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1.
Nat Med ; 27(11): 1928-1940, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34663987

RESUMO

Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.

2.
BMJ Open ; 11(8): e045495, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462277

RESUMO

OBJECTIVE: To investigate the association between body mass index (BMI) and all-cause mortality in a Chinese rural population. DESIGN: Prospective cohort study. SETTING: This study was conducted from 2003 to 2018 in Anqing, Anhui Province, China. PARTICIPANTS: 17 851 participants aged 25-64 years (49.4% female) attending physical examinations and questionnaire were included in this study. The inclusion criterion was families having a minimum of three participating siblings. The exclusion criteria included participants without family number and BMI data at baseline. OUTCOME MEASURES: The outcome measure was all-cause mortality. Generalized estimating equation (GEE) regression analysis was performed to determine the association between baseline BMI and all-cause mortality. RESULTS: During a mean follow-up period of 14.1 years, 730 deaths (8.0%) occurred among men, and 321 deaths (3.6%) occurred among women. The mean BMI for males was 21.3[Formula: see text] kg/m2, and for female it was 22.1±3.1 kg/m2. Baseline BMI was significantly inversely associated with all-cause mortality risk for per SD increase (OR, 0.79 (95% CI, 0.72 to 0.87) for males; OR, 0.88 (95% CI, 0.76 to 1.01) for females). When BMI was stratified with cut points at 20 and 24 kg/m2, compared with the low BMI group, a significantly lower risk of death was found in the high BMI group (BMI ≥24: OR, 0.57 (95% CI, 0.43 to 0.77) in males; 0.65 (95% CI, 0.46 to 0.93) in females) after adjustment for relevant factors. CONCLUSIONS: In this relatively lean rural Chinese population, the risk of all-cause mortality decreased with increasing BMI. The excess risk of all-cause mortality associated with a high BMI was not seen among this rural population.


Assuntos
Mortalidade , População Rural , Adulto , Índice de Massa Corporal , China/epidemiologia , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco
3.
Clin Interv Aging ; 16: 801-810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34017170

RESUMO

Background and Purpose: Elevated high-density lipoprotein cholesterol (HDL-C) levels have displayed protection against cardiovascular disease. However, the association between specific lipoprotein classes and first ischemic stroke (IS) has not been well defined, particularly in higher-risk hypertensive populations. Our study evaluated the associations of HDL-C with first IS in a Chinese hypertensive population. Methods: The study population was obtained from a community-based cohort study of hypertension in Lianyungang and Rongcheng, China. A nested case-control design was used that included 2463 identified first IS cases and 2463 controls matched by age ± 1 year, sex, and region. Results: After adjusting for potential confounders, HDL-C was inversely associated with first IS (adjusted odds ratio [aOR]: 0.91; 95% confidence interval [CI]: 0.85-0.98). HDL-C levels of at least 65.4 mg/dL displayed a significant protective effect for first IS (aOR: 0.82; 95% CI: 0.69-0.98). Conversely, adverse effects of first IS were observed for low-density lipoprotein cholesterol (LDL-C) levels ≥138.1 mg/dL (aOR: 1.20; 95% CI: 1.02-1.42) and triglyceride (TG) levels ≥140.8 mg/dL (aOR: 1.27; 95% CI: 1.09-1.49). The risk associations of LDL-C and TG with first IS were attenuated in the presence of high HDL-C (≥53.0 mg/dL); an increased risk of first IS was only found in the presence of low HDL-C (<53.0 mg/dL) when LDL-C (aOR: 1.66; 95% CI: 1.19-2.31) and TG (aOR: 1.47; 95% CI: 1.17-1.84) were combined with HDL-C for analysis. Conclusion: In this community-based Chinese hypertensive population, higher HDL-C was a significant protective factor of first IS. These data add to the evidence describing the relationship between lipids and IS and suggest that HDL-C maybe is a marker of IS risk in Chinses hypertensive population.


