RESUMO
Exposure to diesel exhaust particles (DEPs) is associated with acute inflammatory responses in the lung and exacerbation of respiratory diseases. However, the mechanism by which DEPs trigger the inflammatory responses remains unclear. Here, we demonstrated that the IFN response factors IRF3 and IRF7 played pivotal roles in DEP-induced pulmonary inflammation. DEPs could not directly induce inflammatory cytokine expression in mouse cells, whereas DEPs triggered autophagy both in vitro and in vivo. The DEP-induced autophagy was augmented in the absence of IRF3 and IRF7, but not in the absence of IFNAR. The expression of Raptor was induced by IRF3 and IRF7 in response to DEPs treatment. Furthermore, administration of the mechanistic target of rapamycin (mTOR) inhibitor alleviated the inflammatory responses in the lung during DEP exposure. Our findings define an IFNAR-independent role of increased autophagy in the absence of IRF3 and IRF7 during pulmonary DEP exposure, and provide the basis to develop new therapeutic approaches to counteract the adverse effects of DEPs and possibly other ambient particulate matters.
Assuntos
Autofagia/fisiologia , Fator Regulador 3 de Interferon/fisiologia , Fator Regulador 7 de Interferon/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/fisiologia , Pneumonia/etiologia , Emissões de Veículos/toxicidade , Animais , Citocinas/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Interferon alfa e beta/fisiologia , Sirolimo/farmacologiaRESUMO
OBJECTIVES: The aim of this study is to investigate whether heat shock protein 70 (Hsp70) gene polymorphisms are implicated in systemic lupus erythematous (SLE) susceptibility, the efficacy of glucocorticoids (GCs) treatment, and improvement of health-related quality of life. METHODS: A total of 499 SLE patients and 499 controls were included in a case-control study, and 468 SLE patients treated with GCs for 12 weeks were involved in a follow-up study. Patients who completed the 12-week follow-up were divided into GCs-sensitive and GCs-insensitive group by using the SLE disease activity index. The SF-36 was used to evaluate the health-related quality of life of SLE patients, and genotyping was performed by improved multiplex ligation detection reaction. RESULTS: rs2075800 was associated with SLE susceptibility (adjusted odds ratio [ORadj], 1.437; 95% confidence interval [CI], 1.113-1.855; Padj = 0.005; PBH = 0.020 by dominant model; ORadj, 1.602; 95% CI, 1.072-2.395; Padj = 0.022; PBH = 0.029 by TT vs CC model; ORadj = 1.396; 95% CI = 1.067-1.826; Padj = 0.015; PBH = 0.029 by TC vs CC model). In the follow-up study, rs2075799 was associated with the improvement in mental health (p = 0.004, PBH = 0.044), but we failed to find any association between the efficacy of GCs and Hsp70 gene polymorphisms. CONCLUSIONS: Hsp70 gene polymorphisms may be associated with susceptibility to SLE and improvement of mental health in Chinese Han population.
Assuntos
Glucocorticoides/farmacologia , Proteínas de Choque Térmico HSP70/genética , Lúpus Eritematoso Sistêmico , Qualidade de Vida , Estudos de Casos e Controles , China/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/psicologia , Masculino , Gravidade do Paciente , Farmacogenética/métodos , Farmacogenética/estatística & dados numéricos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease, and oestrogen is considered to be a predisposing factor for SLE. Although some studies are conducted to explore the association between oestrogen receptor alpha (ERα) gene polymorphisms and SLE susceptibility, their results are inconsistent. METHODS: Meta-analysis was conducted to confirm whether ERα gene polymorphisms were associated with SLE susceptibility, and the strength of association was anticipated by pooled ORs with 95% CIs. Stata software package version 12.0 was used to calculate all the statistical analyses. RESULTS: Twelve studies included 2494 cases and 4176 controls were incorporated in our meta-analysis. A significant association was found for ERα PvuII polymorphism in the overall population (CC+CT vs TT: ORâ¯=â¯1.334, 95% CIâ¯=â¯1.195-1.490, Pâ¯<â¯0.001; CC vs TT: ORâ¯=â¯1.401, 95% CIâ¯=â¯1.096-1.791, Pâ¯=â¯0.007; CT vs TT: ORâ¯=â¯1.284, 95% CIâ¯=â¯1.141-1.444, Pâ¯<â¯0.001; C vs T: ORâ¯=â¯1.221, 95% CIâ¯=â¯1.084-1.375, Pâ¯=â¯0.001), while there was no significant association for ERα XbaI polymorphism. Besides, in stratification analyses by ethnicity, the PvuII polymorphism was associated with an increased risk of SLE in Asians (CC+CT vs TT: ORâ¯=â¯1.379, 95% CIâ¯=â¯1.203-1.581, Pâ¯<â¯0.001; CT vs TT: ORâ¯=â¯1.308, 95% CIâ¯=â¯1.130-1.515, Pâ¯<â¯0.001; C vs T: ORâ¯=â¯1.240, 95% CIâ¯=â¯1.052-1.462, Pâ¯=â¯0.010), while for ESR1 XbaI polymorphism, a significantly increased risk of SLE susceptibility was found in Asians (GA vs AA: ORâ¯=â¯1.271, 95% CIâ¯=â¯1.101-1.467, Pâ¯=â¯0.001). CONCLUSION: Our meta-analysis indicated that the ERα PvuII polymorphism was significantly associated with SLE susceptibility in the overall and Asian populations, while the ERα XbaI GA genotype only played a key role in SLE susceptibility in Asian populations.
