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1.
Am J Clin Nutr ; 114(2): 578-587, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-33964857

RESUMO

BACKGROUND: Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin-dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine ß-synthase (CBS). OBJECTIVES: We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin-related measures with bone mineral density (BMD) and strength. METHODS: We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5'-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing. RESULTS: The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. CONCLUSIONS: Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength.  These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.


Assuntos
Densidade Óssea/fisiologia , Variação Genética , Ácido Metilmalônico/sangue , Complexo Vitamínico B/sangue , Adolescente , Adulto , Idoso , Densidade Óssea/genética , Criança , Pré-Escolar , Feminino , Ácido Fólico/sangue , Ácido Fólico/metabolismo , Genótipo , Humanos , Masculino , Ácido Metilmalônico/metabolismo , Pessoa de Meia-Idade , Vitamina B 12/sangue , Vitamina B 12/metabolismo , Vitamina B 6/sangue , Vitamina B 6/metabolismo , Complexo Vitamínico B/metabolismo , Adulto Jovem
2.
Am J Physiol Lung Cell Mol Physiol ; 321(1): L130-L143, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33909500

RESUMO

Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant (P < 0.00015) when adjusting for lead GWAS single-nucleotide polymorphisms A common gasdermin B (GSDMB) splice variant (rs11078928) previously associated with a decreased risk for asthma was nominally associated with a decreased risk for COPD [minor allele frequency (MAF) = 0.46, P = 1.8e-4]. Two stop variants in coiled-coil α-helical rod protein 1 (CCHCR1), a gene involved in regulating cell proliferation, were associated with COPD (both P < 0.0001). The SERPINA1 Z allele was associated with a random-effects odds ratio of 1.43 for COPD (95% confidence interval = 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants and further define the role of coding variants in COPD pathogenesis.


Assuntos
Exoma/genética , Marcadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Regulação da Expressão Gênica , Humanos , Metanálise como Assunto
3.
Eur J Hum Genet ; 29(5): 839-850, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33500576

RESUMO

Recent studies consider lifestyle risk score (LRS), an aggregation of multiple lifestyle exposures, in identifying association of gene-lifestyle interaction with disease traits. However, not all cohorts have data on all lifestyle factors, leading to increased heterogeneity in the environmental exposure in collaborative meta-analyses. We compared and evaluated four approaches (Naïve, Safe, Complete and Moderator Approaches) to handle the missingness in LRS-stratified meta-analyses under various scenarios. Compared to "benchmark" results with all lifestyle factors available for all cohorts, the Complete Approach, which included only cohorts with all lifestyle components, was underpowered due to lower sample size, and the Naïve Approach, which utilized all available data and ignored the missingness, was slightly inflated. The Safe Approach, which used all data in LRS-exposed group and only included cohorts with all lifestyle factors available in the LRS-unexposed group, and the Moderator Approach, which handled missingness via moderator meta-regression, were both slightly conservative and yielded almost identical p values. We also evaluated the performance of the Safe Approach under different scenarios. We observed that the larger the proportion of cohorts without missingness included, the more accurate the results compared to "benchmark" results. In conclusion, we generally recommend the Safe Approach, a straightforward and non-inflated approach, to handle heterogeneity among cohorts in the LRS based genome-wide interaction meta-analyses.

