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Mendelian randomization study to investigate the causal relationship between plasma Homocysteine and chronic obstructive pulmonary disease

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World Journal of Emergency Medicine 2023年第5期14卷 367-371页

作者： Yanlan Hu Ping Tan Juntao Wang Jun Zeng Quan Li Shijiao Yan Wenjie Hao Lanfen He Xingyue Song Caihong Zhang Chuanzhu Lyu International School of Public Health and One Health Hainan Medical UniversityHaikou 571199China Department of Emergency Medicine Hunan Provincial People’s Hospital/the First Affi liated HospitalHunan Normal UniversityChangsha 410002China Emergency Medicine Center Sichuan Provincial People's HospitalUniversity of Electronic Science and Technology of ChinaChengdu 610072China Emergency Department State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of Medical Science and Peking Union Medical CollegeBeijing 100730China Department of Emergency Hainan Clinical Research Center for Acute and Critical Diseasesthe Second Affi liated Hospital of Hainan Medical UniversityHaikou 570100China International School of Nursing Hainan Medical UniversityHaikou 570100China Key Laboratory of Emergency and Trauma of Ministry of Education Hainan Medical UniversityHaikou 570100China Research Unit of Island Emergency Medicine Chinese Academy of Medical Sciences (No. 2019RU013) Hainan Medical University Haikou 570100 China

BACKGROUND:Several observational studies have shown an association between Homocysteine(Hcy)levels and chronic obstructive pulmonary disease(COPD),but causal relationships are not clear.Our study aimed to explore the causal relationship between plasma Hcy and COPD by two-sample Mendelian randomization(MR).METHODS:A two-sample MR study was performed to infer the causal link.Genetically predicted plasma Hcy was selected as an instrumental variable(Ⅳ)from published genome-wide association study(GWAS)meta-analyses.COPD with different etiologies was extracted as outcome variables from other GWAS meta-analyses.The main MR analysis was performed using the inversevariance weighted(IVW)method.Additional analyses were further performed using Cochran’s Q-test and MR-Egger regression to evaluate the heterogeneity or horizontal pleiotropy of our findings.RESULTS:MR analysis showed no significant association between plasma Hcy and COPD.The results of the groups were consistent with the sensitivity analysis and repeated analysis,without heterogeneity or horizontal pleiotropy.The IVW results showed COPD hospital admissions(odds ratio[OR]1.06,95%confidence interval[CI]0.91-1.24,P=0.42),asthma/COPD(OR 0.97,95%CI0.89-1.06,P=0.55),COPD-related chronic infection(OR 1.50,95%CI 0.57-3.99,P=0.41),COPDI asthma/interstitial lung disease(ILD)-related pneumonia or pneumonia-derived septicemia(OR 0.93,95%CI 0.86-1.02,P=0.13),and COPD-related respiratory insufficiency(OR 1.00,95%CI 0.7-1.44,P=0.99).CONCLUSION:There is no direct causal relationship between plasma Hcy and COPD in our study.As Hcy is known to have deleterious effects on endothelial function and vascular homeostasis,further studies are needed to investigate whether additional factors mediate the association between Hcy and COPD.

关键词： Homocysteine Chronic obstructive pulmonary disease Mendelian randomization

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Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Rats

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Neuroscience Bulletin 2022年第8期38卷 887-900页

作者： Shi-Da Wang Xue Wang Yun Zhao Bing-Hua Xue Xiao-Tian Wang Yu-Xin Chen Zi-Qian Zhang Ying-Rui Tian Fang Xie Ling-Jia Qian Institute of Military Cognitive and Brain Sciences Academy of Military Medical SciencesBeijing100850China 8th People’s Hospital of Qingdao Qingdao266041China School of Public Health Lanzhou UniversityLanzhou730000China

Chronic stress is generally accepted as the main risk factor in the development of cognitive decline;however,the underlying mechanisms remain unclear.Previous data have demonstrated that the levels of Homocysteine(Hcy)are significantly elevated in the plasma of stressed animals,which suggests that Hcy is associated with stress and cognitive decline.To test this hypothesis,we analyzed the cognitive function,plasma concentrations of Hcy,and brain-derived neurotropic factor(BDNF)levels in rats undergoing chronic unpredicted mild stress(CUMS).The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperHomocysteinemia(HHcy)levels in stressed rats.Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS,while Hcy reduction(by means of vitamin B complex supplements)alleviated the cognitive deficits and BDNF reduction in CUMS rats.Furthermore,we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter.In contrast,control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain.These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline.We also used ten-eleven translocation(TET1),an enzyme that induces DNA demethylation,to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline.The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats.Taken together,novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits.In addition,the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter.The results also suggest the possibil

