Plasma Hcy Levels Research Articles

The association of plasma homocysteine levels with short-term mortality in sepsis patients: A meta-analysis.

The association between plasma homocysteine (Hcy) levels and short-term mortality in sepsis patients remains unclear. This meta-analysis aimed to clarify this potential relationship. Following PRISMA 2020 and Cochrane Handbook guidelines, we conducted a comprehensive literature search in the PubMed, Embase, and Web of Science databases up to June 24, 2024. We included cohort studies that assessed the association between plasma Hcy levels and all-cause mortality in adult sepsis patients. Standardized mean differences (SMDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model to account for potential heterogeneity. Nine cohort studies involving 771 sepsis patients were included. Overall, no significant difference in plasma Hcy levels was observed between survivors and non-survivors (SMD: -0.23, 95% CI: -0.84 to 0.37, P = 0.45), with substantial heterogeneity (I² = 86%). Subgroup analysis revealed lower plasma Hcy levels among survivors in Chinese patients (SMD: -1.56, 95% CI: -1.98 to -1.13, P < 0.001) but not in non-Asian patients. Plasma Hcy levels were not significantly associated with all-cause mortality (OR per 1-unit increment: 1.03, 95% CI: 0.95 to 1.11, P = 0.51), with notable heterogeneity (I² = 72%). However, a significant association was found in Chinese patients (OR: 1.09, 95% CI: 1.03 to 1.15, P = 0.003), but not in non-Asian patients. In conclusion, plasma Hcy levels were not generally associated with short-term mortality in sepsis patients. However, significant associations were observed in Chinese patients, suggesting potential ethnic differences that warrant further investigation.

Contribution of haptoglobin phenotypic variation to the presence of hyperhomocysteinemia in type 2 diabetics with and without angiopathy.

The genetic polymorphism of haptoglobin (Hp) has been associated with several cardiovascular risk factors, but a possible relationship between Hp phenotypic variation and increased levels of homocysteine (Hcy) and cysteine (Cy) is still unknown. The objective of this study is to evaluate the relationship between the Hp polymorphism and hyperhomocysteinemia (HHcy) and hypercysteinemia (HCy) in type 2 diabetics (T2D) with and without angiopathy (AGP). A case-control study was carried out on 293 adults: Group I (GI) - 75 subjects with T2D and AGP; Group II (GII) - 75 subjects with T2D without AGP; Group III (GIII) - 143 controls. Plasma levels of Hcy, Cy and vitamin B6 were measured by high performance liquid chromatography (HPLC) and vitamins B9 and B12 determined by electrochemiluminescence (ECL). The Hp polymorphism was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and peroxidase staining. The results were analyzed in SPSS®, version 26.0 with a significance of 95%. Mean Hcy concentrations were significantly lower in carriers of the Hp2-2 phenotype (6.14 µM; p = 0.046) compared to the other genotypes. The presence of Hp2-1 is associated with an approximately 3.3 times greater probability of occurrence of HHcy (p = 0.015) and 3.7 times greater probability occurrence of HCy (p = 0.021) in T2D with AGP. The presence of the Hp2-1 phenotype is associated with the predisposition of HHcy and HCy in individuals with T2D and AGP, possibly through a positive heterosis mechanism. Carriers of the Hp2-2 phenotype appear to have a greater activation of the transsulfuration pathway in the Hcy cycle and consequent protection for its accumulation.