4.
J Bone Miner Res ; 36(4): 729-738, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33434288

RESUMO

Osteoporosis, a disease characterized by low bone mineral density (BMD), increases the risk for fractures. Conventional risk factors alone do not completely explain measured BMD or osteoporotic fracture risk. Metabolomics may provide additional information. We aim to identify BMD-associated metabolomic markers that are predictive of fracture risk. We assessed 209 plasma metabolites by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 1552 Framingham Offspring Study participants, and measured femoral neck (FN) and lumbar spine (LS) BMD 2 to 10 years later using dual-energy X-ray absorptiometry. We assessed osteoporotic fractures up to 27-year follow-up after metabolomic profiling. We identified 27 metabolites associated with FN-BMD or LS-BMD by LASSO regression with internal validation. Incorporating selected metabolites significantly improved the prediction and the classification of osteoporotic fracture risk beyond conventional risk factors (area under the curve [AUC] = 0.74 for the model with identified metabolites and risk factors versus AUC = 0.70 with risk factors alone, p = .001; net reclassification index = 0.07, p = .03). We replicated significant improvement in fracture prediction by incorporating selected metabolites in 634 participants from the Hong Kong Osteoporosis Study (HKOS). The glycine, serine, and threonine metabolism pathway (including four identified metabolites: creatine, dimethylglycine, glycine, and serine) was significantly enriched (false discovery rate [FDR] p value = .028). Furthermore, three causally related metabolites (glycine, phosphatidylcholine [PC], and triacylglycerol [TAG]) were negatively associated with FN-BMD, whereas PC and TAG were negatively associated with LS-BMD through Mendelian randomization analysis. In summary, metabolites associated with BMD are helpful in osteoporotic fracture risk prediction. Potential causal mechanisms explaining the three metabolites on BMD are worthy of further experimental validation. Our findings may provide novel insights into the pathogenesis of osteoporosis. © 2021 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Osteoporose , Fraturas por Osteoporose , Absorciometria de Fóton , Densidade Óssea , Cromatografia Líquida , Humanos , Vértebras Lombares , Metabolômica , Espectrometria de Massas em Tandem
5.
Am J Epidemiol ; 190(1): 95-108, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-32803215

RESUMO

Docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, attenuates interstitial lung disease (ILD) in experimental models, but human studies are lacking. We examined associations of circulating levels of DHA and other polyunsaturated fatty acids with hospitalization and death due to ILD over 12 years in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 6,573). We examined cross-sectional associations with CT lung abnormalities in MESA (2000-2012; n = 6,541), the Framingham Heart Study (2005-2011; n = 3,917), and the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) (2002-2006; n = 1,106). Polyunsaturated fatty acid levels were determined from fasting blood samples and extracted from plasma phospholipids (MESA and AGES-Reykjavik) or red blood cell membranes (Framingham Heart Study). Higher DHA levels were associated with a lower risk of hospitalization due to ILD (per standard-deviation increment, adjusted rate ratio = 0.69, 95% confidence interval (CI): 0.48, 0.99) and a lower rate of death due to ILD (per standard-deviation increment, adjusted hazard ratio = 0.68, 95% CI: 0.47, 0.98). Higher DHA was associated with fewer interstitial lung abnormalities on computed tomography (per natural log increment, pooled adjusted odds ratio = 0.65, 95% CI: 0.46, 0.91). Higher DHA levels were associated with a lower risk of hospitalization and death due to ILD and fewer lung abnormalities on computed tomography in a meta-analysis of data from population-based cohort studies.


Assuntos
Ácidos Graxos Ômega-3/sangue , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Estudos Epidemiológicos , Ácidos Graxos Insaturados/sangue , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco
6.
Hepatology ; 73(2): 548-559, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33125745

RESUMO

BACKGROUND AND AIMS: NAFLD is increasing in prevalence and will soon be the most common chronic liver disease. Liver stiffness, as assessed by vibration-controlled transient elastography (VCTE), correlates with hepatic fibrosis, an important predictor of liver-related and all-cause mortality. Although liver fat is associated with cardiovascular risk factors, the association between hepatic fibrosis and cardiovascular risk factors is less clear. APPROACH AND RESULTS: We performed VCTE, assessing controlled attenuation parameter (CAP; measure of steatosis) and liver stiffness measurement (LSM) in 3,276 Framingham Heart Study adult participants (53.9% women, mean age 54.3 ± 9.1 years) presenting for a routine study visit. We performed multivariable-adjusted logistic regression models to determine the association between LSM and obesity-related, vascular-related, glucose-related, and cholesterol-related cardiovascular risk factors. The prevalence of hepatic steatosis (CAP ≥ 290 dB/m) was 28.8%, and 8.8% had hepatic fibrosis (LSM ≥ 8.2 kPa). Hepatic fibrosis was associated with multiple cardiovascular risk factors, including increased odds of obesity (OR, 1.82; 95% CI, 1.35-2.47), metabolic syndrome (OR, 1.49; 95% CI 1.10-2.01), diabetes (OR, 2.67; 95% CI, 1.21-3.75), hypertension (OR, 1.52; 95% CI, 1.15-1.99), and low high-density lipoprotein cholesterol (OR, 1.47; 95% CI, 1.09-1.98), after adjustment for age, sex, smoking status, alcohol drinks/week, physical activity index, aminotransferases, and CAP. CONCLUSIONS: In our community-based cohort, VCTE-defined hepatic fibrosis was associated with multiple cardiovascular risk factors, including obesity, metabolic syndrome, diabetes, hypertension, and high-density lipoprotein cholesterol, even after accounting for covariates and CAP. Additional longitudinal studies are needed to determine if hepatic fibrosis contributes to incident cardiovascular disease risk factors or events.