关键词： Stress-associated cognitive decline Homocysteine DNA methylation BDNF

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A multisite-binding fluorescent probe for simultaneous monitoring of mitochondrial Homocysteine, cysteine and glutathione in live cells and zebrafish

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Chinese Chemical Letters 2022年第3期33卷 1609-1612页

作者： Huimin Jiang Guoxing Yin Yabing Gan Ting Yu Youyu Zhang Haitao Li Peng Yin Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research(Ministry of Education) College of Chemistry and Chemical EngineeringHunan Normal UniversityChangsha 410081China

Homocysteine(Hcy), cysteine(Cys) and glutathione(GSH) play crucial roles in redox homeostasis during mitochondria functions. Simultaneous differentiation and visualization of mitochondrial biothiols dynamics are significant for understanding cell metabolism and their related diseases. Herein, a multisitebinding fluorescent probe(MCP) was developed for simultaneous sensing of mitochondrial Cys, GSH and Hcy from three fluorescence channels for the first time. This novel probe exhibited rapid fluorescence turn-on, good water-solubility, high selectivity and large spectral separation for discriminating Cys, GSH and Hcy with 131-, 96-, 748-fold fluorescence increasement at 471, 520, 567 nm through different excitation wavelengths, respectively. Importantly, this probe was successfully applied to simultaneous monitoring of mitochondrial Cys, GSH, and Hcy in live cells and zebrafish from three fluorescence channels,promoting the understanding of the functions of Hcy, Cys and GSH.

关键词： Fluorescent probe Multiple sites Biothiols Mitochondrial-targeted Homocysteine Imaging

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Faulty Homocysteine recycling in diabetic retinopathy

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Eye and Vision 2020年第1期7卷 36-46页

作者： Renu A.Kowluru Ghulam Mohammad Nikhil Sahajpal Department of Ophthalmology Visual Sciences and Anatomical SciencesWayne State University4717 St.AntoineDetroitMI 48201USA

Background:Although hyperglycemia is the main instigator in the development of diabetic retinopathy,elevated circulating levels of a non-protein amino acid,Homocysteine,are also associated with an increased risk of retinopathy.Homocysteine is recycled back to methionine by methylenetetrahydrofolate reductase(MTHFR)and/or transsulfurated by cystathionineβ-synthase(CBS)to form cysteine.CBS and other transsulfuration enzyme cystathionine-γ-lyase(CSE),through desulfuration,generates H_(2)S.Methionine cycle also regulates DNA methylation,an epigenetic modification associated with the gene suppression.The aim of this study was to investigate Homocysteine and its metabolism in diabetic retinopathy.Methods:Homocysteine and H_(2)S levels were analyzed in the retina,and CBS,CSE and MTHFR in the retinal microvasculature from human donors with established diabetic retinopathy.Mitochondrial damage was evaluated in retinal microvessels by quantifying enzymes responsible for maintaining mitochondrial dynamics(fission-fusionmitophagy).DNA methylation status of CBS and MTHFR promoters was examined using methylated DNA immunoprecipitation technique.The direct effect of Homocysteine on mitochondrial damage was confirmed in human retinal endothelial cells(HRECs)incubated with 100μM L-Homocysteine.Results:Compared to age-matched nondiabetic control human donors,retina from donors with established diabetic retinopathy had~3-fold higher Homocysteine levels and~50%lower H_(2)S levels.The enzymes important for both transsulfuration and remethylation of Homocysteine including CBS,CSE and MTHFR,were 40–60%lower in the retinal microvasculature from diabetic retinopathy donors.While the mitochondrial fission protein,dynamin related protein 1,and mitophagy markers optineurin and microtubule-associated protein 1A/1B-light chain 3(LC3),were upregulated,the fusion protein mitofusin 2 was downregulated.In the same retinal microvessel preparations from donors with diabetic retinopathy,DNA at the promoters of CBS and MTHFR were hypermethylated.Incu

关键词： Diabetic retinopathy DNA methylation Homocysteine Hydrogen sulfide Mitophagy Epigenetics Mitochondria Oxidative stress Retina

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Homocysteine and IgA nephropathy: observational and Mendelian randomization analyses

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Chinese Medical Journal 2020年第3期133卷 277-284页

作者： Yue-Miao Zhang Xu-Jie Zhou Su-Fang Shi Li-Jun Liu Ji-Cheng Lyu Hong Zhang Renal Division Department of MedicinePeking University First HospitalInstitute of NephrologyPeking UniversityKey Laboratory of Renal DiseaseMinistry of Health of ChinaKey Laboratory of Chronic Kidney Disease Prevention and TreatmentPeking UniversityMinistry of EducationBeijing 100034China.