Assuntos
Receptor alfa de Estrogênio/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Povo Asiático , Genótipo , Humanos , Polimorfismo Genético , Medição de Risco , População BrancaRESUMO
Various studies have investigated the serum sclerostin and bone morphogenetic protein-2 (BMP-2) levels in patients with ankylosing spondylitis (AS), but the results were inconsistent. The aim of this meta-analysis was to synthetically assess the associations of serum levels of sclerostin and BMP-2 with AS. Multiple electronic databases were searched to locate relevant articles published before November 2018. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Totally, 21 studies were included. Meta-analysis results showed no significant difference between AS group and control group in serum sclerostin levels (SMD = 0.098, 95% CI - 0.395 to 0.591, p = 0.697). Nevertheless, serum BMP-2 levels in AS patients were higher than that in controls (SMD = 1.184, 95% CI 0.209 to 2.159, p = 0.017). Subgroup analysis demonstrated that European and South American AS patients had lower serum levels of sclerostin than controls. AS patients with age ≥ 40 years, erythrocyte sedimentation rate (ESR) ≤ 20 mm/h and Bath Ankylosing Spondylitis Functional Index (BASFI) < 4 had statistically significant lower serum sclerostin concentrations compared to controls. Chinese and Korean AS patients as well as patients with lower CRP had higher serum BMP-2 levels than controls, and country may be a source of heterogeneity across the studies. No publication bias existed and sensitivity analysis confirmed the stability of results. Serum BMP-2, but not sclerostin levels may be closely related to the development of AS.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/sangue , Proteína Morfogenética Óssea 2/sangue , Proteínas Morfogenéticas Ósseas/sangue , Espondilite Anquilosante/sangue , Povo Asiático , Marcadores Genéticos/fisiologia , Humanos , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. APPROACH AND RESULTS: This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5±8.5 versus 14.4±8.1 µmol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7±6.1 µmol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4±7.9 µmol/L, group difference: 1.61 µmol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. CONCLUSIONS: Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ≈15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.
Assuntos
Ácido Fólico/uso terapêutico , Homocisteína/sangue , Hiper-Homocisteinemia/tratamento farmacológico , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Complexo Vitamínico B/uso terapêutico , Idoso , Anti-Hipertensivos/uso terapêutico , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , China , Método Duplo-Cego , Enalapril/uso terapêutico , Feminino , Ácido Fólico/sangue , Genótipo , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/diagnóstico , Hiper-Homocisteinemia/genética , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Complexo Vitamínico B/sangueRESUMO
BACKGROUND: Mitochondrial DNA sequences have long been used in phylogenetic studies. However, little attention has been paid to the changes in gene arrangement patterns in the snake's mitogenome. Here, we analyzed the complete mitogenome sequences and structures of 65 snake species from 14 families and examined their structural patterns, organization and evolution. Our purpose was to further investigate the evolutionary implications and possible rearrangement mechanisms of the mitogenome within snakes. RESULTS: In total, eleven types of mitochondrial gene arrangement patterns were detected (Type I, II, III, III-A, III-B, III-B1, III-C, III-D, III-E, III-F, III-G), with mitochondrial genome rearrangements being a major trend in snakes, especially in Alethinophidia. In snake mitogenomes, the rearrangements mainly involved three processes, gene loss, translocation and duplication. Within Scolecophidia, the OL was lost several times in Typhlopidae and Leptotyphlopidae, but persisted as a plesiomorphy in the Alethinophidia. Duplication of the control region and translocation of the tRNALeu gene are two visible features in Alethinophidian mitochondrial genomes. Independently and stochastically, the duplication of pseudo-Pro (P*) emerged in seven different lineages of unequal size in three families, indicating that the presence of P* was a polytopic event in the mitogenome. CONCLUSIONS: The WANCY tRNA gene cluster and the control regions and their adjacent segments were hotspots for mitogenome rearrangement. Maintenance of duplicate control regions may be the source for snake mitogenome structural diversity.
