Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 104
Filtrar
1.
J Hypertens ; 39(4): 633-642, 2021 Apr 01.
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 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
3.
Clin Nutr ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33190990

RESUMO

BACKGROUND & AIMS: In contrast to many observational studies, large-scale randomized trials do not support the protective role of vitamin D for the prevention of colorectal neoplasia. However, in previous studies, individuals with blunted parathyroid hormone (PTH) response to vitamin D insufficiency/deficiency (BPRVID), were not differentiated from those with high PTH response to vitamin D insufficiency/deficiency (HPRVID). Individuals with BPRVID are responsive to magnesium treatment, particularly treatment of magnesium plus vitamin D while those with HPRVID are responsive to vitamin D treatment. We prospectively compared these two distinct groups (i.e. BPRVID and HPRVID) for risk of incident adenoma, metachronous adenoma, and incident colorectal cancer (CRC) METHODS: Three nested case-control studies in the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial. RESULTS: We found optimal 25(OH)D levels were associated with a significantly reduced risk of CRC, primarily among women. The associations between 25(OH)D and CRC risk significantly differed by PTH levels, particularly among women. Compared to individuals with optimal levels for both 25(OH)D and PTH, all others were at an elevated risk of incident CRC, primarily in women. We found those with BPRVID had 2.56-fold significantly increased risk of CRC compared to 1.65-fold non-significantly increased risk for those with HPRVID. Among women, we observed those with BPRVID had 4.79-6.25-fold significantly increased risks of incident CRC and adenoma whereas those with HPRVID had 3.65-fold significantly increased risk of CRC. CONCLUSIONS: Individuals with BPRVID are at higher risks of incident adenoma and CRC compared to those with HPRVID, particularly among women.

4.
Circulation ; 142(17): 1633-1646, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-32981348

RESUMO

BACKGROUND: Abdominal aortic aneurysm (AAA) is an important cause of cardiovascular mortality; however, its genetic determinants remain incompletely defined. In total, 10 previously identified risk loci explain a small fraction of AAA heritability. METHODS: We performed a genome-wide association study in the Million Veteran Program testing ≈18 million DNA sequence variants with AAA (7642 cases and 172 172 controls) in veterans of European ancestry with independent replication in up to 4972 cases and 99 858 controls. We then used mendelian randomization to examine the causal effects of blood pressure on AAA. We examined the association of AAA risk variants with aneurysms in the lower extremity, cerebral, and iliac arterial beds, and derived a genome-wide polygenic risk score (PRS) to identify a subset of the population at greater risk for disease. RESULTS: Through a genome-wide association study, we identified 14 novel loci, bringing the total number of known significant AAA loci to 24. In our mendelian randomization analysis, we demonstrate that a genetic increase of 10 mm Hg in diastolic blood pressure (odds ratio, 1.43 [95% CI, 1.24-1.66]; P=1.6×10-6), as opposed to systolic blood pressure (odds ratio, 1.06 [95% CI, 0.97-1.15]; P=0.2), likely has a causal relationship with AAA development. We observed that 19 of 24 AAA risk variants associate with aneurysms in at least 1 other vascular territory. A 29-variant PRS was strongly associated with AAA (odds ratioPRS, 1.26 [95% CI, 1.18-1.36]; PPRS=2.7×10-11 per SD increase in PRS), independent of family history and smoking risk factors (odds ratioPRS+family history+smoking, 1.24 [95% CI, 1.14-1.35]; PPRS=1.27×10-6). Using this PRS, we identified a subset of the population with AAA prevalence greater than that observed in screening trials informing current guidelines. CONCLUSIONS: We identify novel AAA genetic associations with therapeutic implications and identify a subset of the population at significantly increased genetic risk of AAA independent of family history. Our data suggest that extending current screening guidelines to include testing to identify those with high polygenic AAA risk, once the cost of genotyping becomes comparable with that of screening ultrasound, would significantly increase the yield of current screening at reasonable cost.

