Hyperhomocysteinemia as an Independent Risk Factor for Coronary Heart Disease. Comparison with Conventional Risk Factors

The present study was designed to evaluate the strength of association of raised plasma homocysteine concentration as a risk factor for coronary heart disease independent of conventional risk factor. It was a case control study conducted at Punjab Institute of Cardiology Lahore. A total of 210 subjects aged 25 to 60 years comprising of 105 newly admitted patients of CHD as cases and 105 age and sex matched healthy individuals with no history of CHD as control were recruited for the study. Fasting blood samples were obtained from cases and controls. Plasma homocysteine was analyzed by fluorescence polarization immunoassay (FPIA) method on automated immunoassay analyzer (Abbott IMX). Total cholesterol, triglyceride and HDL cholesterol were analyzed using calorimetric kit methods. The concentration of LDL cholesterol was calculated using Friedewald formula. The patients were also assessed for traditional risk factors such as age, sex, family history of CVD, hypertension, smoking and physical activity, and were compared with control subjects. The collected data was entered in SPSS version 24 for analysis and interpretation.The mean age in controls and experimental groups were 43.00± 8.42 years and 44.72± 8.59 years with statistically same distribution (p- value= 0.144). The mean plasma homocysteine for cases was 22.33± 9.22 µmol/L where as it was 12.59±3.73 µmol/L in control group. Highly significant difference was seen between the mean plasma level of homocysteine in cases and controls (p˂0.001).Simple logistic regression indicates a strong association of coronary heart disease with hyperhomocysteinemia (OR 7.45), which remained significantly associated with coronary heart disease by multivariate logistic regression (OR 7.10, 95%C1 3.12-12.83, p=0.000). The present study concludes that elevated levels of Plasma homocysteine is an independent risk factor for coronary heart disease independent of conventional risk factors and can be used as an indicator for predicting the future possibility for the onset of CVD.

Plasma Homocysteine in Behcet's Disease: A Systematic Review and Meta-Analysis

Aim To evaluate the relevance of plasma homocysteine (HC) in Behcet's disease (BD) and its clinical manifestations. Methods Systematic review of EMBASE and PubMed databases according to PRISMA guidelines from inception to July 2021; random-effects meta-analyses for continuous outcomes. Results The search strategy retrieved 48 case–control (2,669 BD and 2,245 control participants) and 5 cohort studies (708 BD participants). Plasma HC was higher in BD than in controls (p < 0.0001) with wide heterogeneity (I2 = 89.7%) that remained unchanged after sensitivity analysis according to year of article publication, age of BD participants, study size, study quality, method of HC determination, and male/female ratio >1.5; some pooled ethnicities explained a small part of the heterogeneity (I2 = 16.3%). Active BD participants had higher HC than inactive ones (p < 0.0001), with moderate heterogeneity (I2 = 49.2%) that disappeared after removal of an outlier study with very high disease activity. BD participants with any vascular involvement had higher HC than those without (p < 0.0001) with wide heterogeneity (I2 = 89.7%); subgroup analysis on venous thrombosis only changed neither effect size (p < 0.0001) nor heterogeneity (I2 = 72.7%). BD participants with ocular involvement had higher HC than those without (p < 0.0001) with moderate heterogeneity (I2 = 40.3%). Conclusion Although causality cannot be inferred, the consistency of the elevation of plasma HC in BD, particularly in patients with active disease, with vascular and ocular involvement suggests an intrinsic involvement of HC in these clinical manifestations.

The 677C>T variant in methylenetetrahydrofolate reductase causes morphological and functional cerebrovascular deficits in mice

Vascular contributions to cognitive impairment and dementia (VCID) particularly Alzheimers disease and related dementias (ADRDs) are increasing; however, mechanisms driving cerebrovascular decline are poorly understood. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate and methionine cycles. Variants in MTHFR, notably 677C>T, are associated with dementias, but no mouse model existed to identify mechanisms by which MTHFR677C>T increases risk. Therefore, MODEL-AD created a novel knock-in (KI) strain carrying the Mthfr677C>T allele on the C57BL/6J background (Mthfr677C>T) to characterize morphology and function perturbed by the variant. Consistent with human clinical data, Mthfr677C>T mice have reduced enzyme activity in the liver and elevated plasma homocysteine levels. MTHFR enzyme activity as well as critical metabolites in the folate and methionine cycles are reduced in the Mthfr677C>T brain. Mice showed reduced tissue perfusion in numerous brain regions by PET/CT as well as significantly reduced vascular density and increased GFAP-expressing astrocytes in frontal cortex . Electron microscopy revealed cerebrovascular damage including endothelial and pericyte apoptosis, reduced luminal size, and increased astrocyte and microglial presence in the microenvironment. Collectively, these data suggest critical perturbations to cerebrovascular function in Mthfr677C>T mice supporting its use as a model for preclinical studies of VCID.

