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1.
Am J Hum Genet ; 104(1): 112-138, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595373

RESUMO

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.


Assuntos
DNA Mitocondrial/genética , Genes Mitocondriais/genética , Variação Genética/genética , Metabolismo/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Adipócitos/metabolismo , Índice de Massa Corporal , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Estudos de Coortes , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/metabolismo , Locos de Características Quantitativas , Relação Cintura-Quadril
2.
J Clin Med ; 7(12)2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30486327

RESUMO

Diabetic nephropathy (DN) is a major complication in diabetic patients. Microalbuminuria testing is used to identify renal disease; however, its predictive value is questionable. We aimed to identify urinary biomarkers to early diagnosis nephropathy before identifiable alternations in kidney function or urine albumin excretion occurs. Proteomic approaches were used to identify potential urinary biomarkers and enzyme-linked immunosorbent assay was performed to verify the results. The data identified haptoglobin (HPT) and α-1-microglobulin/bikunin precursor (AMBP) as two biomarkers with the highest ability to distinguish between healthy individuals and patients with nephropathy, and between diabetic patients with and without DN. Further, the HPT-to-creatinine ratio (HCR) was evaluated as an independent predictor of early renal functional decline (ERFD) in a cohort with an average follow-up of 4.2 years. The area under the curve (AUC) value for ERFD prediction was significantly improved when the HCR biomarker was included in the model with albumin to creatinine ratio (ACR) and baseline characteristics (AUC values were 0.803 and 0.759 for HCR and ACR, respectively; p value was 0.0423 for difference between models). In conclusion, our results suggest that HCR represents an early indicator of nephropathy, and a marker related to ERFD among diabetic patients in Taiwan.

3.
Medicine (Baltimore) ; 97(40): e12730, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30290684

RESUMO

Subjects with metabolic syndrome (MetS) or obesity have worse arterial stiffness. However, there have been no studies addressing time-sequential changes in pulse wave velocity (PWV) after weight loss and then regaining weight in obese non-diabetic men with MetS.We prospectively enrolled 40 obese, non-diabetic men with MetS undergoing a 3-month weight reduction program. Another 26 lean and healthy men were recruited for comparisons. Oral glucose tolerance test and brachial ankle (ba) PWV were assessed in study subjects. Eighteen obese non-diabetic MetS and 15 lean control subjects had follow-ups at the 60th month.The body weight of obese MetS decreased from 94.8 ±â€Š7.6 to 86.1 ±â€Š9.0 (N = 18, P < .001) after a 3-month weight reduction program but regained gradually thereafter to 93.6 ±â€Š11.6 kg at the 60th month (P < .001 versus 3rd month). baPWV decreased after weight loss slightly (P = .240) while weight regain significantly increased the baPWV (from 3rd month, 1358 ±â€Š168 to 60th month 1539 ±â€Š264 cm/sec, P < .001). Systolic and diastolic blood pressure increments correlated with the increment of baPWV after weight regain. At the 60th month, lean controls (N = 15) had increases in body weight while their baPWV increased non-significantly. The increments of baPWV after weight regain in obese MetS were significantly higher than the increment of baPWV in lean controls after weight gain.In conclusion, regaining body weight after weight reduction worsened arterial stiffness with significant increase of baPWV in obese non-diabetic MetS.


Assuntos
Síndrome Metabólica/fisiopatologia , Obesidade/fisiopatologia , Análise de Onda de Pulso/estatística & dados numéricos , Ganho de Peso/fisiologia , Programas de Redução de Peso/métodos , Adulto , Índice Tornozelo-Braço , Pressão Sanguínea/fisiologia , Humanos , Masculino , Síndrome Metabólica/etiologia , Obesidade/complicações , Obesidade/terapia , Estudos Prospectivos , Resultado do Tratamento , Rigidez Vascular/fisiologia , Perda de Peso/fisiologia
4.
PLoS One ; 13(8): e0202280, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30110378