Assuntos
HDL-Colesterol/sangue , Hipertensão/epidemiologia , AVC Isquêmico/epidemiologia , Idoso , Biomarcadores , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Hipertensão/fisiopatologia , AVC Isquêmico/fisiopatologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco
4.
Exp Clin Transplant ; 19(5): 434-438, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34053421

RESUMO

OBJECTIVES: CYP3A5 and ABCB1 are highly implicated in the pharmacokinetics and pharmacodynamics of immunosuppressive agents, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. The polymorphisms of their coding genes play important roles in the interindividual and intraindividual differences of bioavailability of these drugs. In this study, our objective was to investigate, in a Lebanese population,the frequency of ABCB1C3435T (rs1045642) and CYP3A5*3 (rs776746) polymorphisms and to compare the results to preexisting data from other populations. MATERIALS AND METHODS: We determined the frequencies of the allelic variants of interest for 1824 Lebanese participants, and we compared these results with those from other major ethnic groups. RESULTS: The allelic frequencies were 91.4% (C) and 8.6% (T) for CYP3A5*3 and 50.8% (T) and 49.2% (C) for ABCB1 C3435T. Our results were significantly different from most other world populations, except the European population. CONCLUSIONS: The frequencies of gene variants of interest in our Lebanese population were similar to those found in European populations. Most of our study population were CYP3A5*3 carriers, and more than half may have a lower P-glycoprotein efflux pump. These characteristics might render Lebanese transplant recipients more prone to the development of drug toxicity and in need of lower drug doses.

5.
BMC Public Health ; 21(1): 696, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836720

RESUMO

BACKGROUND: According to the Global Burden of Disease Study 2017, smoking is one of the leading four risk factors contributing to deaths in China. We aimed to evaluate the associations of smoking with all-cause mortality in a Chinese rural population. METHODS: Male participants over age 45 (n = 5367) from a large familial aggregation study in rural China, were included in the current analyses. A total of 528 former smokers and 3849 current smokers accounted for 10 and 71.7% of the cohort, respectively. Generalized Estimating Equations were used to evaluate the association between baseline smoking status and mortality, adjusting for pertinent covariates. RESULTS: There were 579 recorded deaths during the 15-year follow-up. Current smokers (odds ratio [OR],1.60; 95% CI,1.23-2.08) had higher all-cause mortality risks than nonsmokers. Relative to nonsmokers, current smokers of more than 40 pack-years ([OR],1.85; 95% CI,1.33-2.56) had a higher all-cause mortality risk. Compared to nonsmokers, current smokers who started smoking before age 20 ([OR],1.91; 95% CI,1.43-2.54) had a higher all-cause mortality risk, and former smokers in the lower pack-year group who quit after age 41 (median) ([OR],3.19; 95% CI,1.83-5.56) also had a higher risk of death after adjustment. Furthermore, former smokers who were also former drinkers had the highest significant risk of mortality than never smokers or drinkers. (P for interaction = 0.034). CONCLUSIONS: This study provides evidence that current smokers and former smokers have a higher mortality risk than nonsmokers and would benefit from cessation at a younger age.


Assuntos
Fumar Cigarros , Adulto , China/epidemiologia , Estudos de Coortes , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , População Rural , Adulto Jovem
6.
BMC Med Genomics ; 14(1): 90, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33766035

RESUMO

BACKGROUND: Coronary Artery Disease (CAD) is the narrowing or blockage of the coronary arteries. It is closely associated with numerous genetics and environmental factors that have been extensively evaluated in various populations. In recent studies, severe phenotypes have been strongly linked to genetic risk factors. METHODS: This study investigated the association of clinical, demographic, and genetic factors with severe coronary artery stenosis phenotypes in our population composed of 1734 individuals with severe coronary stenosis (≥ 50% in coronary vessels) and comparing them to 757 controls with no evidence of stenosis on angiography. We performed generalized linear model (GLM) genome-wide association studies to evaluate three stratification models and their associations to characteristics of the clinical disease. In model 1, patients were not stratified. In model 2, patients were stratified based on presence or absence of CAD family history (FxCAD). In model 3, patients were stratified by young age of CAD onset. RESULTS: Eight SNPs (single nucleotide polymorphism) were significantly associated with severe CAD phenotypes in the various models [Formula: see text], four of these SNPs were associated with severe CAD and the four others were specifically significant for young CAD patients. While these SNPs were not previously reported for association with CAD, six of them are present in genes that have already been linked to coronary disease. CONCLUSION: In conclusion, this study presents new genetic factors associated with severe stenosis and highlights different risk factors associated with a young age at diagnosis of CAD.