7.
Am J Respir Crit Care Med ; 203(9): 1149-1157, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33080140

RESUMO

Rationale: The association between aging and idiopathic pulmonary fibrosis has been established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated.Objectives: To evaluate the associations among aging biomarkers, ILA, and all-cause mortality.Methods: In the FHS (Framingham Heart Study), we evaluated associations among plasma biomarkers (IL-6, CRP [C-reactive protein], TNFR [tumor necrosis factor α receptor II], GDF15 [growth differentiation factor 15], cystatin-C, HGBA1C [Hb A1C], insulin, IGF1 [insulin-like growth factor 1], and IGFBP1 [IGF binding protein 1] and IGFBP3]), ILA, and mortality. Causal inference analysis was used to determine whether biomarkers mediated age. GDF15 results were replicated in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) Study.Measurements and Main Results: In the FHS, there were higher odds of ILA per increase in natural log-transformed GDF15 (odds ratio [95% confidence interval], 3.4 [1.8-6.4]; P = 0.0002), TNFR (3.1 [1.6-5.8]; P = 0.004), IL-6 (1.8 [1.4-2.4]; P < 0.0001), and CRP (1.7 [1.3-2.0]; P < 0.0001). In the FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but the associations of GDF15 (hazard ratio, 2.0 [1.1-3.5]; P = 0.02), TNFR (1.8 [1.0-3.3]; P = 0.05), and IGFBP1 (1.3 [1.1-1.7]; P = 0.01) approached significance. In the COPDGene Study, higher natural log-transformed GDF15 was associated with ILA (odds ratio, 8.1 [3.1-21.4]; P < 0.0001) and mortality (hazard ratio, 1.6 [1.1-2.2]; P = 0.01). Causal inference analysis showed that the association of age with ILA was mediated by IL-6 (P < 0.0001) and TNFR (P = 0.002) and was likely mediated by GDF15 (P = 0.008) in the FHS and was mediated by GDF15 (P = 0.001) in the COPDGene Study.Conclusions: Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the associations among age, ILA, and mortality.

8.
Am J Respir Crit Care Med ; 201(5): 564-574, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31710517

RESUMO

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterized by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. Genome-wide association studies have reported signals of association implicating multiple pathways including host defense, telomere maintenance, signaling, and cell-cell adhesion.Objectives: To improve our understanding of factors that increase IPF susceptibility by identifying previously unreported genetic associations.Methods: We conducted genome-wide analyses across three independent studies and meta-analyzed these results to generate the largest genome-wide association study of IPF to date (2,668 IPF cases and 8,591 controls). We performed replication in two independent studies (1,456 IPF cases and 11,874 controls) and functional analyses (including statistical fine-mapping, investigations into gene expression, and testing for enrichment of IPF susceptibility signals in regulatory regions) to determine putatively causal genes. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF.Measurements and Main Results: We identified and replicated three new genome-wide significant (P < 5 × 10-8) signals of association with IPF susceptibility (associated with altered gene expression of KIF15, MAD1L1, and DEPTOR) and confirmed associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as yet unreported IPF susceptibility variants contribute to IPF susceptibility.Conclusions: The observation that decreased DEPTOR expression associates with increased susceptibility to IPF supports recent studies demonstrating the importance of mTOR signaling in lung fibrosis. New signals of association implicating KIF15 and MAD1L1 suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.


