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1.
J Hypertens ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33534346

RESUMO

OBJECTIVES: Ethnic disparities in hypertension prevalence are well documented, though the influence of genetic ancestry is unclear. The aim of this study was to evaluate associations of geographic genetic ancestry with hypertension and underlying blood pressure traits. METHODS: We tested genetically inferred ancestry proportions from five 1000 Genomes reference populations (GBR, PEL, YRI, CHB, and LWK) for association with four continuous blood pressure (BP) traits (SBP, DBP, PP, MAP) and the dichotomous outcomes hypertension and apparent treatment-resistant hypertension in 220 495 European American, 59 927 African American, and 21 273 Hispanic American individuals from the Million Veteran Program. Ethnicity stratified results were meta-analyzed to report effect estimates per 10% difference for a given ancestry proportion in all samples. RESULTS: Percentage GBR was negatively associated with BP (P = 2.13 × 10-19, 7.92 × 10-8, 4.41 × 10-11, and 3.57 × 10-13 for SBP, DBP, PP, and MAP, respectively; coefficient range -0.10 to -0.21 mmHg per 10% increase in ancestry proportion) and was protective against hypertension [P = 2.59 × 10-5, odds ratio (OR) = 0.98] relative to other ancestries. YRI percentage was positively associated with BP (P = 1.63 × 10-23, 1.94 × 10-26, 0.012, and 3.26 × 10-29 for SBP, DBP, PP, and MAP, respectively; coefficient range 0.06-0.32 mmHg per 10% increase in ancestry proportion) and was positively associated with hypertension risk (P = 3.10 × 10-11, OR = 1.04) and apparent treatment-resistant hypertension risk (P = 1.86 × 10-4, OR = 1.04) compared with other ancestries. Percentage PEL was inversely associated with DBP (P = 2.84 × 10-5, beta = -0.11 mmHg per 10% increase in ancestry proportion). CONCLUSION: These results demonstrate that risk for BP traits varies significantly by genetic ancestry. Our findings provide insight into the geographic origin of genetic factors underlying hypertension risk and establish that a portion of BP trait ethnic disparities are because of genetic differences between ancestries.

2.
Nat Genet ; 52(12): 1314-1332, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33230300

RESUMO

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

3.
Int Urogynecol J ; 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084962

RESUMO

INTRODUCTION AND HYPOTHESIS: Numerous analytic observational studies assess family history as a risk factor for POP and report a wide range of associations. This review aims to systematically evaluate the role of family history of POP in relation to POP risk and its recurrence. METHODS: A review was performed of the PubMed/MEDLINE database with search criteria specifying family history, risk factors, POP, and their synonyms as title/abstract keywords, as well as MESH terms, up to March 2020. We aggregated evidence across studies with fixed effects (FE) and random effects (RE) meta-analysis. RESULTS: Forty-three articles underwent full-text review. Eighteen independent studies evaluating the relationship between family history of POP and POP risk in 3639 POP cases and 10,912 controls were eligible for meta-analysis. Four studies evaluating family history and POP recurrence in 224 recurrent cases and 400 non-recurrent cases were eligible for inclusion into another meta-analyses. A positive family history of POP is on average associated with 2.3- to 2.7-fold increased risk for POP (RE OR = 2.64; 95% CI = 2.07, 3.35) as well as a 1.4-fold increased risk for POP recurrence (FE OR = 1.44; 95% CI = 1.00, 2.08). Meta-analysis estimates of POP risk varied by study design, definition of family history, and model adjustment status. We found evidence that publication bias and recall bias are a possibility. CONCLUSIONS: Family history of POP is a risk factor for both POP presence and recurrence. However, reported magnitudes may be overestimates due to confounding, recall bias, and publication bias.

4.
Sci Rep ; 10(1): 7561, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32372017

RESUMO

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q < 0.05. Genetically predicted higher LV mass was associated with modifiable cardiac risk factors, diagnoses related to organ dysfunction and conditions associated with abnormal cardiac structure including heart failure and atrial fibrillation. Secondary analyses using polygenic predictors confirmed a significant association between higher LV mass and body mass index and, in men, associations with coronary atherosclerosis and systolic blood pressure. In summary, these analyses show that LV mass-associated genetic variability associates with diagnoses of cardiac diseases and with modifiable risk factors which contribute to these diseases.