Assuntos
Alelos , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Adulto , Doença da Artéria Coronariana , Estenose Coronária , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade
7.
QJM ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33453113

RESUMO

BACKGROUND: The relationship of osteoporosis and stroke is still not fully clarified. Apart from the well-known risk factors for stroke, bone mineral density (BMD) has gained more interest in recent years. AIM: To further elucidate the relationship between BMD and stroke risk, a prospective cohort study in the Chinese rural population was conducted. DESIGN: Retrospective analysis of a family osteoporosis cohort. METHODS: Our subjects were selected from an osteoporosis cohort conducted in Anqing, China. All participants underwent a questionnaire assessment, clinical examinations, and laboratory assessments. During the follow-up period, the number of people who had a stroke was recorded. Generalized estimating equation regression analysis was performed to determine the significance of the association between BMD and stroke. RESULTS: A total of 17868 people were included. A two-way interaction test of sex and BMD on stroke was significant (p = 0.002). There was a significant difference in BMD and stroke morbidity in the male group (p = 0.003). When BMD was assessed as quartiles and the lowest quartile was used as reference, a significantly lower risk for stroke were observed in Q2, Q3 and Q4. Notably, no significant difference was observed in female participants with adjusted odds ratio (p > 0.05). The p-value for interaction was calculated. The BMI (p = 0.014) and waist-to-hip ratio (p = 0.027) were found to be significantly associated with BMD and stroke risk in female participants. CONCLUSIONS: In Chinese rural areas, total BMD may negatively correlated with stroke, especially in men.

8.
Sci Rep ; 11(1): 408, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33432032

RESUMO

We sought to investigate whether epidemiological parameters that define epidemic models could be determined from the epidemic trajectory of infections, recovery, and hospitalizations prior to peak, and also to evaluate the comparability of data between jurisdictions reporting their statistics. We found that, analytically, the pre-peak growth of an epidemic underdetermines the model variates, and that the rate limiting variables are dominated by the exponentially expanding eigenmode of their equations. The variates quickly converge to the ratio of eigenvector components of the positive growth mode, which determines the doubling time. Without a sound epidemiological study framework, measurements of infection rates and other parameters are highly corrupted by uneven testing rates, uneven counting, and under reporting of relevant values. We argue that structured experiments must be performed to estimate these parameters in order to perform genetic association studies, or to construct viable models accurately predicting critical quantities such as hospitalization loads.

9.
Eur J Hum Genet ; 29(4): 581-592, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33273712

RESUMO

Currently, there are 18 different religious communities living in Lebanon. While evolving primarily within Lebanon, these communities show a level of local isolation as demonstrated previously from their Y-haplogroup distributions. In order to trace the origins and migratory patterns that may have led to the genetic isolation and autosomal clustering in some of these communities we analyzed Y-chromosome STR and SNP sample data from 6327 individuals, in addition to whole genome autosomal sample data from 609 individuals, from Mount Lebanon and other surrounding communities. We observed Y chromosome L1b Levantine STR branching that occurred around 5000 years ago. Autosomal DNA analyses suggest that the North Lebanese Mountain Maronite community possesses an ancestral Fertile Crescent genetic component distinct from other populations in the region. We suggest that the Levantine L1b group split from the Caucasus ancestral group around 7300 years ago and migrated to the Levant. This event was distinct from the earlier expansions from the Caucasus region that contributed to the wider Levantine populations. Differential cultural adaption by populations from the North Lebanese Mountains are clearly aligned with the L1b haplotype STR haplogroup clusters, indicating pre-existing and persistent cultural barriers marked by the transmission of L1b lineages. Our findings highlight the value of uniparental haplogroups and STR haplotype data for elucidating biosocial events among these populations.