Assuntos
Fibrose Pulmonar Idiopática/genética , Idoso , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Cinesina/genética , Masculino , Pessoa de Meia-Idade , Medição de Risco , Transdução de Sinais , Fuso Acromático , Serina-Treonina Quinases TOR/metabolismo
9.
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
10.
Am J Respir Crit Care Med ; 200(11): 1402-1413, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31339356

RESUMO

Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6 × 10-27) and subpleural ILAs (P = 1.6 × 10-29). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8 × 10-8) and FCF1P3 (rs73199442, P = 4.8 × 10-8) with ILAs, and near HTRE1 (rs7744971, P = 4.2 × 10-8) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.


Assuntos
Predisposição Genética para Doença/genética , Fibrose Pulmonar Idiopática/genética , Doenças Pulmonares Intersticiais/genética , Idoso , Estudos de Casos e Controles , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Mucina-5B/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Proteínas Semelhantes à Proteína de Ligação a TATA-Box , beta Carioferinas/genética
11.
Sci Rep ; 9(1): 1800, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755687

RESUMO

Genome-Wide Association (GWA) with population-based imputation (PBI) has been successful in identifying common variants associated with complex diseases; however, much heritability remains to be explained and low frequency variants (LFV) may contribute. To identify LFV, a study of unrelated individuals may no longer be as efficient as a family study, where rare population variants can be frequent in families. Family-based imputation (FBI) provides an opportunity to evaluate LFV. To compare the performance of PBI and FBI, we conducted extensive simulations, generating genotypes using SeqSIMLA from various reference panels for families. We masked genotype information for variants unavailable in Framingham 550 K GWA genotype data in less informative subjects selected by GIGI-Pick. We implemented IMPUTE2 with duoHMM in SHAPEIT (Impute2_duoHMM) for PBI, MERLIN and GIGI for FBI and PedBLIMP for a hybrid approach. In general, FBI in both MERLIN and GIGI outperformed other approaches with imputation accuracy greater than 0.99 for the squared correlation and imputation quality scores (IQS) especially for LFV, although imputation accuracy from MERLIN depends on pedigree splitting for larger families. PBI performed worst with the exception of good imputation accuracy for common variants when a closely ancestry matched reference is used. In summary, linkage disequilibrium (LD) information from large available genotype resources provides good imputation for common variants with well-selected reference panels without requiring densely sequenced data in family members, while imputation of LFV with FBI benefits more from information on inheritance patterns within families yielding better imputation.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Genótipo , Algoritmos , Humanos , Desequilíbrio de Ligação/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genética
12.
Am J Respir Crit Care Med ; 199(5): 631-642, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30199657

RESUMO

RATIONALE: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. OBJECTIVE: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. METHODS: Associations of n-3 PUFA biomarkers (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N = 16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N = 11,962) and replicated in one cohort (N = 1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNP associations and their interactions with n-3 PUFAs. RESULTS: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P2df = 9.4 × 10-9 across discovery and replication cohorts). The rs11693320-A allele (frequency, ∼80%) was associated with lower FVC (PSNP = 2.1 × 10-9; ßSNP = -161.0 ml), and the association was attenuated by higher DHA levels (PSNP×DHA interaction = 2.1 × 10-7; ßSNP×DHA interaction = 36.2 ml). CONCLUSIONS: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction.


Assuntos
Dipeptidil Peptidases e Tripeptidil Peptidases/fisiologia , Ácidos Graxos Ômega-3/sangue , Fenômenos Fisiológicos Respiratórios/genética , Idoso , Biomarcadores/sangue , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Ácidos Graxos Insaturados/sangue , Feminino , Volume Expiratório Forçado/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores Sexuais , Fumar/efeitos adversos , Capacidade Vital/genética , Ácido alfa-Linoleico/sangue
13.
Lancet Diabetes Endocrinol ; 7(1): 34-43, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503163