RESUMO

INTRODUCTION: Postprandial hyperglycemia plays a pivotal role in cardiovascular disease. However, few studies have investigated associations between the severity of coronary artery disease (CAD) and postprandial glucose levels in angina patients without known diabetes before coronary angiography. METHODS: Subjects who were admitted for coronary angiography due to angina and were in stable condition after discharge were recruited. A standard 75-g oral glucose tolerance test (OGTT) was performed at outpatient visits approximately 2-4 weeks after hospital discharge, and fasting and post-challenge blood glucose were measured. Twenty-six volunteers in our hospital staff served as the healthy group. CAD severity was graded using the SYNTAX and Jeopardy scoring systems. RESULTS: The subjects in the angina group had a higher body mass index, higher fasting glucose, and higher 2-h postprandial glucose than those in the healthy group. The SYNTAX and Jeopardy scores were significantly associated with 2-h postprandial blood glucose (correlation coefficients = 0.164 and 0.187, respectively) but not with fasting glucose. Linear regression analyses revealed that SYNTAX and Jeopardy scores were independently associated with glucose levels at 120 min after OGTT (SYNTAX 95%CI = 0.003-0.103; Jeopardy score 0.002-0.027) but not with fasting glucose. CONCLUSION: CAD severity is associated with blood glucose levels after oral glucose challenge in patients without known diabetes before coronary angiography, suggesting that CAD patients should be routinely screened for post-challenge blood glucose.

5.
Nat Commun ; 9(1): 2252, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29899519

RESUMO

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.

6.
J Diabetes ; 10(12): 958-964, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29802768

RESUMO

BACKGROUND: The aim of the present study was to investigate the association between serum aryl hydrocarbon receptor (AhR) levels and insulin resistance and ß-cell function in patients undergoing coronary angiography with no history of diabetes. METHODS: Patients with no history of diabetes who had undergone coronary angiography underwent an oral glucose tolerance test (OGTT) 2-4 weeks after discharge from hospital; blood samples were collected for measurements of glucose, insulin, and AhR. Patients' glucose regulation status was determined on the basis of the OGTT. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). ß-Cell function was assessed using the insulinogenic index (IGI). RESULTS: The study included 473 patients (mean (±SD) age 61 ±12 years, 81.8% male, mean body mass index 26.1 ±3.6 kg/m2 ). Overall, mean serum AhR concentrations were 25.1 ±12.2 pg/mL. Patients with normal glucose tolerance had a lower serum AhR concentrations than patients with prediabetes or newly diagnosed diabetes (23.4 ±10.8 vs 26.2 ±13.2 and 26.9 ±12.3 pg/mL, respectively; P = 0.029). Linear regression analysis revealed that serum AhR concentrations were not associated with HOMA-IR, but were negatively associated with IGI after adjustment for several confounders, including HOMA-IR (ß = -0.162; 95% confidence interval - 0.302, -0.022; P = 0.023). CONCLUSIONS: In patients with no history of diabetes, serum AhR concentrations were negatively associated with ß-cell function, independent of several confounders, including insulin resistance.

7.
Sci Rep ; 8(1): 7378, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29743680

RESUMO

Endothelin-1 (ET-1) is associated with endothelial dysfunction and vasoconstriction. Increased circulating ET-1 levels are associated with long-term cardiovascular mortality. Renalase, released from kidney, metabolizes catecholamines and regulates blood pressure. An increase in circulating renalase levels has been reported in patients with chronic kidney disease (CKD) and is associated with coronary artery disease (CAD). We hypothesized the existence of a synergistic effect of serum renalase levels and CKD on ET-1 levels in patients with CAD. We evaluated 342 non-diabetic patients with established CAD. ET-1 and renalase levels were measured in all patients after an overnight fast. Patients with CKD had higher ET-1 (1.95 ± 0.77 vs. 1.62 ± 0.76 pg/ml, P < 0.001) and renalase levels (46.8 ± 17.1 vs. 33.9 ± 9.9 ng/ml, P < 0.001) than patients without CKD. Patients with both CKD and high renalase levels (>the median of 36.2 ng/ml) exhibited the highest serum ET-1 (P value for the trend <0.001). According to multivariate linear regression analysis, the combination of high serum renalase levels with CKD was a significant risk factor for increased serum ET-1 levels (regression coefficient = 0.297, 95% confidence interval = 0.063‒0.531, P = 0.013). In conclusion, our data suggest a synergistic effect of high serum renalase levels and CKD on increases in ET-1 levels in patients with established CAD.