Background:High levels of plasma Homocysteine occur almost uniformly in patients with end-stage renal disease(ESRD).IgA nephropathy(IgAN)is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults.Here,we aimed to detect whether Homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization(MR)approach.Methods:For observational analysis,108 IgAN patients,30 lupus nephritis(LN)patients,50 minimal change disease(MCD)patients,and 206 healthy controls were recruited from April 2014 to April 2015.Their plasma Homocysteine was measured and clinical-pathologic manifestations were collected from medical records.For MR analysis,we further included 1686 IgAN patients.The missense variant methylenetetrahydrofolate reductase C677T(rs1801133)was selected as an instrument,which was genotyped by TaqMan allele discrimination assays.Results:Majority of IgAN patients(93.52%,101/108)showed elevated levels of plasma Homocysteine(>10μmol/L).Plasma Homocysteine in IgAN patients was significantly higher than that in MCD patients(median:18.32 vs.11.15μmol/L,Z=-5.29,PHomocysteine for male ratio(22.22%vs.51.85%vs.70.37%vs.70.37%,χ2=14.29,P<0.01),serum creatinine(median:77.00 vs.100.00 vs.129.00 vs.150.00μmol/L,χ2=34.06,P<0.01),estimated glomerular filtration rate(median:100.52 vs.74.23 vs.52.68 vs.42.67 mL·min-1·1.73 m-2,χ2=21.75,P<0.01),systolic blood pressure(median:120.00 vs.120.00 vs.125.00 vs.130.00 mmHg,χ2=2.97,P=0.05),diastolic blood pressure(median 80.00 vs.75.00 vs.80.00 vs.81.00 mmHg,χ2=11.47,P<0.01),and pathologic tubular atrophy and interstitial fibrosis(T)(T0/T1/T2:62.96%/33.33%/3.70%vs.29.63%/40.74%/29.63%vs.24.00%/48.00%/28

关键词： Homocysteine IgA nephropathy Causality

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The methylenetetrahydrofolate reductase genotype 677CT and non-alcoholic fatty liver disease have a synergistic effect on the increasing Homocysteine levels in subjects from Chongqing,China

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Genes & Diseases 2019年第1期6卷 88-95页

作者： Xiaolin Wang Yongli Zhou Mingjun Zhang Yonghong Wang Bo Qin Health Management Center The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina Department of Infectious Diseases The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

The methylenetetrahydrofolate reductase(MTHFR)genotypes 677CT and 677TT are associated with elevated serum Homocysteine(Hcy)levels by means of lowering the activity of MTHFR,and the increase in serum Hcy may be linked to increased susceptibility to nonalcoholic fatty liver disease(NAFLD).However,there are contradictory reports of the relationship among the MTHFR 677CT gene polymorphism,Hcy,and NAFLD.Therefore,the aim of this study was to identify potential associations and interactions of either Hcy levels or the MTHFR 677CT gene polymorphism with the susceptibility to NAFLD in a Chinese population.The association between the MTHFR 677 CT gene polymorphism and Hcy levels was determined in 243 subjects with NAFLD and 388 healthy subjects without NAFLD using polymerase chain reactionrestriction fragment length polymorphism analysis and high-performance liquid chromatography.In subjects with NAFLD,there was no statistical difference in the genotypic and allelic frequencies of the MTHFR 677 CT gene polymorphism,while serum Hcy levels were significantly higher in subjects with NAFLD.Furthermore,these results strongly suggest that the MTHFR 677CT gene polymorphism and NAFLD have a potential synergistic effect on Hcy elevation,although the MTHFR 677CT gene polymorphism was not correlated with NAFLD in a Chinese population.