Clinical relevance of critical plasma homocysteine levels in predicting rupture risk for small and medium-sized intracranial aneurysms

Plasma homocysteine (Hcy) has been globally recognized as an independent risk factor for various neurovascular diseases. In this study, the authors investigated the relationship between critical Hcy concentration and the risk of rupture in intracranial aneurysms (IAs). This study collected data from 423 patients with both ruptured and unruptured IAs. We compared demographic data, vascular rupture risk factors, and laboratory test results between the two groups. Multivariable logistic regression analysis was employed to determine the correlation between critical plasma Hcy levels and the risk of rupture in small to medium-sized IAs. A total of 330 cases of ruptured intracranial aneurysms (RIA) and 93 cases of unruptured intracranial aneurysms (UIA) were included. Univariate analysis revealed statistically significant differences between the ruptured and unruptured groups in terms of hypertension, hyperlipidemia, plasma Hcy levels, and IA morphology (all P < 0.05). Multivariable logistic regression analysis indicated that hypertension (odds ratio [OR] 0.504; 95% confidence interval [CI] 0.279–0.911; P = 0.023), hyperlipidemia (OR 1.924; 95% CI 1.079–3.429; P = 0.027), and plasma Hcy levels (OR 1.420; 95% CI 1.277–1.578; P < 0.001) were independently associated with the rupture of small to medium-sized IAs, all with statistical significance (P < 0.05). Our study suggests that critical plasma Hcy levels are an independent risk factor for increased rupture risk in small to medium-sized intracranial aneurysms. Therefore, reducing plasma Hcy levels may be considered a valuable strategy to mitigate the risk of intracranial vascular abnormalities rupture and improve patient prognosis.

The impact of homocysteine on patients with diabetic nephropathy: a mendelian randomization study.

Homocysteine (Hcy) has been associated with an increased risk of diabetic nephropathy (DN) in patients, but there is still controversy. This study aims to investigate the causal relationship between plasma Hcy and DN. A Mendelian randomization (MR) study using data from 2 samples was employed to infer causal relationships. The aggregated genetic data associated with Hcy was derived from the largest genome-wide association study (GWAS) to date, involving 44,147 individuals of European ancestry.Data on SNP-diabetic nephropathy, creatinine, and urea nitrogen were obtained from the IEU GWAS database. The analysis method employed a fixed-effect or random-effect inverse variance-weighted approach to estimate effects.Additional analysis methods were used to assess stability and sensitivity. The potential for pleiotropy was evaluated using the MR-Egger intercept test. Using 12 SNPs as instrumental variables, two-sample MR analysis revealed no evidence of a causal relationship between genetically predicted plasma Hcy levels and diabetic nephropathy, as well as creatinine and blood urea nitrogen levels. This finding is consistent with the results obtained from other testing methods. Two-sample Mendelian Randomization analysis found no evidence of a causal relationship between plasma homocysteine levels and diabetic nephropathy, creatinine, or urea.

Non-causal relationship of polycystic ovarian syndrome with homocysteine and B vitamins: evidence from a two-sample Mendelian randomization.

Previous observational studies have identified a correlation between elevated plasma homocysteine (Hcy) levels and polycystic ovary syndrome (PCOS). This study aimed to determine whether a causal relationship exists between Hcy and PCOS at the genetic level. A two-sample Mendelian Randomization (TSMR) study was implemented to assess the genetic impact of plasma levels of Hcy, folate, vitamin B12, and vitamin B6 on PCOS in individuals of European ancestry. Independent single nucleotide polymorphisms (SNPs) associated with Hcy (n=12), folate (n=2), vitamin B12 (n=10), and vitamin B6 (n=1) at genome-wide significance levels (P<5×10-8) were selected as instrumental variables (IVs). Data concerning PCOS were obtained from the Apollo database. The primary method of causal estimation was inverse variance weighting (IVW), complemented by sensitivity analyses to validate the results. The study found no genetic evidence to suggest a causal association between plasma levels of Hcy, folate, vitamin B12, vitamin B6, and PCOS. The effect sizes, determined through random-effect IVW, were as follows: Hcy per standard deviation increase, OR = 1.117, 95%CI: (0.842, 1.483), P = 0.442; folate per standard deviation increase, OR = 1.008, CI: (0.546, 1.860), P = 0.981; vitamin B12 per standard deviation increase, OR = 0.978, CI: (0.808, 1.185), P = 0.823; and vitamin B6 per standard deviation increase, OR = 0.967, CI: (0.925, 1.012), P = 0.145. The fixed-effect IVW results for each nutrient exposure and PCOS were consistent with the random-effect IVW findings, with additional sensitivity analyses reinforcing these outcomes. Our findings indicate no causal link between Hcy, folate, vitamin B12, vitamin B6 levels, and PCOS.