Assuntos
Evolução Molecular , Genoma Mitocondrial , Serpentes/genética , Animais , Rearranjo Gênico , Funções Verossimilhança , Filogenia , Serpentes/classificação , Especificidade da EspécieRESUMO
The associations between PvuII (T>C) and XbaI (A>G) polymorphisms of estrogen receptor alpha (ESR1) gene with type 2 diabetes mellitus (T2DM) or metabolic syndrome (MetS) are reported in many studies, but the results are inconsistent. This present work aims to assess the associations by performing a comprehensive meta-analysis. Relevant studies were searched through several databases. The pooled odd ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations of PvuII and XbaI polymorphisms with the risk of T2DM and MetS by using the STATA 14.0 software. Eight studies for T2DM and three articles about MetS were included in this meta-analysis. The overall results indicated that PvuII, rather than XbaI polymorphism, was associated with T2DM (regressive model: OR=0.673, 95% CI=0.550 to 0.823, praw<0.001, pFDR<0.003). The subgroup analysis based on race revealed an association of PvuII polymorphism with the decreased T2DM risk in Chinese population and a relationship between XbaI polymorphism and the reduced T2DM susceptibility in Caucasians. The difference of country may be one source of the heterogeneity for PvuII polymorphism and T2DM. However, neither PvuII nor XbaI polymorphism was related to the risk of MetS. The C allele of PvuII polymorphism presents a protective role in T2DM risk, especially in Chinese people. The G allele of XbaI polymorphism is related to a reduced risk for T2DM in Caucasian population. Nevertheless, neither of PvuII nor XbaI polymorphism is associated with MetS risk.
Assuntos
Diabetes Mellitus Tipo 2/genética , Receptor alfa de Estrogênio/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome Metabólica/genética , Polimorfismo Genético , Heterogeneidade Genética , Humanos , Viés de PublicaçãoRESUMO
OBJECTIVE: To confirm the association between baseline blood pressure (BP) levels and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in patients with essential hypertension. METHODS: A total of 347 patients were enrolled from the Dongzhi community in Anhui Province, China. The C677T polymorphism of the MTHFR gene was detected using high-throughput TaqMan allelic discrimination assay. Baseline BP was measured using a standardized mercury-gravity monometer. RESULTS: In the whole sample, the frequency of the MTHFR C677T genotypes CC, CT, and TT were 38.6%, 48.1%, and 13.3%, respectively. In a recessive model (CC+CT versus TT genotypes), baseline diastolic blood pressure (DBP) was significantly higher in patients with the TT genotype compared to those with the CT or CC genotypes (P= 0.013). We also divided all patients into three groups based on the tertiles of the baseline BP distribution. Compared to subjects in the lowest tertile of DBP, the adjusted odds of having the TT genotype among subjects in the highest tertile was 2.6 (95% CI: 1.1 to 6.2). However, no significant associations were observed between baseline systolic blood pressure (SBP) and the MTHFR C677T polymorphism. CONCLUSIONS: The MTHFR gene polymorphism could be an important genetic determinant of baseline DBP levels in Chinese essential hypertensive patients.