关键词： Gene polymorphism Homocysteine Methylenetetrahydrofolate reductase Nonalcoholic fatty liver disease Synergistic effect

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Endogenous hydrogen sulfide and ERK1/2-STAT3 signaling pathway may participate in the association between Homocysteine and hypertension

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Journal of Geriatric Cardiology 2019年第11期16卷 822-834页

作者： Lin SHI Xiao-Yun LIU Zhi-Gang HUANG Zhi-Yi MA Yang XI Lu-Yan WANG Ning-Ling SUN Hypertension Research Laboratory Department of CardiologyPeking University People’s HospitalBeijingChina Emergency Department Peking University Shenzhen HospitalShenzhenChina

Background Homocysteine(Hcy)is a risk factor for hypertension,although the mechanisms are poorly understood.Methods We first explored the relationship between Hcy levels and blood pressure(BP)by analyzing the clinical data of primary hypertensive patients admitted to our hospital.Secondly,we explored a rat model to study the effect of Hcy on blood pressure and the role of H2S.An hyperHomocysteinemia(HHcy)rat model was induced to explore the effect of Hcy on blood pressure and the possible mechanism.We carried out tissue histology,extraction and examination of RNA and protein.Finally,we conducted cell experiments to determine a likely mechanism through renin-angiotensin-aldosterone system(RAAS)and extracellular signal-regulated kinase 1/2(ERK1/2)signaling pathway.Results In primary hypertensive inpatients with HHcy,blood pressure was significantly higher as compared with inpatient counterparts lacking HHcy.In the rat model,blood pressure of the Wistar rats was significantly increased with increases in serum Hcy levels and decreased after folate treatment.Angiotensin converting enzyme 1(ACE1)expression in the Wistar Hcy group was enhanced comparing to controls,but was decreased in the Wistar folate group.Angiotensin II receptor type 1(AGTR1)levels in the kidney tissue increased in the Wistar folate group.Both serum H2S and kidney cystathionineγ-lyase decreased with elevated levels of serum Hcy.In vitro,increased concentrations and treatment times for Hcy were associated with increased expression of collagen type 1 and AGTR1.This dose and time dependent response was also observed for p-STAT3 and p-ERK1/2 expression.Conclusion Endogenous H2S might mediate the process of altered blood pressure in response to changes in serum Hcy levels,in a process that is partly dependent on activated RAAS and ERK1/2-STAT3 signaling pathway.

关键词： Angiotensin converting enzyme 1 Blood pressure ERK1/2-STAT3 signaling pathway Homocysteine Hydrogen sulfide

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Relationship between serum Homocysteine levels and long-term outcomes in patients with ST-segment elevation myocardial infarction

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Chinese Medical Journal 2019年第9期132卷 1028-1036页

作者： Jin Si Xue-Wen Li Yang Wang Ying-Hua Zhang Qing-Qing Wu Lei-Min Zhang Xue-Bing Zuo Jing Gao Jing Li Department of Cardiology Xuanwu HospitalCapital Medical UniversityBeijing 100053China Department of Cardiology Tianjin Medical UniversityTianjin 300070China Cadre's Ward Characteristic Medical Center of Chinese People's Armed Police ForceTianjin 300162China Medical Research & Biometrics Center National Center for Cardiovascular DiseasesFuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100037China Department of Cardiology Beijing Luhe HospitalCapital Medical UniversityBeijing 101149China Department of Cardiology Qinghe Substation Hospital of Beijing Municipal Administration of PrisonsTianjin 300481China

Background:The mortality of cardiovascular disease is constantly rising,and novel biomarkers help us predict residual risk.This study aimed to evaluate the predictive value of serum Homocysteine (HCY) levels on prognosis in patients with ST-segment elevation myocardial infarction (STEMI).Methods:The 419 consecutive patients with STEMI,treated at one medical center,from March 2010 to December 2015 were retrospectively investigated.Peripheral blood samples were obtained within 24 h of admission and HCY concentrations were measured using an enzymatic cycling assay.The patients were divided into high HCY level (H-HCY) and low HCY level (L-HCY) groups.Short- and long-term outcomes were compared,as were age-based subgroups (patients aged 60 years and younger vs.those older than 60 years).Statistical analyses were mainly conducted by Student t-test,Chi-squared test,logistic regression,and Cox proportional-hazards regression.Results:The H-HCY group had more males (84.6% vs.75.4%,P=0.018),and a lower prevalence of diabetes (20.2% vs.35.5%,P<0.001),compared with the L-HCY group.During hospitalization,there were seven mortalities in the L-HCY group and 10 in the H-HCY group (3.3% vs.4.8%,P= 0.440).During the median follow-up period of 35.8 (26.9–46.1) months,33 (16.2%) patients in the L-HCY group and 48 (24.2%) in the H-HCY group experienced major adverse cardiovascular and cerebrovascular events (MACCE)(P=0.120).History of hypertension (hazard ratio [HR]:1.881,95% confidence interval [CI]:1.178–3.005,P=0.008) and higher Killip class (HR:1.923,95% CI:1.419–2.607,P<0.001),but not HCY levels (HR:1.007,95% CI:0.987–1.027,P=0.507),were significantly associated with long-term outcomes.However,the subgroup analysis indicated that in older patients,HCY levels were significantly associated with long-term outcomes (HR:1.036,95% CI:1.011–1.062,P=0.005).Conclusion:Serum HCY levels did not independently predict in-hospital or long-term outcomes in patients with STEMI;however,among elderly patients with STEMI,this study revealed a risk