5.
J Am Med Inform Assoc ; 27(11): 1675-1687, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32974638

RESUMO

OBJECTIVE: Developing algorithms to extract phenotypes from electronic health records (EHRs) can be challenging and time-consuming. We developed PheMap, a high-throughput phenotyping approach that leverages multiple independent, online resources to streamline the phenotyping process within EHRs. MATERIALS AND METHODS: PheMap is a knowledge base of medical concepts with quantified relationships to phenotypes that have been extracted by natural language processing from publicly available resources. PheMap searches EHRs for each phenotype's quantified concepts and uses them to calculate an individual's probability of having this phenotype. We compared PheMap to clinician-validated phenotyping algorithms from the Electronic Medical Records and Genomics (eMERGE) network for type 2 diabetes mellitus (T2DM), dementia, and hypothyroidism using 84 821 individuals from Vanderbilt Univeresity Medical Center's BioVU DNA Biobank. We implemented PheMap-based phenotypes for genome-wide association studies (GWAS) for T2DM, dementia, and hypothyroidism, and phenome-wide association studies (PheWAS) for variants in FTO, HLA-DRB1, and TCF7L2. RESULTS: In this initial iteration, the PheMap knowledge base contains quantified concepts for 841 disease phenotypes. For T2DM, dementia, and hypothyroidism, the accuracy of the PheMap phenotypes were >97% using a 50% threshold and eMERGE case-control status as a reference standard. In the GWAS analyses, PheMap-derived phenotype probabilities replicated 43 of 51 previously reported disease-associated variants for the 3 phenotypes. For 9 of the 11 top associations, PheMap provided an equivalent or more significant P value than eMERGE-based phenotypes. The PheMap-based PheWAS showed comparable or better performance to a traditional phecode-based PheWAS. PheMap is publicly available online. CONCLUSIONS: PheMap significantly streamlines the process of extracting research-quality phenotype information from EHRs, with comparable or better performance to current phenotyping approaches.

6.
Trends Genet ; 36(11): 807-809, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32709459

RESUMO

The causes for disparities in implementation of precision medicine are complex, due in part to differences in clinical care and a lack of engagement and recruitment of under-represented populations in studies. New tools and large genetic cohorts can change these circumstances and build access to personalized medicine for disadvantaged populations.

7.
Nat Genet ; 52(7): 680-691, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541925

RESUMO

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.


Assuntos
Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Afro-Americanos , Cromossomos Humanos X , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/etnologia , Angiopatias Diabéticas/genética , Europa (Continente) , Feminino , Estudos de Associação Genética , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Polimorfismo de Nucleotídeo Único , Medição de Risco
8.
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
9.
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
10.
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
11.
Hum Hered ; 84(2): 73-81, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31480066

RESUMO

BACKGROUND: Heritability estimates (including twin and single nucleotide polymorphism [SNP]-based heritability studies) for fibroids have been inconsistent across prior studies ranging between 9 and 69%. These inconsistencies are due to variations in study design and included populations. A major design issue has been lack of imaging confirmation to identify controls, where asymptomatic women without imaging confirmation may be misclassified as controls leading to an attenuation of heritability estimates. To reconcile the differences in prior heritability estimates and the impact of misclassification of controls on heritability, we determined SNP-based heritability and characterized the genetic architecture of pelvic image-confirmed fibroid cases and controls. METHODS: Analyses were performed among women of European American descent using genome-wide SNP data from BioVU, a clinical database composed of DNA linked to de-identified electronic health records. We estimated the genetic variance explained by all SNPs using Genome-Wide Complex Trait Analysis on imputed data. Fibroid cases and controls were identified using a previously reported phenotyping algorithm that required pelvic imaging confirmation. RESULTS: In total, we used 1,067 image-confirmed fibroid cases and 1,042 image-confirmed fibroid controls. The SNP-based heritability estimate for fibroid risk was h2 = 0.33 ± 0.18 (p = 0.040). We investigated the relationship between heritability per chromosome and chromosome length (r2 < 1%), with chromosome 8 explaining the highest proportion of variance for fibroid risk. There was no enrichment for intergenic or genic SNPs for the fibroid SNP-based heritability. Excluding loci previously associated with fibroid risk from genome-wide association study did not attenuate fibroid heritability suggesting that loci associating with fibroid risk are yet to be discovered. CONCLUSIONS: We observed that fibroid SNP-based heritability was higher than the previous estimate using genome-wide SNP data that relied on self-reported outcomes, but within the range of prior twin pair studies. Furthermore, these data support that imprecise phenotyping can significantly affect the ability to estimate heritability using genotype data.