Assuntos
Povo Asiático/genética , Pressão Sanguínea/genética , Hipertensão Essencial/genética , Hipertensão Essencial/fisiopatologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Alelos , China , Diástole/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Sístole/genéticaRESUMO
The aim of the present study was to examine the association between peripheral differential leukocyte counts and dyslipidemia in a Chinese hypertensive population. A total of 10,866 patients with hypertension were enrolled for a comprehensive assessment of cardiovascular risk factors using data from the China Stroke Primary Prevention Trial. Plasma lipid levels and total leukocyte, neutrophil, and lymphocyte counts were determined according to standard methods. Peripheral differential leukocyte counts were consistently and positively associated with serum total cholesterol (TC), LDL cholesterol (LDL-C), and TG levels (all P < 0.001 for trend), while inversely associated with HDL cholesterol levels (P < 0.05 for trend). In subsequent analyses where serum lipids were dichotomized (dyslipidemia/normolipidemia), we found that patients in the highest quartile of total leukocyte count (≥7.6 × 109 cells/l) had 1.64 times the risk of high TG [95% confidence interval (CI): 1.46, 1.85], 1.34 times the risk of high TC (95% CI: 1.20, 1.50), and 1.24 times the risk of high LDL-C (95% CI: 1.12, 1.39) compared with their counterparts in the lowest quartile of total leukocyte count. Similar patterns were also observed with neutrophils and lymphocytes. In summary, these findings indicate that elevated differential leukocyte counts are directly associated with serum lipid levels and increased odds of dyslipidemia.
Assuntos
Doenças Cardiovasculares/sangue , Dislipidemias/sangue , Hipertensão/sangue , Contagem de Leucócitos , Idoso , Doenças Cardiovasculares/patologia , China , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/genética , Dislipidemias/patologia , Feminino , Humanos , Hipertensão/genética , Hipertensão/patologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/sangueRESUMO
BACKGROUND: Hyperhomocysteinemia is a risk factor for cardiovascular disease. To date, limited prospective studies have examined the joint effects of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, hyperhomocysteinemia and conventional vascular risk factors on risk of stroke and stroke death. METHODS: A total of 39 165 subjects from nine communities within Anqing, Anhui Province, China were prospectively followed from March 1995 to April 2005, with an average follow-up period of 6.2 years. None of the subjects had any history of vascular events at baseline. At follow-up, 251 incident stroke cases were identified. Using a nested, case-control study design, this analysis includes 106 cases with complete MTHFR C677T genotyping data and plasma samples. We selected 106 controls without vascular events matched for age, sex, community and years of plasma storage. Plasma total homocysteine (tHcy) level was measured by high-performance liquid chromatography. RESULTS: Hypertension was independently associated with incident stroke and stroke death after adjusting for important covariates including plasma log-transformed Hcy level. Relative to non-carriers of the MTHFR 677TT genotype with no hypertension, the adjusted odds ratio (95% confidence interval) of stroke and stroke death among hypertensive carriers of the MTHFR 677TT genotype was 10.6 (3.2 to 34.8), 5.8 (1.6 to 21.3), respectively. After excluding subjects with plasma Hcy above 20 µmol/L, the relative odds for stroke, but not for stroke death, was more significantly pronounced (OR = 24.1, 95% CI: 2.3 to 246.1) among subjects with moderate plasma Hcy levels. However, there was no significant interactive effect between hypertensive status and the MTHFR C677T variant on the odds of the two outcomes as estimated by interaction models. CONCLUSIONS: Our major findings suggest that joint effects of the MTHFR C677T polymorphism and hypertension are consistent in predicting a significantly high risk of stroke. In addition for moderate plasma levels of Hcy, the predicted effects on the risk for the primary end point of stroke were more pronounced. These results may help to modify current approaches to vascular disease prevention in Chinese hypertensive patients.