8.
Sci Rep ; 8(1): 5485, 2018 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615787

RESUMO

Night shift work is associated with cardiovascular disease and central nervous system disorders in female nurses. Brain-derived neurotrophic factor (BDNF) exerts protective effects on neural and endothelial functions. This study examined the association between serum BDNF levels and pulse pressure after rest in female nurses working night shifts. In this study, blood samples were collected for BDNF measurement after a night shift when nurses had been working night shifts for three continuous weeks. Blood pressure was assessed before and after a one-hour morning rest within a week of resuming the night shift after one month without any night shift work. The pulse pressure of nurses (n = 48, age 29 ± 5 years) was significantly reduced (from 43 ± 7 to 41 ± 6 mmHg, P = 0.003) after rest, and serum BDNF were significantly and inversely correlated with pulse pressure changes (r = -0.435, P = 0.002). Higher serum BDNF was an independent factor for greater reduction in pulse pressure (95%CI = -0.609 ‒ -0.174, P = 0.001). Using a receiver operating characteristic curve analysis, serum BDNF >20.6 ng/mL predicted a pulse pressure reduction after a one-hour rest (sensitivity 66.7%, specificity 77.8%). In conclusion, higher serum BDNF predicted greater recovery of pulse pressure after a one-hour rest in female nurses after night shift work.

9.
Clin Chim Acta ; 483: 130-134, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29704473

RESUMO

BACKGROUND: We aimed to examine the association of serum high mobility group box 1 (HMGB1) level with cardiovascular risk in patients undergoing coronary angiography with no history of diabetes. METHODS: We enrolled patients with no history of diabetes who had been admitted for coronary angiography due to suspected or known coronary artery disease. Two to four weeks after the patients were discharged from the hospital, an oral glucose tolerance test (OGTT) was conducted and serum HMGB1 level was measured. Patients' 10-year coronary heart disease (CHD) risk was assessed using the Framingham Risk Scoring. RESULTS: A total of 476 patients were enrolled. Overall, mean serum HMGB1 level was 6.1 ±â€¯1.3 pg/ml. Using linear regression analysis, high-density lipoprotein cholesterol was negatively associated with serum HMGB1 (ß coefficient - 0.033, 95% CI -0.063 to -0.003, p = 0.033) after adjustment for several confounders. With regard to cardiovascular risk, levels of serum HMGB1 were positively associated with 10-year CHD risk (ß coefficient 0.506, 95% CI 0.030 to 0.983, p = .037), independent of patients' undiagnosed abnormal glucose regulation. CONCLUSIONS: In patients undergoing coronary angiography with no history of diabetes, levels of serum HMGB1 were positively associated with 10-year CHD risk, independent of patients' undiagnosed abnormal glucose regulation.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Angiografia Coronária , Proteína HMGB1/sangue , Doenças Cardiovasculares/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Risco
10.
Clin Chem Lab Med ; 56(8): 1345-1352, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-29596050

RESUMO

BACKGROUND: The oral glucose tolerance test (OGTT) is recommended to screen for diabetes in patients with coronary artery disease. We hypothesized that testing for glycated hemoglobin (HbA1c), in addition to the OGTT, in screening for abnormal glucose regulation may help to reveal patients with ß-cell function impairment. METHODS: Patients with no history of diabetes who were admitted for coronary angiography were recruited to undergo an OGTT and HbA1c test 2-4 weeks after hospital discharge. ß-cell function and insulin resistance were assessed using the homeostasis model assessment (HOMA-ß and HOMA-IR, respectively). For patients with normal glucose tolerance (NGT) based on the OGTT, we compared HOMA-ß between two subgroups of patients using an HbA1c cutoff of 39 mmol/mol or 42 mmol/mol. For patients with prediabetes based on an OGTT, we compared the HOMA-ß between two subgroups of patients using an HbA1c cutoff of 48 mmol/mol. RESULTS: A total of 1044 patients were analyzed. In patients with NGT by OGTT (n=432), those with an HbA1c ≥42 mmol/mol had a lower HOMA-ß compared to those with an HbA1c <42 mmol/mol (107±82 vs. 132±96, p=0.018). In patients with prediabetes by OGTT (n=423), those with an HbA1c ≥48 mmol/mol had a lower HOMA-ß compared to those with an HbA1c <48 mmol/mol (91±52 vs. 120±88, p=0.003). No significant between-group difference in HOMA-IR was noted. CONCLUSIONS: The use of HbA1c in addition to the OGTT in screening for abnormal glucose regulation helped to reveal patients with early ß-cell function impairment.