Assuntos
Predisposição Genética para Doença , Cardiopatias/epidemiologia , Cardiopatias/etiologia , Ventrículos do Coração/patologia , Herança Multifatorial , Remodelação Ventricular , Ecocardiografia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias/diagnóstico , Cardiopatias/mortalidade , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Razão de Chances , Tamanho do Órgão , Fenótipo , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Remodelação Ventricular/genética
5.
PM R ; 12(11): 1099-1105, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32198840

RESUMO

BACKGROUND: A lack of studies with large sample sizes of patients with rotator cuff tears is a barrier to performing clinical and genomic research. OBJECTIVE: To develop and validate an electronic medical record (EMR)-based algorithm to identify individuals with and without rotator cuff tear. DESIGN: We used a deidentified version of the EMR of more than 2 million subjects. A screening algorithm was applied to classify subjects into likely rotator cuff tear and likely normal rotator cuff groups. From these subjects, 500 likely rotator cuff tear and 500 likely normal rotator cuff were randomly chosen for algorithm development. Chart review of all 1000 subjects confirmed the true phenotype of rotator cuff tear or normal rotator cuff based on magnetic resonance imaging and operative report. An algorithm was then developed based on logistic regression and validation of the algorithm was performed. RESULTS: The variables significantly predicting rotator cuff tear included the number of times a Current Procedural Terminology code related to rotator cuff procedures was used (odds ratio [OR] = 3.3; 95% confidence interval [CI]: 1.6-6.8 for ≥3 vs 0), the number of times a term related to rotator cuff lesions occurred in radiology reports (OR = 2.2; 95% CI: 1.2-4.1 for ≥1 vs 0), and the number of times a term related to rotator cuff lesions occurred in physician notes (OR = 4.5; 95% CI: 2.2-9.1 for 1 or 2 times vs 0). This phenotyping algorithm had a specificity of 0.89 (95% CI: 0.79-0.95) for rotator cuff tear, area under the curve (AUC) of 0.842, and diagnostic likelihood ratios (DLRs), DLR+ and DLR- of 5.94 (95% CI: 3.07-11.48) and 0.363 (95% CI: 0.291-0.453). CONCLUSION: Our informatics algorithm enables identification of cohorts of individuals with and without rotator cuff tear from an EMR-based data set with moderate accuracy.

6.
Nat Genet ; 51(10): 1459-1474, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.


Assuntos
Doenças Cardiovasculares/sangue , Marcadores Genéticos , Gota/sangue , Doenças Metabólicas/sangue , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Coortes , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gota/epidemiologia , Gota/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Proteínas de Neoplasias/genética , Especificidade de Órgãos
7.
Br J Cancer ; 121(9): 796-804, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31543516

RESUMO

BACKGROUND: We aimed to evaluate the associations between calcium and various stages of colorectal carcinogenesis and whether these associations are modified by the calcium to magnesium (Ca:Mg) ratio. METHODS: We tested our hypotheses in the prostate lung, colorectal and ovarian cancer screening trial. RESULTS: Calcium intake did not show a dose-response association with incident adenoma of any size/stage (P-trend = 0.17), but followed an inverse trend when restricted to synchronous/advanced adenoma cases (P-trend = 0.05). This inverse trend was mainly in participants with Ca:Mg ratios between 1.7 and 2.5 (P-trend = 0.05). No significant associations were observed for metachronous adenoma. Calcium intake was inversely associated with CRC (P-trend = 0.03); the association was primarily present for distal CRC (P-trend = 0.01). The inverse association between calcium and distal CRC was further modified by the Ca:Mg ratio (P-interaction < 0.01); significant dose-response associations were found only in participants with a Ca:Mg ratio between 1.7 and 2.5 (P-trend = 0.04). No associations for calcium were found in the Ca:Mg ratio above 2.5 or below 1.7. CONCLUSION: Higher calcium intake may be related to reduced risks of incident advanced and/or synchronous adenoma and incident distal CRC among subjects with Ca:Mg intake ratios between 1.7 and 2.5.