Assuntos
Predisposição Genética para Doença/genética , Hipertensão/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/genética , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Jejum/sangue , Feminino , Genótipo , Homocisteína/sangue , Humanos , Hipertensão/enzimologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/enzimologiaRESUMO
OBJECTIVE: To investigate the correlation between smoking status and carotid plaque in rural population residing in Eastern part of China. METHODS: Between July and September of 2013, an epidemiological survey was carried out in residents aged 40 or above men who were enrolled randomly in rural areas of Anqing, Anhui province and Lianyungang, Jiangsu province. The data on epidemiological characteristics including smoking status, physical examination were collected using standardized protocol, and carotid ultrasonography was applied to examine the incidence of carotid plaque among never smokers, former smokers and current smokers. Logistic regress analysis was performed to determine the effect of smoking on carotid plaque. RESULTS: In the study, a total of 625 male participants were included in the study. 51.4% (321 cases) were current smokers, 21.3% (133 cases) were former smokers, and 27.4% (171 cases) were never smokers. 32.0% (200/625) had carotid plaque. The incidence of carotid plaques was significantly higher in current smokers (35.2%, 113/321) than that in never smokers(23.4%,40/171) (χ(2) = 7.26, P = 0.007) and the incidence in former smokers (35.3%, 47/133) was also higher than that in never smokers (23.4%, 40/171) (χ(2) = 5.23, P = 0.022). Multiple logistic regression analysis showed that current cigarette smoking is significantly associated with the increased risk of carotid plaque (OR = 1.84, 95% CI: 1.13-2.98, P = 0.014) in comparison with never smokers, and there was an interaction between current smoking and age in association with carotid plaque. Compared with the young (≤60 years old) and never smoking group (8%, 3/40), prevalence of carotid plaque among the elderly (>70 years old) and smoking group (55%, 31/56) was significantly higher (OR = 8.06, 95% CI: 2.07-31.45) after adjusting for age, systolic blood pressure, diastolic blood pressure, blood glucose, total cholesterol, triglyceride high-density lipoprotein, body mass index, drinking and regional differences. CONCLUSION: It found that cigarette smoking was associated with increased risk of carotid plaque in rural elderly population residing in Eastern part of China.
Assuntos
Estenose das Carótidas , Fumar , Idoso , Consumo de Bebidas Alcoólicas , Glicemia , Pressão Sanguínea , Índice de Massa Corporal , China , Colesterol , Humanos , Lipoproteínas HDL , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , População Rural , TriglicerídeosRESUMO
BACKGROUND: Cardio-cerebrovascular disease is an important public health challenge worldwide, and its complex etiology has not been elucidated fully. The study investigated the relationship between two common polymorphisms, C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene, baseline lipids and the lipid-lowering efficacy of simvastatin in a Chinese hyperlipidemic population. METHODS: All participants were recruited from Anhui, China. By the extreme sampling method, we selected subjects with a low response (n=108) and high response (n=106) based on their adjusted lipid-lowering response to simvastatin administrated for 8 consecutive weeks. Both MTHFR C677T and A1298C loci were genotyped by the MALDI-TOF MS platform. Serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were measured at baseline and after 8 weeks of oral 20 mg/d tablets of simvastatin. RESULTS: Patients with the 677TT genotype had significantly higher baseline TC, HDL-C, and change in HDL-C (ΔHDL-C) levels after treatment than those with 677CC+CT genotypes (ß = 0.207, P = 0.045; ß = 0.182, P = 0.026; and ß = 0.16, P = 0.002, respectively). Patients with 1298AC+CC genotypes had significantly higher baseline LDL-C and change in LDL-C (ΔLDL-C) levels (ß = 0.276, P =0.043; ß = 0.359, P = 0.025, respectively) than those with 1298AA genotype. We found statistical interactions between the two SNPs in association with baseline HDL-C (P for interaction = 0.034), TC (P for interaction = 0.069), and TG (P for interaction = 0.034). Baseline TC (P = 0.027) and HDL-C (P = 0.046) and change in HDL-C (P = 0.019) were different among those with the MTHFR A-T haplotype compared with A-C. CONCLUSION: Our major findings suggest that both MTHFR C677T and A1298C polymorphisms could be important genetic determinants of lipid traits and drug efficacy of simvastatin. This will contribute to a better understanding of strategies for personalized medication in Chinese patients with dyslipidemia.