Causal Relationships between Homocysteine and the Polycystic Ovary Syndrome: A Mendelian Randomization Analysis.

Polycystic ovary syndrome (PCOS) is an endocrine disease attributed to multiple genetic variants and environmental factors. We aimed to find the causal association of homocysteine (Hcy) with PCOS. A two-sample Mendelian randomization (MR) analysis was performed. We selected 14 single-nucleotide polymorphisms (SNPs) as instrumental variables to predict the risk of PCOS from genome-wide association studies (GWAS). The summary statistics of PCOS were obtained from 3 large genome-wide association studies in the European population, involving 4,138 cases and 20,129 controls, 3,609 cases and 229,788 controls, 994 cases and 165,817 controls, separately. The IVM analyses revealed that plasma Hcy levels were not causally associated with the risk of PCOS in the meta-analysis (combined effect = 1.032, 95% confidence interval (CI): 0.885-1.203, p=0.688). There was no sufficient evidence to support the causal association of the Hcy with the risk of PCOS.

Genetic variants of folate metabolism and the risk of multiple sclerosis

ABSTRACT Background and aims Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of unknown cause. Alterations in one-carbon metabolism have impact in the pathophysiology by genetic susceptibility to MS and increased the risk of MS. The aim of this study was to investigate the contribution of the gene polymorphism on Methylenetetrahydrofolate Reductase (MTHFR), Methionine Synthase Reductase (MTRR), Methionine Synthase (MTR) enzymes and of the essential factors (homocysteine, Hcy; cysteine, Cys; and vitamin B12, VitB12) in folate metabolism. Methods Eligible MS patients (n = 147) and health controls (n = 127) were participated. The gene polymorphisms were analyzed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and the levels of plasma Hcy, Cys and VitB12 were measured by Enzyme Linked Immunuabsorbent Assay (ELISA). Results and conclusion Our results showed that the levels of Hcy and VitB12 were lower and the levels of Cys were higher in MS compared to controls. The observation of high Cys values in all 3 gene polymorphisms suggests that the transsulfiration pathway of Hcy is directed towards Cys formation since the methionine synthesis pathway does not work. We could not find any association with all gene polymorphisms with the risk of MS. The T allele of MTHFR C677T and G allele of MTR A2756G are risk factors for serum Cys level on MS. As for MTR A2756G, serum vitB12 was observed in MS patients with G allele.

Homocysteine modifies the association of coronary stenosis and HIV infection in an inner city African American population.

People with HIV (PWH) whose disease is controlled on anti-retroviral regimens remain at an increased risk for coronary artery disease (CAD). Traditional cardiovascular risk factors do not fully explain the residual risk in PWH suggesting contributions from nontraditional factors. Homocysteine (Hcy) may be one of these as prior work in adults without HIV demonstrate that Hcy may impair endothelial function by decreasing the availability of nitric oxide, promoting the development of atherosclerosis. In addition, plasma Hcy levels are higher in PWH than in individuals living without HIV. The aim of this study was to investigate whether Hcy levels influence the association between HIV and coronary stenosis in an inner city African American population. African Americans from the Heart Study in Baltimore, with and without HIV, recruited from inner-city Baltimore between June 2004 and February 2015, were included in this analysis. Participants underwent coronary CT angiography to evaluate the presence of coronary stenosis, defined as luminal stenosis >10%. Hcy was measured from stored serum samples. In this analysis, the median [IQR] age of the 664 participants was 56 [50-66] years; 68.1% were living with HIV and 43.1% were women. Elevated Hcy (>15µmol/L) was more prevalent in those with coronary stenosis (23.3%, 95% CI: 18.4%-28.2%) than in those without coronary stenosis (13.1%, 95% CI: 9.7%-16.5%) (p = 0.0007), and HIV was associated with coronary stenosis in those participants with an elevated Hcy (Prevalence Ratio: 1.94, 95% CI: 1.04-3.64, p = 0.0038) and not in those with a Hcy ≤15µmol/L (Prevalence Ratio: 1.02, 95% CI: 0.83-1.25, p = 0.87). Our data suggest an association between elevated Hcy levels (>15µmol/L) and the prevalence of coronary stenosis in PWH from this inner city African American population.