11.
Clin Chim Acta ; 476: 1-8, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29080692

RESUMO

BACKGROUND: Arterial stiffening blunts postprandial vasodilatation. We hypothesized that brain-derived neurotrophic factor (BDNF) may modulate postprandial central pulse pressure, a surrogate marker for arterial stiffening. METHODS: A total of 82 non-diabetic subjects received a 75-g oral glucose tolerance test (OGTT) after overnight fasting. Serum BDNF concentrations were determined at 0, 30, and 120min to calculate the area under the curve (AUC). Brachial and central blood pressures were measured using a noninvasive central blood pressure monitor before blood withdrawals at 0 and 120min. RESULTS: With the median AUC of BDNF of 45(ng/ml)∗h as the cutoff value, the central pulse pressure after glucose intake was significantly higher in the subjects with a low BDNF than in those with a high BDNF (63±16 vs. 53±11mmHg, P=0.003), while the brachial pulse pressure was not significantly different between the 2 groups (P=0.099). In a multivariate linear regression model, a lower AUC of BDNF was an independent predictor of a higher central pulse pressure after oral glucose intake (linear regression coefficient-0.202, 95% confidence interval-0.340 to -0.065, P=0.004). CONCLUSION: After oral glucose challenge, a lower serum BDNF response is significantly associated with a higher central pulse pressure.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Glucose/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea , Jejum/sangue , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade
12.
Medicine (Baltimore) ; 96(36): e7851, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28885336

RESUMO

Intraocular pressure is associated with metabolic syndrome. C-reactive protein (CRP) is associated with cardiovascular disease, irrespective of the presence of metabolic syndrome. In this study, we examined the synergistic effect of CRP and metabolic syndrome on intraocular pressure.A total of 1041 subjects were included for data analyses in this cross-sectional study. Intraocular pressure was measured using a noncontact tonometer, and serum CRP levels were measured using a commercially available kit.The intraocular pressure was significantly higher in the subjects with metabolic syndrome than in those without (14.1 ±â€Š3.0 vs 13.4 ±â€Š3.0 mm Hg, P = .002). Furthermore, intraocular pressures significantly increased according to CRP tertiles (13.1 ±â€Š3.0, 13.7 ±â€Š3.0, and 13.8 ±â€Š3.0 mm Hg from the lowest to highest tertile of CRP, respectively; P = .002). The highest intraocular pressure was observed in subjects with metabolic syndrome in the highest CRP tertile (P value for trend < .001). Multivariate linear regression analysis revealed that the influence of CRP was independent of metabolic syndrome and that high CRP levels were significantly associated with high intraocular pressure (95% confidence interval: 0.080-1.297, P = .027).In conclusion, systemic inflammation, reflected by serum CRP levels, is associated with high intraocular pressure in subjects with and without metabolic syndrome.


Assuntos
Proteína C-Reativa/análise , Inflamação/epidemiologia , Pressão Intraocular/fisiologia , Síndrome Metabólica/epidemiologia , Adulto , Fatores Etários , Estudos Transversais , Feminino , Humanos , Hipertensão/epidemiologia , Hipertrigliceridemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade , Fatores de Risco , Fatores Sexuais , Fumar/epidemiologia , Tonometria Ocular
13.
Nat Genet ; 49(10): 1450-1457, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28869590

RESUMO

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Ásia/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Biomarcadores , Comorbidade , Doença das Coronárias/epidemiologia , Doença das Coronárias/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Europa (Continente)/epidemiologia , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Cadeias HLA-DRB5/genética , Humanos , Redes e Vias Metabólicas/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Terapia de Alvo Molecular , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Fatores de Risco
14.
Diabetes ; 66(12): 3130-3141, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28951389

RESUMO

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.