Assuntos
Dislipidemias , Metilenotetra-Hidrofolato Redutase (NADPH2) , Sinvastatina , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Dislipidemias/genética , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Sinvastatina/uso terapêuticoRESUMO
Aim: We investigated the effect of ABCG1 gene DNA methylation in the lipid-lowering efficacy of simvastatin. Materials & methods: An extreme sampling approach was used to select 211 individuals from the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin after eight consecutive weeks. DNA methylation was measured before treatment by the MethylTarget bisulfite sequencing method. Results:ABCG1_A DNA methylations were negatively associated with baseline high-density lipoprotein cholesterol (HDL-C) and the change in HDL-C after treatment. ABCG1_C methylations were also related to the change in triglyceride and HDL-C. Moreover, mean ABCG1_A and ABCG1_C methylations explain 7.2% of the ΔTC (total cholesterol) and 17.5% of the ΔHDL-C level variability, respectively. Conclusion: DNA methylations at the ABCG1 gene play significant inhibitory effects in the lipid-lowering therapy of simvastatin.
Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Anticolesterolemiantes/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/genética , Sinvastatina/uso terapêutico , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Anticolesterolemiantes/farmacologia , HDL-Colesterol/antagonistas & inibidores , HDL-Colesterol/sangue , Metilação de DNA/fisiologia , Feminino , Humanos , Hiperlipidemias/sangue , Lipídeos/antagonistas & inibidores , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Sinvastatina/farmacologia , Resultado do TratamentoRESUMO
Hypertension is an important public health challenge worldwide. Epigenetic studies are providing novel insight into the underlying mechanisms of hypertension. We investigated the effect of DNA methylation in ATP-binding cassette transporter 1 (ABCA1) gene on blood pressure levels in a Chinese hyperlipidemic population. We randomly selected 211 individuals with hyperlipidemia who had not received any lipid-lowering treatment at baseline from our previous statin pharmacogenetics study (n = 734). DNA methylation loci at the ABCA1 gene were measured by MethylTarget, a next generation bisulfite sequencing-based multiple targeted cytosine-guanine dinucleotide methylation analysis method. Mean DNA methylation level was used in statistical analysis. In all subjects, higher mean ABCA1_B methylation was positively associated with systolic blood pressure (SBP) (ß = 8.27, P = 0.008; ß = 8.78, P = 0.005) and explained 2.7% and 5.8% of SBP variation before and after adjustment for lipids, respectively. We further divided all patients into three groups based on the tertile of body mass index (BMI) distribution. In the middle tertile of BMI, there was a significantly positive relationship between mean ABCA1_A methylation and SBP (ß = 0.89, P = 0.003) and DBP (ß = 0.32, P = 0.030). Mean ABCA1_A methylation explained 11.0% of SBP variation and 5.3% of DBP variation, respectively. Furthermore, mean ABCA1_A methylation (ß = 0.79; P = 0.007) together with age and gender explained up to 24.1% of SBP variation. Our study provides new evidence that the ABCA1 DNA methylation profile is associated with blood pressure levels, which highlights that DNA methylation might be a significant molecular mechanism involved in the pathophysiological process of hypertension.
Assuntos
Metilação de DNA , Transportador 1 de Cassete de Ligação de ATP/genética , Pressão Sanguínea/genética , China/epidemiologia , HumanosRESUMO
OBJECTIVE: Our aim was to detect the effects of DNA methylations in the phosphoethanolamine/ phosphocholine phosphatase (PHOSPHO1) gene on the therapeutic efficacy of simvastatin. METHODS: We used an extreme sampling approach by selecting 211 individuals from approximately the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin (n=104 for the high response group and n=107 for the low response group) from a total of 734 subjects with hyperlipidemia. They received a daily oral dose of 20 mg simvastatin for eight consecutive weeks. DNA methylation loci at the PHOSPHO1 gene were measured using high-throughput next-generation sequencing-based sequencing technology. Fasting serum lipids were measured at baseline and after eight weeks of simvastatin treatment. RESULTS: Mean PHOSPHO1 DNA methylation had a significant negative correlation with high-density lipoprotein cholesterol (HDL-C) variation (ß=-0.014, P=0.045) in the high response group. After stratifying by body mass index (BMI), the associations between the PHOSPHO1 DNA methylations and the change in HDL-C in response to simvastatin were more significant in obese subjects with a BMI of 25 kg/m2 or higher (ß=-0.027, P=0.002). Mean PHOSPHO1 methylation and traditional predictors could explain up to 24.7% (adjusted R2) of the change in HDL-C response in obese patients. There was a statistically significant additive interaction term (P=0.028) between BMI and mean PHOSPHO1 methylation in the model of the change in HDL-C in response to simvastatin. CONCLUSION: Our findings suggest that PHOSPHO1 DNA methylations are associated with a change in HDL-C in response to simvastatin treatment, and this association is especially dependent on the extent of patient obesity.