Association of homocysteine with white matter dysconnectivity in schizophrenia

Several studies have shown white matter (WM) dysconnectivity in people with schizophrenia (SZ). However, the underlying mechanism remains unclear. We investigated the relationship between plasma homocysteine (Hcy) levels and WM microstructure in people with SZ using diffusion tensor imaging (DTI). Fifty-three people with SZ and 83 healthy controls (HC) were included in this retrospective observational study. Tract-Based Spatial Statistics (TBSS) were used to evaluate group differences in WM microstructure. A significant negative correlation between plasma Hcy levels and WM microstructural disruption was noted in the SZ group (Spearman’s ρ = −.330, P = 0.016) but not in the HC group (Spearman’s ρ = .041, P = 0.712). These results suggest that increased Hcy may be associated with WM dysconnectivity in SZ, and the interaction between Hcy and WM dysconnectivity could be a potential mechanism of the pathophysiology of SZ. Further, longitudinal studies are required to investigate whether high Hcy levels subsequently cause WM microstructural disruption in people with SZ.

Homocysteine modulates CXCL10/CXCR3 axis activity to induce endothelial dysfunction.

Elevated homocysteine (Hcy) levels have been linked to the development of cardiovascular diseases, notably endothelial dysfunction, a critical precursor to atherosclerosis. In this extensive investigation, we explore the intricate pathways through which Hcy influences endothelial dysfunction, with particular attention to the CXCL10/CXCR3 axis. Employing a dual approach encompassing both in vitro and in vivo models, we scrutinize the repercussions of Hcy exposure on endothelial functionality. Our results reveal that Hcy significantly impairs crucial endothelial processes, including cell migration, proliferation, and tube formation. Concomitantly, Hcy upregulates the expression of adhesion molecules, exacerbating endothelial dysfunction. In a murine hyperhomocysteinemia (HHcy) model, we observed a parallel increase in plasma Hcy levels and adverse vascular effects. Moreover, our study unraveled a pivotal role of the CXCL10/CXCR3 axis in Hcy-induced endothelial dysfunction. Hcy exposure led to the upregulation of CXCL10 and CXCR3, both in vitro and in HHcy mice. Importantly, the blockade of this axis, achieved through specific antibodies or NBI-74330, mitigated the detrimental effects of Hcy on endothelial function. In conclusion, our findings illuminated the central role of the CXCL10/CXCR3 axis in mediating Hcy-induced endothelial dysfunction, providing valuable insights for potential therapeutic strategies in managing HHcy-related cardiovascular diseases.

Homocysteine, hyperhomocysteinemia, and H-type hypertension.

Homocysteine (Hcy) is a sulphur-containing nonessential amino acid derived from the intermediate metabolites of methionine. Methionine is obtained from dietary proteins, such as poultry, meat, eggs, seafood, and dairy products. Abnormalities in Hcy metabolic pathways, deficiencies in dietary methionine, folate, and vitamins B12, B6, and B2 and genetic defects, polymorphisms, or mutations in Hcy metabolism-related enzymes may lead to an increase in plasma Hcy levels. Generally, a plasma Hcy level higher than 10 or 15 μmol/L has been defined as hyperhomocysteinemia (HHcy). An individual with essential hypertension complicated with HHcy is considered to have H-type hypertension (HTH). Currently, HHcy is considered a novel independent risk factor for various cardiovascular diseases. To provide a useful reference for clinicians, the research progress on Hcy, HHcy, and HTH in recent years was systematically reviewed here, with a focus on the source and metabolic pathways of Hcy, plasma Hcy levels and influencing factors, detection methods for plasma Hcy levels, relationship between Hcy concentration and hypertension, pathogenesis of HTH, cardiovascular complications of HTH, and treatment of HTH.