RESUMO

BACKGROUND: Although areal bone mineral density (aBMD) assessed by dual-energy x-ray absorptiometry (DXA) is the clinical standard for determining fracture risk, most older adults who sustain a fracture have T scores greater than -2·5 and thus do not meet the clinical criteria for osteoporosis. Importantly, bone fragility is due to low BMD and deterioration in bone structure. We assessed whether indices of high-resolution peripheral quantitative CT (HR-pQCT) were associated with fracture risk independently of femoral neck aBMD and the Fracture Risk Assessment Tool (FRAX) score. METHODS: We assessed participants in eight cohorts from the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazard ratios (HRs) to estimate the association between HR-pQCT bone indices (per 1 SD of deficit) and incident fracture, adjusting for age, sex, height, weight, and cohort, and then additionally for femoral neck DXA aBMD or FRAX. FINDINGS: 7254 individuals (66% women and 34% men) were assessed. Mean baseline age was 69 years (SD 9, range 40-96). Over a mean follow-up of 4·63 years (SD 2·41) years, 765 (11%) participants had incident fractures, of whom 633 (86%) had femoral neck T scores greater than -2·5. After adjustment for age, sex, cohort, height, and weight, peripheral skeleton failure load had the greatest association with risk of fracture: tibia HR 2·40 (95% CI 1·98-2·91) and radius 2·13 (1·77-2·56) per 1 SD decrease. HRs for other bone indices ranged from 1·12 (95% CI 1·03-1·23) per 1 SD increase in tibia cortical porosity to 1·58 (1·45-1·72) per 1 SD decrease in radius trabecular volumetric bone density. After further adjustment for femoral neck aBMD or FRAX score, the associations were reduced but remained significant for most bone parameters. A model including cortical volumetric bone density, trabecular number, and trabecular thickness at the distal radius and a model including these indices plus cortical area at the tibia were the best predictors of fracture. INTERPRETATION: HR-pQCT indices and failure load improved prediction of fracture beyond femoral neck aBMD or FRAX scores alone. Our findings from a large international cohort of men and women support previous reports that deficits in trabecular and cortical bone density and structure independently contribute to fracture risk. These measurements and morphological assessment of the peripheral skeleton might improve identification of people at the highest risk of fracture. FUNDING: National Institutes of Health National Institute of Arthritis Musculoskeletal and Skin Diseases.


Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/diagnóstico por imagem , Osso Esponjoso/diagnóstico por imagem , Osso Cortical/diagnóstico por imagem , Fraturas Ósseas/epidemiologia , Fraturas por Osteoporose/epidemiologia , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Doenças Ósseas Metabólicas/epidemiologia , Feminino , Colo do Fêmur/diagnóstico por imagem , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico por imagem , Osteoporose/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Tomografia Computadorizada por Raios X
14.
Ann Am Thorac Soc ; 16(4): 447-454, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30543456

RESUMO

RATIONALE: There is increasing evidence that aberrant processes occurring in the airways may precede the development of idiopathic pulmonary fibrosis (IPF); however, there has been no prior confirmatory data derived from imaging studies. OBJECTIVES: To assess quantitative measures of airway wall thickness (AWT) in populations characterized for interstitial lung abnormalities (ILA) and for IPF. METHODS: Computed tomographic imaging of the chest and measures of AWT were available for 6,073, 615, 1,167, and 38 participants from COPDGene (Genetic Epidemiology of COPD study), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study), and the Framingham Heart Study (FHS) and in patients with IPF from the Brigham and Women's Hospital Herlihy Registry, respectively. To evaluate these associations, we used multivariable linear regression to compare a standardized measure of AWT (the square root of AWT for airways with an internal perimeter of 10 mm [Pi10]) and characterizations of ILA and IPF by computed tomographic imaging of the chest. RESULTS: In COPDGene, ECLIPSE, and FHS, research participants with ILA had increased measures of Pi10 compared with those without ILA. Patients with IPF had mean measures of Pi10 that were even greater than those noted in research participants with ILA. After adjustment for important covariates (e.g., age, sex, race, body mass index, smoking behavior, and chronic obstructive pulmonary disease severity when appropriate), research participants with ILA had increased measures of Pi10 compared with those without ILA (0.03 mm in COPDGene, 95% confidence interval [CI], 0.02-0.03; P < 0.001; 0.02 mm in ECLIPSE, 95% CI, 0.005-0.04; P = 0.01; 0.07 mm in FHS, 95% CI, 0.01-0.1; P = 0.01). Compared with COPDGene participants without ILA older than 60 years of age, patients with IPF were also noted to have increased measures of Pi10 (2.0 mm, 95% CI, 2.0-2.1; P < 0.001). Among research participants with ILA, increases in Pi10 were correlated with reductions in lung volumes in some but not all populations. CONCLUSIONS: These results demonstrate that measurable increases in AWT are consistently noted in research participants with ILA and in patients with IPF. These findings suggest that abnormalities of the airways may play a role in, or be correlated with, early pathogenesis of pulmonary fibrosis.