Assuntos
Metilação de DNA , Hiperlipidemias , HDL-Colesterol , Humanos , Monoéster Fosfórico Hidrolases , Sinvastatina/farmacologia , TriglicerídeosRESUMO
Aim: We aimed to identify genetic variants associated with ACE inhibitor (ACEI)-induced cough. Materials & methods: A nested case-control study was performed among hypertensive Chinese patients receiving enalapril-only therapy. Whole-exome sequencing and genome-wide association analysis were performed. Results: We identified that PNPT1 rs13015243 (odds ratio [OR]: 0.47; 95% CI: 0.34-0.66; p = 7.45 × 10-6), PNPT1 rs13009649 (OR: 0.48; 95% CI: 0.35-0.67; p = 9.96 × 10-6) and PCGF3 rs1044147 (OR: 2.67; 95% CI: 1.71-4.17; p = 9.91 × 10-6) were significantly associated with ACEI-induced cough. Nearly genome-wide significant associations in previously reported candidate risk genes CLASP1, ACE, CES1, CPN1, XPNPEP1, PDE11A or SLC38A were detected in our dataset. Conclusion: Our results suggest that ACEI-induced cough is associated with noncoding SNPs of PNPT1 and PCGF3, all of which are independent of the bradykinin pathway. Study registration: NCT03259399.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Tosse/induzido quimicamente , Tosse/genética , Exorribonucleases/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Complexo Repressor Polycomb 1/genética , Idoso , Estudos de Casos e Controles , Feminino , Variação Genética/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Six asthma candidate genes, ADAM33, NPSR1, PHF11, DPP10, HLA-G, and CYFIP2, located at different chromosome regions have been positionally cloned following the reported linkage studies. For ADAM33, NPSR1, and CYFIP2, the associations with asthma or asthma-related phenotypes have been studied in East Asian populations such as Chinese and Japanese. However, for PHF11, DPP10, and HLA-G, none of the association studies have been conducted in Asian populations. Therefore, the aim of the present study is to test the associations between these three positionally cloned genes and asthma or asthma-related phenotypes in a Chinese population. METHODS: Two, five, and two single nucleotide polymorphisms (SNPs) in the identified top regions of PHF11, DPP10, and HLA-G, respectively, were genotyped in 1183 independent samples. The study samples were selected based on asthma affectation status and extreme values in at least one of the following three asthma-related phenotypes: total serum immunoglobulin E levels, bronchial responsiveness test, and skin prick test. Both single SNP and haplotype analyses were performed. RESULTS: We found that DPP10 was significantly associated with bronchial hyperresponsiveness (BHR) and BHR asthma after the adjustment for multiple testing; while the associations of PHF11 with positive skin reactions to antigens and the associations of HLA-G with BHR asthma were only nominally significant. CONCLUSION: Our study is the first one to provide additional evidence that supports the roles of DPP10 in influencing asthma or BHR in a Chinese population.
Assuntos
Asma/genética , Estudos de Associação Genética , Povo Asiático/genética , Hiper-Reatividade Brônquica/genética , China , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
OBJECTIVE: This study aimed to assess the association between two tag single nucleotide polymorphisms (SNPs) (rs68177277 and rs11624293) of G protein-coupled receptor 65 (GPR65) gene and ankylosing spondylitis (AS) susceptibility in a Chinese Han population. METHODS: 673 patients with AS diagnosed according to the modified New York criteria and 679 age- and gender-matched healthy controls were recruited. SNP genotyping for rs68177277 and rs11624293 polymorphisms were performed using the SNPscan technique. Disease activity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). RESULTS: Genotype and allele distribution of rs11624293 but not rs68177277 were significantly different between AS and controls (pâ¯=â¯0.004 and pâ¯=â¯0.002). Compared to the wild-type T/T genotype and T allele at rs11624293, the frequencies of C/T genotype and C allele were significantly higher in AS than controls after adjusting for age and gender (ORâ¯=â¯1.527, 95%CIs: 1.190-1.958; ORâ¯=â¯1.515, 95%CIs: 1.183-1.942, respectively). Dominant and co-dominant model of rs11624293 were predictive of AS susceptibility. In AS patients, the genotype of rs11624293 was significantly associated with BASFI scores in those with low disease activity (BASDAIâ¯<â¯4, pâ¯=â¯0.007). CONCLUSIONS: The results of our study suggest that rs11624293 polymorphism of GPR65 gene is associated with the susceptibility and severity of AS in Chinese Han population.