Relationship between homocysteine, vitamin B9, vitamin B12 levels methylenetetrahydrofolate reductase (C677T, A1298C) polymorphisms, and cryptogenic stroke in Tunisian adults´ patients: a case-control study.

the relationship between elevated plasma homocysteine (Hcy) and stroke has been established, but this association remains indistinct in cryptogenic stroke in adults. Our aim is to investigate the association between homocysteine, vitamins B9 and B12, and cryptogenic stroke. Furthermore, to determine the correlation between methylenetetrahydrofolate reductase (MTHFR) polymorphism and biochemical levels in plasma. we conducted a retrospective case-control study including 100 cryptogenic stroke patients aged 18-50 years and 100 participants with age-and-sex-matched healthy controls. Clinical, radiological, and outcome data from cerebral venous thrombosis (CVT) patients were recorded. Homocysteine, vitamin B9, and vitamin B12 were analyzed. Deoxyribonucleic acids (DNAs) from both groups were tested. MTHFR C677T mutation was assessed by restriction fragment length polymorphism (PCR). All analyses were performed using Statistical Package for the Social Sciences (SPSSV.20) software. Multivariable logistic regression analysis was performed to identify factors associated with stroke risk and clinical outcomes. a total of 200 cases were included in this study, 50% (n=100) patients with cryptogenic stroke (mean age of 40.49 ± 6.2 years, sex-ratio= 1.5) and 50% (n=100) healthy cases (mean age of 39.09 ± 5.8 years, sex-ratio= 1.5). The elevated plasma level of Hcy and vitamin B9 levels deficiency increase the risk of cryptogenic stroke occurrence (aOR: 2.5; 95% (0.71-5.25), P=0.01), (aOR: 3.1; 95% (1.6-9.6), p=0.02 respectively). Additionally, vitamin B9 deficiency was significantly associated with elevated Hcy levels (4.57 ± 3.59; p=0.001). Genetic analysis revealed a significant association between homozygous TT genotype of the MTHFR C677T polymorphism, elevated Hcy levels (20.4 ± 7.07; p=0.001) and vitamin B9 deficiency (4.9±3.9; p=0.001). Furthermore, the combined CT/AC genotype was associated with elevated Hcy level (21.6 ± 9.6; p=0.001) and vitamin B9 deficiency (2.9 ± 1.0; p=0.04). the presence of homozygote MTHFR C677T or dual heterozygous MTHFR C66T and A1298C, which leads to elevated Hcy and deficiency of vitamin B9 plasma levels, is correlated with an increased risk of cryptogenic stroke occurrence among adult Tunisian patients.

Homocysteine, vitamin B12, folic acid levels and its association with Mild Cognitive Impairment in urban and rural dwelling Indians