Assuntos
Retinopatia Diabética/etiologia , Lipídeos/sangue , Análise da Randomização Mendeliana , Idoso , Retinopatia Diabética/sangue , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
15.
BMC Genomics ; 18(1): 591, 2017 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-28789618

RESUMO

BACKGROUND: Fasting glucose and fasting insulin are glycemic traits closely related to diabetes, and understanding the role of genetic factors in these traits can help reveal the etiology of type 2 diabetes. Although single nucleotide polymorphisms (SNPs) in several candidate genes have been found to be associated with fasting glucose and fasting insulin, copy number variations (CNVs), which have been reported to be associated with several complex traits, have not been reported for association with these two traits. We aimed to identify CNVs associated with fasting glucose and fasting insulin. RESULTS: We conducted a genome-wide CNV association analysis for fasting plasma glucose (FPG) and fasting plasma insulin (FPI) using a family-based genome-wide association study sample from a Han Chinese population in Taiwan. A family-based CNV association test was developed in this study to identify common CNVs (i.e., CNVs with frequencies ≥ 5%), and a generalized estimating equation approach was used to test the associations between the traits and counts of global rare CNVs (i.e., CNVs with frequencies <5%). We found a significant genome-wide association for common deletions with a frequency of 5.2% in the Scm-like with four mbt domains 1 (SFMBT1) gene with FPG (association p-value = 2×10-4 and an adjusted p-value = 0.0478 for multiple testing). No significant association was observed between global rare CNVs and FPG or FPI. The deletions in 20 individuals with DNA samples available were successfully validated using PCR-based amplification. The association of the deletions in SFMBT1 with FPG was further evaluated using an independent population-based replication sample obtained from the Taiwan Biobank. An association p-value of 0.065, which was close to the significance level of 0.05, for FPG was obtained by testing 9 individuals with CNVs in the SFMBT1 gene region and 11,692 individuals with normal copies in the replication cohort. CONCLUSIONS: Previous studies have found that SNPs in SFMBT1 are associated with blood pressure and serum urate concentration, suggesting that SFMBT1 may have functional implications in some metabolic-related traits.


Assuntos
Glicemia/metabolismo , Grupos Étnicos/genética , Jejum/sangue , Deleção de Genes , Genômica , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética , China/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Repressoras/deficiência
16.
Sci Rep ; 7(1): 7987, 2017 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801571

RESUMO

C-reactive protein (CRP) encoded by CRP gene is a reflection of systemic inflammation. Many studies associated CRP level with diabetes and glucose levels, but the association of CRP gene with these traits is unclear. We conducted a cross-sectional study consisting of 945 siblings from 330 families collected by the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) to investigate associations between CRP polymorphisms, circulating CRP, diabetes, and glucose levels. Five single-nucleotide polymorphisms were analyzed: rs3093059, rs2794521, rs1417938, rs1800947, and rs1205. The generalized estimating equation approach was used to deal with correlated data within families. CRP level was positively correlated with diabetes prevalence and levels of fasting and 2-hour glucose (each P < 0.008). Alleles C at rs3093059 and G at rs1205 were associated with elevated CRP level (each P < 1.2 × 10-6). Allele C at rs3093059 was associated with fasting glucose (ß = 0.20, P = 0.045) and G at rs1205 was associated with 2-hour glucose (ß = 0.46, P = 0.00090) post oral glucose tolerance test, but only the latter passed Bonferroni correction. No polymorphism was associated with diabetes. Since 2-hour glucose is an indicator of glucose tolerance, this study indicated CRP gene is associated with glucose intolerance.

17.
Circ Res ; 121(6): e37-e52, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28724746

RESUMO

RATIONALE: Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. OBJECTIVE: TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of Nε-(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. METHODS AND RESULTS: Serum Nε-(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between Nε-(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). CONCLUSIONS: This study demonstrates that inhibiting the Nε-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Quimiocina CXCL12/metabolismo , Retinopatia Diabética/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lisina/análogos & derivados , Lisina/sangue , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
18.
Biomarkers ; 22(8): 798-804, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28675064