关键词： Homocysteine Acute ST-segment elevation myocardial infarction Percutaneous coronary intervention Clinical outcome

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Genome-wide DNA hypermethylation and Homocysteine increase a risk for myopia

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International Journal of Ophthalmology(English edition) 2019年第1期12卷 38-45页

作者： Edward Hsi Yung-Song Wang Chia-Wei Huang Ming-Lung Yu Suh-Hang Hank Juo Chung-Ling Liang Centre for Myopia and Eye Disease Department of Medical ResearchChina Medical University(Taiwan) Hospital Department of Genome Medicine Kaohsiung Medical University Institute of Fisheries Science National Taiwan University Department of Biotechnology Kaohsiung Medical University Hepatobiliary Division Department of Internal MedicineKaohsiung Medical University Hospital Faculty of Medicine College of Medicine Kaohsiung Medical University Centre for Myopia and Eye Disease Department of Medical Research China Medical University(Taiwan) Hospital Graduate Institute of Biomedical Sciences China Medical University(Taiwan) Institute of New Drug Development China Medical University(Taiwan) Drug Development Center China Medical University(Taiwan) Department of Ophthalmology Asia University Hospital Department of Optometry College of Medical and Health ScienceAsia University

AIM: To test for the association between genome-wide methylation and myopia in human and mice. METHODS: Long interspersed nucleotide element 1(LINE-1) methylation levels were used to surrogate genome-wide methylation level. We first tested for the association between high myopia(Homocysteine and methionine in the rodent myopic eyes than normal eyes. Dopamine treatment to the cells reduced both LINE-1 methylation and DNA methyltransferase levels. CONCLUSION: LINE-1 hypermethylation may be associated with high myopia in human and mice. Homocysteine and methionine are accumulated in myopic eyes, which may provide excess methyl group for genome-wide methylation.

关键词： methylation myopia LINE-1 Homocysteine dopamine

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omocysteine： A Potential Common Route for Cardiovascular Risk and DNA Methylation in Psoriasis

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Chinese Medical Journal 2017年第16期130卷 1980-1986页

作者： Wen-Ming Wang Hong-Zhong Jin Department of Dermatology Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 China

Objective： Homocysteine is a sulfur-containing amino acid with potential clinical significance. Abnormal Homocysteine levels have been found in patients with psoriasis. This review summarizes the possible correlations among Homocysteine, cardiovascular risk, and DNA methylation in psoriasis. Data Sources： We retrieved the articles published in English from the PubMed database up to January 2017, using the keywords including ＂psoriasis,＂＂Homocysteine,＂＂cardiovascular risk,＂＂DNA methylation,＂＂methylenetetrahydrofolate reductase,＂＂MTHFR,＂ and ＂MTHFR C677T.＂ Study Selection： Articles about the roles of Homocysteine in the cardiovascular risk and DNA methylation in psoriasis were obtained and reviewed. Results： Observational studies consistently reported that elevated Homocysteine is an independent risk factor for cardiovascular diseases. Several studies also consistently reported an association between psoriasis and increased cardiovascular risk. A substantial body of evidence also suggested that an elevated Homocysteine level is related to the demethylation of DNA. Data from clinical trials also demonstrated that MTHFR C677T polymorphisms as well as DNA methylation aberrations are associated with psoriasis. Conclusions： This review highlighted the relationships among Homocysteine, cardiovascular risk, and DNA methylation, suggesting that Homocysteine may be a biological link between cardiovascular risk and DNA methylation in psoriasis.

关键词： Cardiovascular Disease DNA Methylation Homocysteine Psoriasis

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