AbstractBackgroundHomocysteine (Hcy) is a sulfur containing amino acid generated in the metabolism of methionine involving co‐factors such as B vitamins and folic acid. Deficiency of these co‐factors have been associated with increased Hcy levels (Hutto, 1997). Relationship between differing levels of plasma Hcy, vitamin B12, folic acid and cognitive impairment is inconclusive.MethodCross sectional analysis was done using the baseline data from two ongoing longitudinal studies such as Tata Longitudinal Study of Ageing (TLSA, N = 984) and Srinivaspura Aging, Neuro Senescence and COGnition (SANSCOG, N = 4404), an urban and rural cohorts (Sundarakumar et al, 2020) respectively. Hcy, vitamin B12, folic acid levels were compared between the subjects of both cohorts. Comparison of these levels between healthy and MCI (Mild Cognitive Impairment) subjects within and across the cohorts were done. CDR (Clinical Dementia Rating) scale was used to classify subjects having normal cognition and MCI, considering score of 0.5 as MCI. Mann‐Whitney U test was used to compare these levels between the groups.ResultHcy, vitamin B12, folic acid levels between the two cohorts showed significant difference, with higher levels of Hcy (median (IQR)) = (17.08 (11) vs 14.63 (10); p &lt;0.001), vitamin B12 (247 (252) vs 220 (143); p &lt;0.001) and folic acid (8.55 (9) vs 5.55(4); p &lt;0.05) in TLSA than SANSCOG. Significant difference seen in Hcy (17.73(11) vs 14.73 (10); p &lt;0.001), vitamin B12 (246 (249) vs 220 (136); p &lt;0.001) and folic acid (8.42 (9) vs 5.53 (4): p &lt;0.001) levels for healthy subjects between cohorts, higher levels were seen in TLSA subjects. Hcy (16.08 (8) vs 14.43 (12); p &lt;0.001) vitamin B12 (305 (341) vs 216 (174); p = 0.03) and folic acid (8.52 (9) vs 5.34 (4): p &lt;0.001) levels were significantly high in TLSA than SANSCOG for MCI subjects. However, these levels were not significantly different between healthy and MCI subjects within cohorts.ConclusionConsistently elevated levels of Hcy was observed in urban cohort. Though elevated level of Hcy was observed with normal vitamin B12 and folic acid, it was not associated with MCI.

Associations between homocysteine, vitamin B12, and folate and the risk of all-cause mortality in American adults with stroke.

Associations between plasma homocysteine (Hcy), vitamin B12, and folate and the risk of all-cause mortality are unclear. This study aimed to examine whether plasma Hcy, vitamin B12, and folate levels independently predict the risk of all-cause mortality in American adults with stroke. Data from the United States National Health and Examination Survey (NHANES; 1999-2006) were used and linked with the latest (2019) National Death Index (NDI). Cox proportional hazards models and restricted cubic splines were used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of all-cause mortality for Hcy, folate, and B12 levels in adults with stroke. Sample weights were calculated to ensure the generalizability of the results. A total of 431 participants were included (average age: 64.8 years). During a median follow-up of 10.4 years, 316 deaths occurred. Hcy was positively associated with all-cause mortality in adults with stroke (HR, 1.053; 95% CI: 1.026-1.080). Stroke patients with plasma Hcy levels in the fourth quartile had a 1.631-fold higher risk of all-cause mortality (HR, 1.631; 95% CI: 1.160-2.291) than those in the first quartile. The association between plasma Hcy and all-cause mortality was strong significant in older patients (p for interaction = 0.020). Plasma folate and vitamin B12 concentrations were inversely correlated with Hcy concentrations [B-value (95% CI): -0.032 (-0.056- -0.008), -0.004 (-0.007- -0.002), respectively]. No significant associations were observed between folate, vitamin B12 levels, and all-cause mortality in adults with stroke. Plasma Hcy levels were positively associated with all-cause mortality in older adults with stroke. Folate and vitamin B12 levels were inversely correlated with Hcy. Plasma Hcy may serve as a useful predictor in mortality risk assessment and targeted intervention in adults with stroke.

No causal effect of genetically determined circulating homocysteine levels on psoriasis in the European population: evidence from a Mendelian randomization study.

