosome 15 included intronic variants of RYR3 and was within an African-specific genomic region associated with higher eGFR. The genome-wide association study failed to identify significant associations in these regions. We validated the chromosome 14 and 15 loci associated with eGFR in the WHI Black participants. CONCLUSIONS: This study provides evidence of shared ancestry-specific genomic regions influencing eGFR in Hispanic or Latino individuals and Black individuals and illustrates the potential for leveraging genetic ancestry in recently admixed populations for the discovery of novel candidate loci for kidney phenotypes.


Assuntos
Afro-Americanos/genética , Loci Gênicos/genética , Taxa de Filtração Glomerular/genética , Insuficiência Renal Crônica/genética , /genética , Adulto , Mapeamento Cromossômico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos
19.
Genome Biol ; 23(1): 13, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996498

RESUMO

BACKGROUND: Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk. RESULTS: To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 ( https://forge2.altiusinstitute.org/ ), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology. CONCLUSION: In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Epigenômica , Predisposição Genética para Doença , Humanos , Fenótipo , Sequências Reguladoras de Ácido Nucleico
20.
Medicine (Baltimore) ; 100(49): e28089, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34889260

RESUMO

ABSTRACT: Viral infections, including hepatitis C, can cause secondary glomerular nephropathies. Studies suggest that hepatitis C virus infection (HCV+) is a risk factor for chronic kidney disease (CKD) but evidence of this relationship is lacking among Hispanics/Latinos. We examined the association between HCV+ and incident CKD in a prospective cohort of Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos. HCV+ was defined by detectable HCV antibodies with additional confirmation through HCV RNA or recombinant immunoblot assay testing. Incident CKD was defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or sex-specific threshold for albuminuria measured during follow-up. We used Poisson regression to estimate incidence rate ratios (IRR) of CKD and changes in eGFR- or albuminuria-based risk stages, separately. We used linear regression to estimate associations with continuous, annualized changes in eGFR and albuminuria.Over a follow-up period of 5.9 years, 712 incident CKD events occurred among 10,430 participants. After adjustment for demographic characteristics and comorbidities, HCV+ was not associated with incident CKD, defined by eGFR and albuminuria thresholds (IRR 1.29, 95% Confidence Interval 0.61, 2.73). HCV+ was significantly associated with higher eGFR risk stages (IRR 2.39, 95% CI 1.47, 3.61) with most participants transitioning from stage G1 to G2. HCV+ was associated with a continuous, annualized eGFR decline of -0.69 mL/min/m2/year (95% CI -1.23, -0.16). This large, cohort study did not find evidence of a strong association between HCV+ and new-onset CKD among Hispanics/Latinos. HCV infection may not be associated with risk of CKD among Hispanics/Latinos, although treatment with direct-acting antivirals is recommended for all HCV+ individuals, including those with established CKD or end-stage kidney disease.


Assuntos
Hepacivirus/isolamento & purificação , Hepatite C Crônica/etnologia , Insuficiência Renal Crônica/etnologia , Albuminúria/epidemiologia , Antivirais/uso terapêutico , Feminino , Taxa de Filtração Glomerular/fisiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos , Insuficiência Renal Crônica/tratamento farmacológico , Fatores de Risco
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