10.
PLoS One ; 15(11): e0242019, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237940

RESUMO

Aortic valve stenosis (AVS) is a prevalent condition among the elderly population that eventually requires aortic valve replacement. The lack of reliable biomarkers for AVS poses a challenge for its early diagnosis and the application of preventive measures. Untargeted gas chromatography mass spectrometry (GC-MS) metabolomics was applied in 46 AVS cases and 46 controls to identify plasma and urine metabolites underlying AVS risk. Multivariate data analyses were performed on pre-processed data (e.g. spectral peak alignment), in order to detect changes in metabolite levels in AVS patients and to evaluate their performance in group separation and sensitivity of AVS prediction, followed by regression analyses to test for their association with AVS. Through untargeted analysis of 190 urine and 130 plasma features that could be detected and quantified in the GC-MS spectra, we identified contrasting levels of 22 urine and 21 plasma features between AVS patients and control subjects. Following metabolite assignment, we observed significant changes in the concentration of known metabolites in urine (n = 14) and plasma (n = 15) that distinguish the metabolomic profiles of AVS patients from healthy controls. Associations with AVS were replicated in both plasma and urine for about half of these metabolites. Among these, 2-Oxovaleric acid, elaidic acid, myristic acid, palmitic acid, estrone, myo-inositol showed contrasting trends of regulation in the two biofluids. Only trans-Aconitic acid and 2,4-Di-tert-butylphenol showed consistent patterns of regulation in both plasma and urine. These results illustrate the power of metabolomics in identifying potential disease-associated biomarkers and provide a foundation for further studies towards early diagnostic applications in severe heart conditions that may prevent surgery in the elderly.


Assuntos
Estenose da Valva Aórtica/metabolismo , Valva Aórtica/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Plasma/metabolismo , Urina/química , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/urina , Estudos de Casos e Controles , Ecocardiografia/métodos , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Próteses Valvulares Cardíacas , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Análise Multivariada , Análise de Regressão , Urinálise/métodos
11.
Artigo em Inglês | MEDLINE | ID: mdl-33023897

RESUMO

INTRODUCTION: Previous studies in mostly Western populations have yielded conflicting findings on the association of vitamin B12 with diabetes risk, in part due to differences in study design and population characteristics. This study sought to examine the vitamin B12-diabetes association in Chinese adults with hypertension by both cross-sectional and longitudinal analyses. RESEARCH DESIGN AND METHODS: This report included a total of 16 699 participants from the China Stroke Primary Prevention Trial, with pertinent baseline and follow-up data. Diabetes mellitus was defined as either physician-diagnosed diabetes, use of glucose-lowering drugs, or fasting blood glucose (FBG) ≥7.0 mmol/L. New-onset diabetes was defined as any new case of onset diabetes during the follow-up period or FBG ≥7.0 mmol/L at the exit visit. RESULTS: At baseline, there were 1872 (11.2%) patients with diabetes; less than 1.5% had clinical vitamin B12 deficiency (<148.0 pmol/L). Over a median follow-up period of 4.5 years, there were 1589 (10.7%) cases of new-onset diabetes. Cross-sectional analyses showed a positive association between baseline vitamin B12 levels and FBG levels (ß=0.18, 95% CI 0.15 to 0.21) and diabetes (OR=1.16, 95% CI 1.10 to 1.21). However, longitudinal analyses showed no association between baseline vitamin B12 and new-onset diabetes or changes in FBG levels. Among a subset of the sample (n=4366) with both baseline and exit vitamin B12 measurements, we found a positive association between an increase in vitamin B12 and an increase in FBG. CONCLUSIONS: In this large Chinese population of patients with hypertension mostly sufficient with vitamin B12, parallel cross-sectional and longitudinal analyses provided new insight into the conflicting findings of previous studies, and these results underscore the need for future studies to consider both baseline vitamin B12 and its longitudinal trajectory in order to better elucidate the role of vitamin B12 in the development of diabetes. Such findings would have important clinical and public health implications.