Although numerous studies demonstrated a link between plasma homocysteine (Hcy) levels and psoriasis, there still exists a certain level of controversy. Therefore, we conducted a Mendelian randomization study to investigate whether homocysteine plays a causative role in the development or exacerbation of psoriasis. A two-sample Mendelian randomization (MR) analysis was conducted. Summary-level data for psoriasis were acquired from the latest R9 release results from the FinnGen consortium (9,267 cases and 364,071 controls). Single nucleotide polymorphisms (SNPs) robustly linked with plasma Hcy levels at the genome-wide significance threshold (p < 5 × 10-8) (18 SNPs) were recognized from the genome-wide meta-analysis on total Hcy concentrations (n = 44,147 participants) in individuals of European ancestry. MR analyses were performed utilizing the random-effect inverse variance-weighted (IVW), weighted median, and MR-Egger regression methods to estimate the associations between the ultimately filtrated SNPs and psoriasis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. MR analyses revealed no causal effects of plasma Hcy levels on psoriasis [IVW: odds ratio (OR) = 0.995 (0.863-1.146), p = 0.941; weighed median method: OR = 0.985 (0.834-1.164), p = 0.862; MR-Egger regression method: OR = 0.959 (0.704-1.305), p = 0.795]. The sensitivity analyses displayed no evidence of heterogeneity and directional pleiotropy, and the causal estimates of Hcy levels were not influenced by any individual SNP. Our study findings did not demonstrate a causal effect of genetically determined circulating Hcy levels on psoriasis.

Ablation of the gut microbiota alleviates high-methionine diet-induced hyperhomocysteinemia and glucose intolerance in mice

A high-methionine (HM) diet leads to hyperhomocysteinemia (HHcy), while gastrointestinal tissue is an important site of net homocysteine (Hcy) production. However, the role of the gut microbiota in host HHcy remains obscure. This study aimed to determine whether gut microbiota ablation could alleviate host HHcy and glucose intolerance and reveal the underlying mechanism. The results showed that the HM diet-induced HHcy and glucose intolerance in mice, while antibiotic administration decreased the plasma level of Hcy and reversed glucose intolerance. HM diet increased intestinal epithelial homocysteine levels, while antibiotic treatment decreased intestinal epithelial homocysteine levels under the HM diet. Gut microbiota depletion had no effect on the gene expression and enzyme activity of CBS and BHMT in the livers of HM diet-fed mice. The HM diet altered the composition of the gut microbiota with marked increases in the abundances of Faecalibaculum and Dubosiella, which were also positively correlated with plasma Hcy concentrations. An in-depth analysis of the bacterial cysteine and methionine metabolism pathways showed that the abundances of two homocysteine biosynthesis-related KEGG orthologies (KOs) were markedly increased in the gut microbiota in HM diet-fed mice. Hcy was detected from Dubosiella newyorkensis-cultured supernatant by liquid chromatography–tandem mass spectrometry (LC‒MS) analysis. In conclusion, these findings suggested that the HM diet-induced HHcy and glucose intolerance in mice, by reshaping the composition of the gut microbiota, which might produce and secrete Hcy.

Genome-wide analysis of DNA methylation and its relationship with serum homocysteine levels in patients with hypertension.

Homocysteine (Hcy) is an independent risk factor for cardiovascular diseases, and elevated plasma Hcy levels could aggravate vascular injury in hypertension. Hyperhomocysteinemia can change the methylation status of global DNA and specific genes. In the present study, we aim to examine the comprehensive influence of Hcy levels on DNA methylation status in patients with hypertension. Epigenome-wide methylation profiles of the peripheral leukocyte DNA of 218 patients with hypertension were analyzed using the Illumina Infinium Methylation EPIC BeadChip. Differentially methylated positions (DMPs) associated with serum Hcy levels were identified by mixed linear regression with the adjustment of potential confounders. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted to determine the potential functions of the identified DMPs. The association between the methylation level of DMPs and carotid-femoral pulse wave velocity (Cf-PWV) was also analyzed. Five DMPs at cg13169662, cg03179312, cg21976560, cg25262698, and cg09433843 showed significant association with serum Hcy levels (false discovery rate-corrected P < 0.05). An additional six CpG sites met the threshold for suggestive significance ( P < 1 × 10 -6 ), among which three DMPs (cg25781123, cg26463106, and cg06679221) were annotated to THUMPD3 . Furthermore, the methylation levels of cg13169662 and cg25262698 (RPRD1A) were significantly associated with Cf-PWV. Our results suggest that Hcy could induce DNA methylation alteration in patients with hypertension. Further functional research is warranted to elucidate the concrete role of DMPs in hypertension.