Assuntos
Fibrose Pulmonar Idiopática/patologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/diagnóstico por imagem , Enfisema Pulmonar/patologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Fibrose Pulmonar Idiopática/fisiopatologia , Modelos Lineares , Modelos Logísticos , Pulmão/patologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Enfisema Pulmonar/fisiopatologia , Sistema de Registros , Espirometria , Tomografia Computadorizada por Raios X
15.
BMC Proc ; 12(Suppl 9): 27, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275881

RESUMO

Background: DNA methylation, an epigenetic modification, can be affected by environmental factors and thus regulate gene expression levels that can lead to alterations of certain phenotypes. Network analysis has been used successfully to discover gene sets that are expressed differently across multiple disease states and suggest possible pathways of disease progression. We applied this framework to compare DNA methylation levels before and after lipid-lowering medication and to identify modules that differ topologically between the two time points, revealing the association between lipid medication and these triglyceride-related methylation sites. Methods: We performed quality control using beta-mixture quantile normalization on 463,995 cytosine-phosphate-guanine (CpG) sites and deleted problematic sites, resulting in 423,004 probes. We identified 14,850 probes that were nominally associated with triglycerides prior to treatment and performed weighted gene correlation network analysis (WGCNA) to construct pre- and posttreatment methylation networks of these probes. We then applied both WGCNA module preservation and generalized Hamming distance (GHD) to identify modules with topological differences between the pre- and posttreatment. For modules with structural changes between 2 time points, we performed pathway-enrichment analysis to gain further insight into the biological function of the genes from these modules. Results: Six triglyceride-associated modules were identified using pretreatment methylation probes. The same 3 modules were not preserved in posttreatment data using both the module-preservation and the GHD methods. Top-enriched pathways for the 3 differentially methylated modules are sphingolipid signaling pathway, proteoglycans in cancer, and metabolic pathways (p values < 0.005). One module in particular included an enrichment of lipid-related pathways among the top results. Conclusions: The same 3 modules, which were differentially methylated between pre- and posttreatment, were identified using both WGCNA module-preservation and GHD methods. Pathway analysis revealed that triglyceride-associated modules contain groups of genes that are involved in lipid signaling and metabolism. These 3 modules may provide insight into the effect of fenofibrate on changes in triglyceride levels and these methylation sites.

16.
BMC Genet ; 19(Suppl 1): 84, 2018 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-30255775

RESUMO

BACKGROUND: Single-probe analyses in epigenome-wide association studies (EWAS) have identified associations between DNA methylation and many phenotypes, but do not take into account information from neighboring probes. Methods to detect differentially methylated regions (DMRs) (clusters of neighboring probes associated with a phenotype) may provide more power to detect associations between DNA methylation and diseases or phenotypes of interest. RESULTS: We proposed a novel approach, GlobalP, and perform comparisons with 3 methods-DMRcate, Bumphunter, and comb-p-to identify DMRs associated with log triglycerides (TGs) in real GAW20 data before and after fenofibrate treatment. We applied these methods to the summary statistics from an EWAS performed on the methylation data. Comb-p, DMRcate, and GlobalP detected very similar DMRs near the gene CPT1A on chromosome 11 in both the pre- and posttreatment data. In addition, GlobalP detected 2 DMRs before fenofibrate treatment in the genes ETV6 and ABCG1. Bumphunter identified several DMRs on chromosomes 1 and 20, which did not overlap with DMRs detected by other methods. CONCLUSIONS: Our novel method detected the same DMR identified by two existing methods and detected two additional DMRs not identified by any of the existing methods we compared.