Assuntos
Diabetes Mellitus , Acidente Vascular Cerebral , Adulto , China/epidemiologia , Estudos Transversais , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/prevenção & controle , Humanos , Prevenção Primária , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Vitamina B 12 , Vitaminas
12.
Diabetes Ther ; 11(11): 2691-2701, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32978754

RESUMO

INTRODUCTION: The worldwide prevalence of diabetes has been increasing for decades; diabetes can lead to serious health problems and even death, but the effects of maintaining low fasting blood glucose (FBG) remain controversial. The purpose of this study was to investigate the relationship between FBG levels and all-cause mortality in a long-term follow-up cohort and to find a relatively safe range of FBG levels. METHODS: This study included 17,902 adults from a community-based cohort study in rural China who were prospectively followed from 2003 to 2018. Generalized estimating equations were used to evaluate the association between FBG and all-cause mortality, adjusting for pertinent covariates and auto-correlations among siblings. RESULTS: A total of 1053 (5.9%) deaths occurred during 15 years of follow-up. There was a significant U-shaped association between all-cause mortality and FBG. Compared with the reference group (FBG of 5.6 - < 6.1 mmol/l), the risk of death among individuals with FBG levels < 5.6 mmol/l significantly increased by 38% (OR 1.34; 95% CI 1.13-1.59), while the risk of death among individuals with FBG ≥ 6.1 mmol/l or participants with a self-reported history of diabetes significantly increased by 51% (OR 1.49; 95% CI 1.20-1.85). Additionally, the U-shaped association remained steady in any stratification of risk factors. CONCLUSION: Our study showed a significant U-shaped relationship between FBG levels and risk of all-cause mortality in this rural Chinese population. When FBG was within the range of 5.6 - < 6.1 mmol/l, the risk of all-cause mortality was the lowest.

13.
Cell Rep ; 30(7): 2306-2320.e5, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32075738

RESUMO

Exposure to natural metabolites contributes to the risk of cardiometabolic diseases (CMDs). Through metabolome profiling, we identify the inverse correlation between serum concentrations of 4-cresol and type 2 diabetes. The chronic administration of non-toxic doses of 4-cresol in complementary preclinical models of CMD reduces adiposity, glucose intolerance, and liver triglycerides, enhances insulin secretion in vivo, stimulates islet density and size, and pancreatic ß-cell proliferation, and increases vascularization, suggesting activated islet enlargement. In vivo insulin sensitivity is not affected by 4-cresol. The incubation of mouse isolated islets with 4-cresol results in enhanced insulin secretion, insulin content, and ß-cell proliferation of a magnitude similar to that induced by GLP-1. In both CMD models and isolated islets, 4-cresol is associated with the downregulated expression of the kinase DYRK1A, which may mediate its biological effects. Our findings identify 4-cresol as an effective regulator of ß-cell function, which opens up perspectives for therapeutic applications in syndromes of insulin deficiency.


Assuntos
Linfócitos B/metabolismo , Glicemia/metabolismo , Cresóis/uso terapêutico , Diabetes Mellitus Tipo 2/genética , Secreção de Insulina/efeitos dos fármacos , Metabolômica/métodos , Obesidade/metabolismo , Animais , Proliferação de Células , Cresóis/farmacologia , Homeostase , Humanos , Camundongos , Ratos
14.
Curr Biol ; 29(22): 3953-3959.e4, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31679935

RESUMO

North Africa is located at the crossroads of the Mediterranean Sea, the Middle East, and the Sahara Desert. Extensive migrations and gene flow in the region have shaped many different cultures and ancestral genetic components through time [1-6]. DNA data from ancient Moroccan sites [7, 8] has recently shed some light to the population continuity-versus-replacement debate, i.e., the question of whether current North African populations descend from Palaeolithic groups or, on the contrary, subsequent migrations swept away all pre-existing genetic signal in the region. In the present study, we analyze 21 complete North African genomes and compare them with extant and ancient genome data in order to address the demographic continuity-versus-replacement debate, to assess whether these demographic events were homogeneous (including Berber and Arabic-speaking groups), and to explore the effect of Neolithization and posterior migration waves. The North African genetic pool is defined as a melting pot of genetic components, including an endemic North African Epipalaeolithic component at low frequency that forms a declining gradient from Western to Eastern North Africa. This scenario is consistent with Neolithization having shaped most of the current genetic variation in the region when compared to posterior back-to-North-Africa migration waves such as the Arabization. A common and distinct genetic history of the region is shown, with internal different proportions of genetic components owing to differential admixture with surrounding groups as well as to genetic drift due to isolation and endogamy in certain populations.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Fluxo Gênico/genética , África ao Sul do Saara , África do Norte , Grupo com Ancestrais do Continente Europeu/genética , Fósseis , Pool Gênico , Variação Genética , Genética Populacional/métodos , Genoma/genética , Haplótipos , História Antiga , Migração Humana/história , Humanos , Polimorfismo de Nucleotídeo Único
15.
PLoS One ; 14(8): e0221672, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437235