Assuntos
Grupo com Ancestrais do Continente Europeu , Imageamento Tridimensional , Padrões de Herança/genética , Leiomioma/diagnóstico por imagem , Leiomioma/genética , Polimorfismo de Nucleotídeo Único/genética , Cromossomos Humanos/genética , DNA Intergênico/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade
12.
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
13.
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.

14.
Cancer Med ; 8(5): 2503-2513, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31001917

RESUMO

An association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom-designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high-grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 1.2 × 10-6 , BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6-3.4, P = 1.6 × 10-5 , BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2-1.7, P = 2.3 × 10-5 , BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.


Assuntos
Afro-Americanos/genética , Carcinoma Epitelial do Ovário/genética , Glucuronosiltransferase/genética , Neoplasias Ovarianas/genética , Receptores de Calcitriol/genética , Teorema de Bayes , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Receptores ErbB/genética , Feminino , Estudos de Associação Genética , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Vitamina D/biossíntese
15.
Sci Rep ; 9(1): 6077, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988330

RESUMO

Benign prostatic hyperplasia (BPH) results in a significant public health burden due to the morbidity caused by the disease and many of the available remedies. As much as 70% of men over 70 will develop BPH. Few studies have been conducted to discover the genetic determinants of BPH risk. Understanding the biological basis for this condition may provide necessary insight for development of novel pharmaceutical therapies or risk prediction. We have evaluated SNP-based heritability of BPH in two cohorts and conducted a genome-wide association study (GWAS) of BPH risk using 2,656 cases and 7,763 controls identified from the Electronic Medical Records and Genomics (eMERGE) network. SNP-based heritability estimates suggest that roughly 60% of the phenotypic variation in BPH is accounted for by genetic factors. We used logistic regression to model BPH risk as a function of principal components of ancestry, age, and imputed genotype data, with meta-analysis performed using METAL. The top result was on chromosome 22 in SYN3 at rs2710383 (p-value = 4.6 × 10-7; Odds Ratio = 0.69, 95% confidence interval = 0.55-0.83). Other suggestive signals were near genes GLGC, UNCA13, SORCS1 and between BTBD3 and SPTLC3. We also evaluated genetically-predicted gene expression in prostate tissue. The most significant result was with increasing predicted expression of ETV4 (chr17; p-value = 0.0015). Overexpression of this gene has been associated with poor prognosis in prostate cancer. In conclusion, although there were no genome-wide significant variants identified for BPH susceptibility, we present evidence supporting the heritability of this phenotype, have identified suggestive signals, and evaluated the association between BPH and genetically-predicted gene expression in prostate.


Assuntos
Predisposição Genética para Doença , Padrões de Herança , Hiperplasia Prostática/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Estudos de Casos e Controles , Registros Eletrônicos de Saúde/estatística & dados numéricos , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Próstata/patologia , Hiperplasia Prostática/epidemiologia , Hiperplasia Prostática/patologia
16.
JAMA Cardiol ; 4(2): 136-143, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30673079

RESUMO

Importance: Thyroid hormone levels are tightly regulated through feedback inhibition by thyrotropin, produced by the pituitary gland. Hyperthyroidism is overwhelmingly due to thyroid disorders and is well recognized to contribute to a wide spectrum of cardiovascular morbidity, particularly the increasingly common arrhythmia atrial fibrillation (AF). Objective: To determine the association between genetically determined thyrotropin levels and AF. Design, Setting, and Participants: This phenome-wide association study scanned 1318 phenotypes associated with a polygenic predictor of thyrotropin levels identified by a previously published genome-wide association study that included participants of European ancestry. North American individuals of European ancestry with longitudinal electronic health records were analyzed from May 2008 to November 2016. Analysis began March 2018. Main Outcomes and Measures: Clinical diagnoses associated with a polygenic predictor of thyrotropin levels. Exposures: Genetically determined thyrotropin levels. Results: Of 37 154 individuals, 19 330 (52%) were men. The thyrotropin polygenic predictor was positively associated with hypothyroidism (odds ratio [OR], 1.10; 95% CI, 1.07-1.14; P = 5 × 10-11) and inversely associated with diagnoses related to hyperthyroidism (OR, 0.64; 95% CI, 0.54-0.74; P = 2 × 10-8 for toxic multinodular goiter). Among nonthyroid associations, the top association was AF/flutter (OR, 0.93; 95% CI, 0.9-0.95; P = 9 × 10-7). When the analyses were repeated excluding 9801 individuals with any diagnoses of a thyroid-related disease, the AF association persisted (OR, 0.91; 95% CI, 0.88-0.95; P = 2.9 × 10-6). To replicate this association, we conducted an inverse-variance weighted average meta-analysis using AF single-nucleotide variant weights from a genome-wide association study of 17 931 AF cases and 115 142 controls. As in the discovery analyses, each SD increase in predicted thyrotropin was associated with a decreased risk of AF (OR, 0.86; 95% CI, 0.79-0.93; P = 4.7 × 10-4). In a set of AF cases (n = 745) and controls (n = 1680) older than 55 years, directly measured thyrotropin levels that fell within the normal range were inversely associated with AF risk (OR, 0.91; 95% CI, 0.83-0.99; P = .04). Conclusions and Relevance: This study suggests a role for genetically determined variation in thyroid function within a physiologically accepted normal range as a risk factor for AF. The clinical decision to treat subclinical thyroid disease should incorporate the risk for AF as antithyroid medications to treat hyperthyroidism may reduce AF risk and thyroid hormone replacement for hypothyroidism may increase AF risk.