Assuntos
Metilação de DNA , Epigenômica/métodos , Carnitina O-Palmitoiltransferase/genética , Ilhas de CpG , Fenofibrato/uso terapêutico , Estudo de Associação Genômica Ampla , Humanos , Hipertrigliceridemia/tratamento farmacológico , Hipertrigliceridemia/genética , Hipoglicemiantes/uso terapêutico , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Triglicerídeos/sangue
17.
J Bone Miner Res ; 33(10): 1851-1858, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29813182

RESUMO

Weight loss in older adults is associated with increased bone loss and fracture. Little is known about the potential impact of weight loss on cortical and trabecular bone density, microarchitecture, and strength. In this study, participants were members of the Framingham Offspring Cohort (769 women, 595 men; mean age 70 ± 8 years), who underwent high-resolution peripheral quantitative computed tomography (HR-pQCT) scanning at the tibia and radius in 2012 to 2016. Weight measurements taken every 4 to 6 years were used to assess recent weight change over 6 years and long-term change over 40 years. General linear models, adjusting for age, sex, height, smoking, and diabetes, were used to evaluate the association between HR-pQCT indices and relative long-term and recent weight change. We found that long-term and recent weight loss were associated with lower cortical density and thickness, higher cortical porosity, and lower trabecular density and number. Associations were stronger for the tibia than radius. Failure load was lower in those individuals with long-term but not short-term weight loss. Deterioration in both cortical and trabecular indices, especially at the weight-bearing skeleton, characterizes bone fragility associated with long-term and recent weight loss in older adults. © 2018 American Society for Bone and Mineral Research.


Assuntos
Peso Corporal , Densidade Óssea/fisiologia , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Osteoporose/patologia , Osteoporose/fisiopatologia , Idoso , Fenômenos Biomecânicos , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Osteoporose/diagnóstico por imagem , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/patologia , Rádio (Anatomia)/fisiopatologia , Tíbia/diagnóstico por imagem , Tíbia/patologia , Tíbia/fisiopatologia , Fatores de Tempo , Tomografia Computadorizada por Raios X
18.
J Relig Health ; 57(5): 1918-1930, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29627925

RESUMO

Spirituality has been shown to be important to many individuals dealing with a cancer diagnosis. While African-American breast cancer survivors have been reported to have higher levels of spirituality compared to White women, little is known about how levels of spirituality may vary among African-American breast cancer survivors. The aims of this study were to examine factors associated with spirituality among African-American survivors and test whether spirituality levels were associated with women's attitudes about treatment or health care. The primary outcome, spirituality, was nine-item scale (Cronbach's α = .99). Participants completed standardized telephone interviews that captured sociocultural, healthcare process, and treatment attitudes. Medical records were abstracted post-adjuvant therapy for treatment and clinical information. In bivariate analysis, age was not correlated with spirituality (p = .40). Married/living as married women had higher levels of spirituality (m = 32.1) than single women (m = 30.1). Contextual factors that were associated with higher levels spirituality were: collectivism (r = .44; p < 0.0001, Afrocentric worldview (r = .185; p = .01), and self-efficacy scale (r = .17; p = .02). In multivariable analysis, sociodemographic factors were not significant. Collectivism remained a robust predictor (p < 0.0001). Attitudes about the efficacy of cancer treatment were not associated with spirituality. The high levels of spirituality in African-American survivors suggest consideration of integrating spiritual care within the delivery of cancer treatment. Future studies should consider how spirituality may contribute to positive coping and/or behaviors in African-American women with high levels of spirituality.