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0218443.].

16.
J Diabetes Metab Disord ; 18(1): 163-172, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31275887

RESUMO

Background: A two-way relationship between diabetes and periodontitis is now clinically established. Both conditions share common mechanisms of pathogenesis that are related to altered immune-inflammatory responses at local and/or systemic levels. The aim of this study is to investigate whether periodontitis is associated with the development and progression of diabetes and to evaluate the health impact of coexistence of both diseases. Material and methods: Male Sprague Dawley rats (10 weeks old) were randomized into seven groups (n = 12): Group 1) Control; Groups 2 and 6) Periodontitis induced at two or six weeks; Groups 3 and 5) Diabetes induced at two or six weeks; Groups 4 and 7) Periodontitis followed by diabetes, and diabetes followed by periodontitis at two or six weeks. For diabetes induction, animals received a one-time intravenous injection of streptozotocin (50 mg/kg). Periodontitis was induced by Lipoppolysaccharide injection (20 µg/rat) through the palatal gingival and by placing a ligature of 0/0 braided silk around the cervix of the upper right second molar. Body weight, glycaemia as well as urine were collected weekly. Rats were sacrificed at the end of week 10, gingival tissue was removed, fixed in formaldehyde and processed for histopathological study. Results: Body weight was significantly decreased (25%) following diabetes induction (p < 0.01). 40% weight loss was observed when diabetes was induced first compared to 30% when periodontitis was first induced in the animals (p < 0.01). Rats treated with streptozotocin showed a three-fold increase in diabetes compared to the control group (p < 0.01). In rats where periodontitis was induced after diabetes, glucose levels increased significantly (450 mg/dL) compared to glucose levels (410 mg/dL) where periodontitis was induced first (p < 0.01). Histopathological studies showed greater alveolar bone loss when both diabetes and periodontitis were present. Conclusion: When periodontitis occurs after diabetes it aggravates the symptoms of the two pathologies. When diabetes is induced after periodontitis, no symptoms aggravation is observed for diabetes, although periodontitis gets worse.

17.
PLoS One ; 14(6): e0218443, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211820

RESUMO

Low serum levels of high-density lipoprotein cholesterol (HDL-C) have been shown to be a risk factor for coronary artery disease independent of low-density lipoprotein cholesterol (LDL-C) in different populations. In this study, we investigated genetic variants through genome-wide association studies to determine their association with HDL-C levels in a sample of 2,700 patients. We identified several SNPs associated with HDL-C levels in the Lebanese population using unadjusted and adjusted by biological factors models. We replicated the association of rs3764261 within CETP with HDL-C levels in the study population, and found other previously unidentified SNPs to be significant at the suggestive level, in both previously identified and unidentified genes. This paper reports the first genome-wide analysis of HDL-C in the Lebanese, Middle Eastern, population and supports the importance of genome-wide association studies across different and minor ethnicities to understand better the etiology of complex human diseases.