Assuntos
Fibrilação Atrial/genética , Hipertireoidismo/genética , Hipotireoidismo/genética , Glândula Tireoide/metabolismo , Tireotropina/genética , Idoso , Análise de Variância , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/etiologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertireoidismo/complicações , Hipertireoidismo/patologia , Hipotireoidismo/complicações , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Fatores de Risco , Testes de Função Tireóidea/métodos , Glândula Tireoide/fisiopatologia
17.
Heart Rhythm ; 16(5): 710-716, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30528449

RESUMO

BACKGROUND: Postoperative arrhythmias after pediatric congenital heart disease (CHD) surgery are a known cause of morbidity and are associated with mortality. A comprehensive evaluation of early postoperative ventricular arrhythmias (VAs) after CHD surgery has not been reported. OBJECTIVES: We sought to determine the incidence of in-hospital VAs after CHD surgery and assess the clinical relevance of this arrhythmia during the postoperative hospital course. METHODS: Patients undergoing CHD surgery at our center from September 2007 through December 2016 were prospectively enrolled. Univariate and multivariate analysis was used to assess the association between postoperative VAs and in-hospital mortality, adjusting for postoperative extracorporeal membrane oxygenation and stage 1 single ventricle palliation operations. RESULTS: A total of 2503 postoperative courses in 1835 patients were included. In all, 464 (18.5%) had VAs, of whom 135 (29.1%) received treatment. Monomorphic ventricular tachycardia was the most frequently treated ventricular arrhythmia (TVA; n=91 [62.3%]). TVAs were associated with increased postoperative extracorporeal membrane oxygenation (13.3% vs 5.5%; P < .001) and in-hospital mortality (14.9% vs 4.0%; P < .001). In multivariate analysis, TVA was an independent risk factor for in-hospital mortality (adjusted odds ratio 2.44; 95% confidence interval 1.21-4.92). CONCLUSION: Early postoperative VAs after CHD surgery are more common than previously reported. Postoperative VAs are associated with increased in-hospital mortality, and the subgroup of TVAs is an independent risk factor for in-hospital mortality.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiopatias Congênitas/cirurgia , Complicações Pós-Operatórias , Taquicardia Ventricular , Fibrilação Ventricular , Feminino , Mortalidade Hospitalar , Humanos , Incidência , Lactente , Masculino , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/mortalidade , Período Pós-Operatório , Medição de Risco , Fatores de Risco , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/epidemiologia , Taquicardia Ventricular/etiologia , Estados Unidos/epidemiologia , Fibrilação Ventricular/diagnóstico , Fibrilação Ventricular/etiologia , Fibrilação Ventricular/mortalidade
18.
Eur J Hum Genet ; 27(2): 269-277, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30262922