Assuntos
Cálcio/administração & dosagem , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Magnésio/administração & dosagem , Idoso , Carcinogênese , Detecção Precoce de Câncer , Feminino , Humanos , Incidência , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/epidemiologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia
8.
Am J Hypertens ; 32(12): 1146-1153, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31545351

RESUMO

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/genética , Proteínas de Ligação a DNA/genética , Resistência a Medicamentos/genética , Hipertensão/tratamento farmacológico , Hipertensão/genética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Afro-Americanos/genética , Idoso , Anti-Hipertensivos/efeitos adversos , Pressão Sanguínea/efeitos dos fármacos , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas Associadas à Distrofina/genética , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etnologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Miosina Tipo V/genética , Neuropeptídeos/genética , Farmacogenética , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologia
9.
Nat Commun ; 10(1): 4130, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.


Assuntos
Albuminúria/genética , Mapeamento Cromossômico , Estudo de Associação Genômica Ampla , Metanálise como Assunto , Animais , Creatinina/urina , Diabetes Mellitus/genética , Diabetes Mellitus/urina , Drosophila melanogaster/genética , Regulação da Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Humanos , Fenômica , Fatores de Risco
10.
Nat Commun ; 10(1): 3842, 2019 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.


Assuntos
Mapeamento Cromossômico/métodos , Taxa de Filtração Glomerular/genética , Rim/fisiopatologia , Insuficiência Renal Crônica/genética , Transcriptoma/genética , Adulto , Idoso , Animais , Linhagem Celular , Estudos de Coortes , Biologia Computacional , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Rim/citologia , Rim/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA-Seq , Insuficiência Renal Crônica/fisiopatologia , Estados Unidos , United States Department of Veterans Affairs , Veteranos
11.
Circulation ; 140(12): 1031-1040, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31337231

RESUMO

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.


Assuntos
Afro-Americanos , Apolipoproteína L1/genética , Doença da Artéria Coronariana/genética , Genótipo , Infarto do Miocárdio/genética , Doença Arterial Periférica/genética , Adulto , Alelos , Doença da Artéria Coronariana/epidemiologia , Registros Eletrônicos de Saúde , Feminino , Predisposição Genética para Doença , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Doença Arterial Periférica/epidemiologia , Polimorfismo Genético , Estudos Retrospectivos , Risco , Estados Unidos/epidemiologia , Veteranos
12.
Front Genet ; 10: 511, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249589

RESUMO

Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10-5) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10-8), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10-9) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10-8). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10-24). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10-8), OBFC1 in esophageal mucosa (P = 8.7 × 10-8), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10-6), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10-6) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.

13.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
15.
Sensors (Basel) ; 19(9)2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086036

RESUMO

Diamond is a good candidate for harsh environment sensing due to its high melting temperature, Young's modulus, and thermal conductivity. A sensor made of diamond will be even more promising when combined with some advantages of optical sensing (i.e., EMI inertness, high temperature operation, and miniaturization). We present a miniature diamond-based fiber optic pressure sensor fabricated using dual polymer-ceramic adhesives. The UV curable polymer and the heat-curing ceramic adhesive are employed for easy and reliable optical fiber mounting. The usage of the two different adhesives considerably improves the manufacturability and linearity of the sensor, while significantly decreasing the error from the temperature cross-sensitivity. Experimental study shows that the sensor exhibits good linearity over a pressure range of 2.0-9.5 psi with a sensitivity of 18.5 nm/psi (R2 = 0.9979). Around 275 °C of working temperature was achieved by using polymer/ceramic dual adhesives. The sensor can benefit many fronts that require miniature, low-cost, and high-accuracy sensors including biomedical and industrial applications. With an added antioxidation layer on the diamond diaphragm, the sensor can also be applied for harsh environment applications due to the high melting temperature and Young's modulus of the material.

16.
Nat Genet ; 51(3): 452-469, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778226

RESUMO

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Homeostase/genética , Lipídeos/genética , Proteínas/genética , Animais , Distribuição da Gordura Corporal/métodos , Índice de Massa Corporal , Estudos de Casos e Controles , Drosophila/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Fatores de Risco , Relação Cintura-Quadril/métodos
17.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
19.
Nat Genet ; 50(10): 1412-1425, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30224653

RESUMO

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.


Assuntos
Pressão Sanguínea/genética , Locos de Características Quantitativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Células Cultivadas , Feminino , Loci Gênicos , Predisposição Genética para Doença , Testes Genéticos/métodos , Genética Populacional/métodos , Estudo de Associação Genômica Ampla , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/genética , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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