Assuntos
HDL-Colesterol/genética , Doença da Artéria Coronariana/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , LDL-Colesterol/genética , Estudos de Coortes , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Líbano/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
18.
Genome Biol ; 20(1): 77, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31023378

RESUMO

BACKGROUND: Population demography and gene flow among African groups, as well as the putative archaic introgression of ancient hominins, have been poorly explored at the genome level. RESULTS: Here, we examine 15 African populations covering all major continental linguistic groups, ecosystems, and lifestyles within Africa through analysis of whole-genome sequence data of 21 individuals sequenced at deep coverage. We observe a remarkable correlation among genetic diversity and geographic distance, with the hunter-gatherer groups being more genetically differentiated and having larger effective population sizes throughout most modern-human history. Admixture signals are found between neighbor populations from both hunter-gatherer and agriculturalists groups, whereas North African individuals are closely related to Eurasian populations. Regarding archaic gene flow, we test six complex demographic models that consider recent admixture as well as archaic introgression. We identify the fingerprint of an archaic introgression event in the sub-Saharan populations included in the models (~ 4.0% in Khoisan, ~ 4.3% in Mbuti Pygmies, and ~ 5.8% in Mandenka) from an early divergent and currently extinct ghost modern human lineage. CONCLUSION: The present study represents an in-depth genomic analysis of a Pan African set of individuals, which emphasizes their complex relationships and demographic history at population level.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Fluxo Gênico , Migração Humana , África , Variação Genética , Humanos , Filogeografia , Densidade Demográfica , Sequenciamento Completo do Genoma
19.
J Clin Transl Endocrinol ; 16: 100185, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30899673

RESUMO

Aims: The Middle East has the fastest rising rate of Type 2 Diabetes Mellitus (T2DM) worldwide, with Lebanon having 15.8% of its population affected. This study aims at studying Polycystic Ovarian Syndrome (PCOS), Gestational Diabetes Mellitus (GDM), and macrosomia as risk factors of T2DM in Lebanon. Such epidemiological and statistical study has never been conducted before in the Middle East region and would be useful for clinical diagnosis. Methods: Our cohort is comprised of 1453 Lebanese individuals, with 897 controls and 556 patients. We tested the correlation between T2DM and the covariates GDM, PCOS, and macrosomia independently. We conducted multinomial logistic regression and cross tabulations with T2DM as an outcome. Results: The results showed a significant association of the independent factors GDM and macrosomia with T2DM. The risk of having T2DM was increased by 4.192 times with the GDM, and by 2.315 times with macrosomia respectively. Conclusion: In conclusion, GDM and macrosomia, but not PCOS, are significant risk factors for T2DM in our Lebanese cohort. Our results, reported for the first time in the Middle East, present insights into risk factors management and disease prevention.

20.
Lipids Health Dis ; 18(1): 38, 2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30711004

RESUMO

BACKGROUND: Lipoproteins are major players in the development and progression of atherosclerotic plaques leading to coronary stenosis and myocardial infarction. Epidemiological, genetic and experimental observations have implicated the association of sphingolipids and intermediates of sphingolipid synthesis in atherosclerosis. We aimed to investigate relationships between quantitative changes in serum sphingolipids, the regulation of the metabolism of lipoproteins (LDL, HDL), and endophenotypes of coronary artery disease (CAD). METHODS: We carried out untargeted liquid chromatography - mass spectrometry (UPLC-MS) lipidomics of serum samples of subjects belonging to a cross-sectional study and recruited on the basis of absence or presence of angiographically-defined CAD, and extensively characterized for clinical and biochemical phenotypes. RESULTS: Among the 2998 spectral features detected in the serum samples, 1328 metabolic features were significantly correlated with at least one of the clinical or biochemical phenotypes measured in the cohort. We found evidence of significant associations between 34 metabolite signals, corresponding to a set of sphingomyelins, and serum HDL cholesterol. Many of these metabolite associations were also observed with serum LDL and total cholesterol levels but not as much with serum triglycerides. CONCLUSION: Among patients with CAD, sphingolipids in the form of sphingomyelins are directly correlated with serum levels of lipoproteins and total cholesterol. Results from this study support the fundamental role of sphingolipids in modulating lipid serum levels, highlighting the importance to identify novel targets in the sphingolipid metabolic pathway for anti-atherogenic therapies.


Assuntos
Colesterol/sangue , Esfingomielinas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Espectrometria de Massas , Metabolômica/instrumentação , Metabolômica/métodos , Pessoa de Meia-Idade , Adulto Jovem
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