RESUMO

High blood pressure (BP) is a major risk factor for cardiovascular disease (CVD) and is more prevalent in African Americans as compared to other US groups. Although large, population-based genome-wide association studies (GWAS) have identified over 300 common polymorphisms modulating inter-individual BP variation, largely in European ancestry subjects, most of them do not localize to regions previously identified through family-based linkage studies. This discrepancy has remained unexplained despite the statistical power differences between current GWAS and prior linkage studies. To address this issue, we performed genome-wide linkage analysis of BP traits in African-American families from the Family Blood Pressure Program (FBPP) and genotyped on the Illumina Human Exome BeadChip v1.1. We identified a genomic region on chromosome 1q31 with LOD score 3.8 for pulse pressure (PP), a region we previously implicated in DBP studies of European ancestry families. Although no reported GWAS variants map to this region, combined linkage and association analysis of PP identified 81 rare and low frequency exonic variants accounting for the linkage evidence. Replication analysis in eight independent African ancestry cohorts (N = 16,968) supports this specific association with PP (P = 0.0509). Additional association and network analyses identified multiple potential candidate genes in this region expressed in multiple tissues and with a strong biological support for a role in BP. In conclusion, multiple genes and rare variants on 1q31 contribute to PP variation. Beyond producing new insights into PP, we demonstrate how family-based linkage and association studies can implicate specific rare and low frequency variants for complex traits.


Assuntos
Cromossomos Humanos Par 1/genética , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Afro-Americanos/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/etnologia , Desequilíbrio de Ligação
19.
Blood Adv ; 2(22): 3088-3096, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30442686

RESUMO

Abdominal aortic aneurysm (AAA) is associated with high morbidity and mortality and is an established cause of unbalanced hemostasis. A number of hemostatic biomarkers have been associated with AAA; however, the utility of hemostatic biomarkers in AAA diagnosis and prognosis is unclear. The aim of the present study was to characterize the potential prognostic value of D-dimer and markers of altered hemostasis in a large cohort of patients with AAAs characterized by either fast or slow aneurysm growth (frequency matched for baseline diameter) and subaneurysmal dilations. We measured plasma concentrations of thrombin-antithrombin (TAT) complex, platelet factor 4 (PF4), and D-dimer in 352 patients with either fast-growing AAAs (>2 mm/y), slow-growing AAAs (<2 mm/y), subaneurysmal aortic dilations, or nonaneurysmal aortas. Plasma D-dimer and TAT were significantly elevated in both AAA and subaneurysmal dilation patients compared with controls. Individuals with D-dimer levels ≥500 ng/mL had 3.09 times the odds of subaneurysms, 6.23 times the odds of slow-growing AAAs, and 7.19 times the odds of fast-growing AAAs than individuals with D-dimer level <500 ng/mL. However, no differences in D-dimer concentration were noted between fast- and slow-growing aneurysms. Plasma D-dimer and TAT were strong independent predictors of AAA growth rate with multivariate analysis revealing a 500-ng/mL increase in D-dimer or 1-µg/mL increase in TAT led to additional 0.21-mm and 0.24-mm changes in aortic diameter per year, respectively. Rising levels of plasma TAT, in addition to D-dimer, may predict disease progression and aneurysm growth in patients with AAA or subaneurysmal dilation.


Assuntos
Aneurisma da Aorta Abdominal/diagnóstico , Biomarcadores/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Idoso , Antitrombina III , Aneurisma da Aorta Abdominal/patologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Peptídeo Hidrolases/sangue , Fator Plaquetário 4/sangue , Prognóstico , Fatores de Risco
20.
Nat Commun ; 9(1): 3522, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30166544

RESUMO

Defining the full spectrum of human disease associated with a biomarker is necessary to advance the biomarker into clinical practice. We hypothesize that associating biomarker measurements with electronic health record (EHR) populations based on shared genetic architectures would establish the clinical epidemiology of the biomarker. We use Bayesian sparse linear mixed modeling to calculate SNP weightings for 53 biomarkers from the Atherosclerosis Risk in Communities study. We use the SNP weightings to computed predicted biomarker values in an EHR population and test associations with 1139 diagnoses. Here we report 116 associations meeting a Bonferroni level of significance. A false discovery rate (FDR)-based significance threshold reveals more known and undescribed associations across a broad range of biomarkers, including biometric measures, plasma proteins and metabolites, functional assays, and behaviors. We confirm an inverse association between LDL-cholesterol level and septicemia risk in an independent epidemiological cohort. This approach efficiently discovers biomarker-disease associations.


Assuntos
Biomarcadores/análise , Registros Eletrônicos de Saúde , Estudo de Associação Genômica Ampla/métodos , Teorema de Bayes , Biomarcadores/sangue , LDL-Colesterol/sangue , Humanos , Estudos Prospectivos , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...