Assuntos
Genótipo , Receptores Acoplados a Proteínas G/genética , Espondilite Anquilosante/genética , Adulto , Estudos de Casos e Controles , China , Progressão da Doença , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Risco , Adulto JovemRESUMO
BACKGROUND: Nickel-induced allergic contact dermatitis (Ni-ACD) is a global health problem. More detailed knowledge on the skin uptake of haptens is required. This study aimed to investigate the penetration process and distribution of nickel in skin tissues with late phase and early phase of Ni-ACD to understand the mechanisms of metal allergy. METHODS: Forty Hartley guinea pigs were divided into four groups according to the NiSO4 sensitizing concentration and the NiSO4 challenged concentration: the 5% NiSO4-group, 5% to 10% (sensitization-challenge; late phase group); 10% NiSO4-group, 10% to 10% (sensitization-challenge; early-phase group); and the positive and negative controls. Pathological biopsies were performed on each group. The depth profile of nickel element concentration in the skin of guinea pigs was detected by synchrotron radiation micro X-ray fluorescence spectroscopy (SR-µ-XRF) and micro X-ray absorption near-edge spectroscopy (µ-XANES). RESULTS: In each section, the nickel element concentration in both the 5% NiSO4-group and 10% NiSO4-group was significantly higher than that in the negative control group. In the upper 300-µm section of skin for the early phase group, the nickel element concentration was significantly higher than that in the lower section of skin. In deeper sections (>200âµm) of skin, the concentration of nickel in the early phase group was approximately equal to that in the late phase group. The curve of the late phase group was flat, which means that the nickel element concentration was distributed uniformly by SR-µ-XRF. According to the XANES data for the 10% NiSO4 metal salt solution, structural changes occurred in the skin model sample, indicating that nickel was not present in the Ni aqueous ionic state but in the nickel-binding protein. CONCLUSIONS: This study showed that the distribution of the nickel element concentration in ACD skin tissue was different between the early phase and late phase groups. The nickel element was not present in the Ni aqueous ionic state but bound with certain proteins to form a complex in the stratum corneum in ACD model tissue.
Assuntos
Dermatite Alérgica de Contato/etiologia , Dermatite Alérgica de Contato/metabolismo , Níquel/metabolismo , Níquel/toxicidade , Espectrometria por Raios X/métodos , Animais , Dermatite Alérgica de Contato/patologia , Feminino , Cobaias , Masculino , Distribuição Aleatória , Pele/metabolismo , Pele/patologiaRESUMO
This study was conducted to clarify the associations of tumor necrosis factor-α induced protein 3 (TNFAIP3) and TNFAIP3-interacting protein 1 (TNIP1) genetic polymorphisms with ankylosing spondylitis (AS) susceptibility. Five single nucleotide polymorphisms (SNPs) in TNFAIP3 gene and four in TNIP1 gene were genotyped in 667 AS patients and 667 matched healthy controls. Genotypes and haplotype analysis were conducted by using SPSS 23.0 and Haploview 4.2 software. The T allele and CT genotype in TNFAIP3 rs10499194 were significantly associated with a reduced AS risk (T allele vs. C allele, OR = 0.619, 95% CI = 0.430-0.889, P = 0.009; CT vs. CC, OR = 0.603, 95% CI = 0.416-0.875, P = 0.007). However, no association remained significant after Bonferroni correction. The rs13207033A- rs10499194T haplotype of TNFAIP3 conferred a protective effect on AS susceptibility. Stratification analyses suggested that rs10499194 polymorphism decreased the risk of AS in the male subgroup, subgroup aged ≥ 29, HLA-B27 positive subgroup as well as the subgroups of BASFI < 4 and BASDAI < 4 (all P < 0.05). Furthermore, the functional annotation suggested a potential function of rs10499194 mutation. Our results demonstrated that TNFAIP3 rs10499194 polymorphism may be associated with a reduced risk of AS.