RESUMO

CONTEXT: Inflammation is one of the mechanisms underlying cardiac syndrome X (CSX). OBJECTIVES: Few studies have compared the expression of inflammatory or adhesion molecules between coronary artery disease (CAD) versus CSX. MATERIALS AND METHODS: Ninety-two CSX and 145 CAD subjects without known diabetes mellitus underwent coronary angiogram for angina. RESULTS: Vascular cell adhesion molecule (VCAM)-1 (median, 507 versus 431 ng/ml, p = 0.001) was significantly higher in the CAD group. In the binary regression, VCAM-1 was a significant differential factor for CAD versus CSX. DISCUSSION AND CONCLUSION: Adhesion molecules might be implicated in the differential expression of macro versus microvascular coronary disease. TRIAL REGISTRATION NUMBER: NCT01198730 at https://clinicaltrials.gov.


Assuntos
Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Diabetes Mellitus/sangue , Angina Microvascular/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Estudos Transversais , Diabetes Mellitus/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Modelos Logísticos , Masculino , Angina Microvascular/diagnóstico , Pessoa de Meia-Idade , Curva ROC , Estudos Retrospectivos
19.
Clin Chim Acta ; 472: 80-85, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28735064

RESUMO

BACKGROUND: We investigated the associations of fibroblast growth factor 21 (FGF-21) with cardiovascular risk and ß-cell function in patients who had no history of diabetes. METHODS: We enrolled 269 outpatients who had been referred for an oral glucose tolerance test (OGTT). Plasma glucose, insulin, and FGF-21 were measured before and at 2h after the OGTT. ß-cell function was assessed using the insulinogenic index, corrected for insulin resistance. Patients' 10-year coronary heart disease (CHD) risk was assessed using the Chinese Multi-provincial Cohort Study functions. RESULTS: Overall, there was a 10% decrease in FGF-21 after OGTT (p<0.001). The decrease of FGF-21 after OGTT in patients with normal glucose tolerance, prediabetes, and diabetes was 8%, 10%, and 21%, respectively (all p<0.05). Patients with a history of admission for coronary angiography had a higher 10-year CHD risk and fasting FGF-21 (both p<0.001). In multivariate regression analysis, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with ß-cell function. CONCLUSIONS: In patients who had no history of diabetes, fasting FGF-21 was positively associated with 10-year CHD risk, while FGF-21 relative change 2h after OGTT was positively associated with ß-cell function.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/patologia , Fatores de Crescimento de Fibroblastos/sangue , Células Secretoras de Insulina/patologia , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
20.
Diabetol Metab Syndr ; 9: 29, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28473872

RESUMO

BACKGROUND: There is a high hospitalization rate for diabetic patients. Since retinopathy and albuminuria are both important manifestations of microvascular disease in diabetes, our aim was to investigate the effect of retinopathy and albuminuria on long-term mortality in type 2 diabetic inpatients through this observational cohort study. METHODS: Type 2 diabetic inpatients given a primary diagnosis of poor glucose control were consecutively enrolled during their hospitalization periods. Clinical information was collected through review of each patient's medical records, and mortality data were obtained from the national registry in Taiwan. RESULTS: A total of 761 type 2 diabetic inpatients were enrolled in the study with a median follow-up period of 6.6 years (interquartile range, 4.0-9.6 years). Patients in the Albuminuria(-)/Retinopathy(+), Albuminuria(+)/Retinopathy(-) and Albuminuria(+)/Retinopathy(+) groups had significantly higher risks of all-cause mortality and cardiovascular mortality than those in the Albuminuria(-)/Retinopathy(-) group. However, among patients with albuminuria, there was no significant difference in cumulative mortality between those with and without retinopathy (P = 0.821). A decrease in the estimated glomerular filtration rate (eGFR), but not retinopathy, was an independent predictor of all-cause mortality (95% CI 0.647‒0.893; P < 0.001) and cardiovascular mortality (95% CI 0.564‒0.921; P = 0.009) in type 2 diabetic inpatients with albuminuria. CONCLUSIONS: Albuminuria in type 2 diabetic inpatients is a strong predictor of long-term mortality after discharge from the hospital. Retinopathy is an independent predictor of mortality in type 2 diabetic inpatients without albuminuria but not in those with albuminuria. A low eGFR is a better predictor of mortality than retinopathy in type 2 diabetic inpatients with albuminuria.

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