Assuntos
Adaptação Psicológica , Afro-Americanos/psicologia , Neoplasias da Mama/etnologia , Neoplasias da Mama/psicologia , Sobreviventes de Câncer/psicologia , Espiritualidade , Neoplasias da Mama/enfermagem , Feminino , Humanos , Masculino , Estados Unidos
19.
J Cancer Surviv ; 12(1): 74-81, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29147853

RESUMO

PURPOSE: Advances in precision medicine (PM) have potential to reduce and/or eliminate breast cancer disparities in both treatment and survivorship. However, compared to white Americans, black Americans are often underrepresented in genetic research. This report assessed factors that influence receipt of buccal cells via saliva kits. METHODS: This prospective study recruited women with confirmed hormonal-positive (HR+) breast cancer (BC). A standardized telephone survey collected sociodemographic, socio-cultural (e.g., religiosity), and healthcare process factors. Clinical information was abstracted from medical records. After the baseline survey, return postage-paid envelopes and mouthwash collection kits were mailed. Univariate and adjusted logistic regression models estimated the probability of biospecimen donation. RESULTS: Seventy percent of the sample provided buccal cells which were of good quality. No differences were noted by race or other demographic factors. In the multivariable logistic model, time spent with providers (OR 1.61 per 1-point increase; 95% CI 1.242, 2.088) and religiosity (OR 0.957 per 1-point increase; 95% CI 0.931, 0.984) remained associated with biospecimen provision. Women with lower-stage cancer (vs. higher stage III+) were more likely to donate biospecimens (p < 0.05). CONCLUSIONS: Cancer care experiences predicted specimen donation. Understanding the contextual reasons for lower receipt among women with higher religiosity scores and higher stage warrants further examination. IMPLICATIONS FOR CANCER SURVIVORS: PM is relevant to cancer survivors because of its potential to inform targeted therapies, understand disease resistance, and aide in prediction of toxicity and/or recurrence. Future efforts to launch precision medicine trials with BC survivors may benefit from engaging medical oncologists and/or leveraging patient-provider encounters for trial participation.


Assuntos
Afro-Americanos/estatística & dados numéricos , Bancos de Espécimes Biológicos/normas , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Medicina de Precisão/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Sobreviventes de Câncer , Feminino , Humanos , Pessoa de Meia-Idade , Manejo de Espécimes/métodos
20.
J Bone Miner Res ; 33(1): 54-62, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28929525

RESUMO

Older adults with type 2 diabetes (T2D) tend to have normal or greater areal bone mineral density (aBMD), as measured by DXA, than those who do not have diabetes (non-T2D). Yet risk of fracture is higher in T2D, including 40% to 50% increased hip fracture risk. We used HR-pQCT to investigate structural mechanisms underlying skeletal fragility in T2D. We compared cortical and trabecular bone microarchitecture, density, bone area, and strength in T2D and non-T2D. In secondary analyses we evaluated whether associations between T2D and bone measures differed according to prior fracture, sex, and obesity. Participants included 1069 members of the Framingham Study, who attended examinations in 2005 to 2008 and underwent HR-pQCT scanning in 2012 to 2015. Mean age was 64 ± 8 years (range, 40 to 87 years), and 12% (n = 129) had T2D. After adjustment for age, sex, weight, and height, T2D had lower cortical volumetric BMD (vBMD) (p < 0.01), higher cortical porosity (p = 0.02), and smaller cross-sectional area (p = 0.04) at the tibia, but not radius. Trabecular indices were similar or more favorable in T2D than non-T2D. Associations between T2D and bone measures did not differ according to sex or obesity status (all interaction p > 0.05); however, associations did differ in those with a prior fracture and those with no history of fracture. Specifically, cortical vBMD at the tibia and cortical thickness at the radius were lower in T2D than non-T2D, but only among those individuals with a prior fracture. Cortical porosity at the radius was higher in T2D than non-T2D, but only among those who did not have a prior fracture. Findings from this large, community-based study of older adults suggest that modest deterioration in cortical bone and reductions in bone area may characterize diabetic bone disease in older adults. Evaluation of these deficits as predictors of fracture in T2D is needed to develop prevention strategies in this rapidly increasing population of older adults. © 2017 American Society for Bone and Mineral Research.


Assuntos
Densidade Óssea , Osso e Ossos/patologia , Osso Cortical/diagnóstico por imagem , Osso Cortical/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Osso e Ossos/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Tamanho do Órgão
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