Associations between homocysteine and B vitamins and stroke: a cross-sectional study.

Homocysteine (Hcy) is a predictor for stroke. B vitamins are required for the metabolism of Hcy. We designed a study to investigate the associations of plasma Hcy and B vitamins with the prevalence of stroke in adults. A total of 8,371 adults were included in the National Health and Examination Survey (NHANES) between 2003-2006 in the United States. Multivariate regression analysis and smooth curve fitting were conducted to evaluate the associations of stroke prevalence with Hcy, folate, vitamin B6, and B12. A segmented regression model was used to analyze the threshold effects. Sample weights were calculated to ensure the results' generalizability. The mean age of all participants was 46.43 years (51.8% women), and the prevalence of stroke was 2.72%. A nonlinear and positive association was found between plasma Hcy levels and the prevalence of stroke. Furthermore, L-shaped associations were found between plasma vitamin B6 and folate levels and stroke, with the turning point at 65.2 nmol/L for vitamin B6 and 26 nmol/L for folate, respectively. Vitamin B12 revealed a U-shaped relationship with stroke, with the turning points at 492.98 pmol/L for vitamin B12. Non-linear associations of plasma Hcy and B vitamins levels with stroke prevalence were found in American adults. These associations may have an implication that higher plasma Hcy levels should be reduced, and plasma vitamin B6, vitamin B12 and folate levels should be moderately improved in stroke prevention. Future studies are needed to verify the causality of these associations and elucidate the underlying mechanisms.

Plasma homocysteine levels and associated factors in community-dwelling adolescents: the EVA-TYROL study.

Homocysteine (Hcy) has been associated with an adverse cardiovascular risk profile in adolescents. Assessment of the association between plasma Hcy levels and clinical/laboratory factors might improve our understanding of the pathogenesis of cardiovascular disease. Hcy was measured in 1,900 14- to 19-year-old participants of prospective population-based EVA-TYROL Study (44.3% males, mean age 16.4 years) between 2015 and 2018. Factors associated with Hcy were assessed by physical examination, standardized interviews, and fasting blood analysis. Mean plasma Hcy was 11.3 ± 4.5 µmol/L. Distribution of Hcy was characterized by extreme right skew. Males exhibited higher Hcy and sex differences increased with increasing age. Univariate associations with Hcy emerged for age, sex, body mass index, high-density lipoprotein cholesterol, and for factors pertaining to blood pressure, glucose metabolism, renal function, and diet quality, whereas the most important multivariate predictors of Hcy were sex and creatinine. Clinical and laboratory factors associated with Hcy in adolescents were manifold, with sex and high creatinine identified as strongest independent determinants. These results may aid when interpreting future studies investigating the vascular risk of homocysteine.

Effect of plasma homocysteine levels on methylation and expression of thrombomodulin gene in patients with retinal vein occlusion

Objective: To explore the effect of plasma homocysteine (Hcy) levels on methylation and expression of thrombomodulin (TM) gene in patients with retinal vein occlusion (RVO).Methods: 11 cases of patients who were diagnosed as RVO in Department of Ophthalmology in Baogang Hospital from January 2019 to December 2020 were included in this research. 11 cases of healthy people who came to our physical examination center for physical examination during the same period were included into the control group. Fasting cubital venous blood was collected in the morning, plasma Hcy levels were measured by means of enzyme cycle assay, TM gene methylation was detected by methylation-specificity polymerase chain reaction (MSP), and the correlation between characteristic changes in plasma Hcy and TM gene methylation was analyzed in the research subjects.Results: Plasma Hcy expression levels were higher in the RVO group than those in the control group (p &lt; .01). In the control group, the TM primer set region was basically unmethylated, while in the RVO group, the TM primer set region was partially methylated.Conclusions: Plasma Hcy affects the occurrence and development of RVO through methylation of TM encoding gene.