57 The Saga of Just One QTL; From Laying Hen Bone Strength to One Carbon Metabolism

Skeletal damage is a challenge for laying hens, as the adaptations for egg laying make them susceptible to osteoporosis. We know that activity, growth and puberty influence skeletal quality genetics. However, in this story, we follow the process of resolving a QTL for skeletal quality to a single gene. Providing both a nutritional and a genetic solution and illustrating another level of complexity. Using divergently selected populations in an F2 cross, a QTL for skeletal quality was described. Utilising a series of experiments in the commercial founder line the QTL was fine mapped on chromosome 1 and the differences in physiology of hens that segregated for markers at the locus defined e.g. tibia breaking strength 200.4 vs 218.1 Newton (p&lt; 0.002). Transcriptome profiling of tibia from the high and low bone strength genotype revealed a highly differentially expressed gene co localising to the QTL, the enzyme cystathionine beta synthase (CBS). CBS is a component of one carbon metabolism. Plasma homocysteine, the substrate of CBS had a higher concentration in the genotype associated with poor bone quality. Homocysteine interferes with crosslinking of the collagen matrix, critical to bone formation. Homocysteine can be re-methylated into methionine, a limiting amino acid in laying hens, using betaine as a methyl donor. Testing the hypothesis that reducing plasma homocysteine by feeding betaine, a widely available feed additive, would improve bone quality in laying hens proved successful.This is just one component of a complex trait and its elucidation took us along unexpected routes. However, I am optimistic that with modern tools and an open mind we can progress more quickly. Alongside understanding the factors that determine skeletal quality genetics, the discovery of the mechanisms behind complex traits, although rarely easy, offer the potential for novel interventions to improve animal health and production.

Association between Plasma Homocysteine Concentrations and the First Ischemic Stroke in Hypertensive Patients with Obstructive Sleep Apnea: A 7-Year Retrospective Cohort Study from China

Purpose. This study was aimed at investigating the association between baseline plasma homocysteine (Hcy) concentrations and the risk of the first ischemic stroke (IS) and at investigating any possible influential modifying factors in hypertensive patients with obstructive sleep apnea (OSA). Methods. Cox proportional hazards regression was employed to investigate the relationship between plasma Hcy concentration and the first IS. A generalized additive model was applied to determine the nonlinear relationship. In addition, we conducted subgroup analysis. Results. A total of 2350 hypertensive patients with OSA without a history of IS were enrolled in this study. At a median follow-up of 7.15 years, we identified 93 cases of the first IS. After adjusting for potential confounding, the findings revealed that plasma Hcy concentration was strongly and positively associated with the occurrence of the first IS (per SD increment; HR = 1.37 , 95% CI: 1.30-1.44). A nonlinear relationship was found between plasma Hcy concentration and the risk of developing the first IS with inflection points for plasma Hcy of 5 μmol/L. In stratified analysis, a greater positive correlation was found between baseline plasma Hcy concentrations and new-onset IS in patients with DBP ≥ 90 mmHg (per SD increment; HR = 1.48 , 95% CI: 1.33-1.65 vs. <90 mmHg: HR = 1.20 , 95% CI: 1.02-1.42; P ‐ interaction = 0.04 ) and BMI ≥ 24 and <28 kg/m2 (per SD increment; HR = 1.46 , 95% CI: 1.26-1.70 vs. <24 kg/m2: HR = 1.13 , 95% CI: 0.95-1.33 vs. ≥28 kg/m2: HR = 1.46 , 95% CI: 1.25-1.70; P ‐ interaction = 0.03 ). Conclusion. Elevated plasma Hcy concentrations are independently associated with the risk of the first IS in hypertensive patients with OSA. Plasma Hcy concentrations ≥ 5 μ mol / L surely increased the risk of the first IS in hypertensive patients with OSA.

Levels of plasma homocysteine dynamics speciality in the development of acute postresection hepatic failure

This study aims to evaluate the level of plasma homocysteine in patients with acute post-resection hepatic failure, depending on the degree of the disease. Materials and Methods. The article presents the results of a study of plasma homocysteine levels in 40 patients with c different classes of acute post-resection liver failure. Indications for liver resection were: primary liver cancer 11 (27%), metastatic liver lesions 21 (53%), parasitic liver diseases 3 (7%), benign liver formations 5 (13%). Patients were divided into 3 groups - Patients with Post hepatectomy liver failure (PHLF) class developed in the postoperative period A, B and C. Results. Analysis of the data showed that the initially normal level of plasma homocysteine before liver resection (surgical treatment) and after has different developmental options. Depending on the class of post-resection hepatic failure, the level of plasma homocysteine changes and has deviations from the reference values. In a comparative analysis of the average homocysteine values in the group of patients with post-resection hepatic insufficiency of class A, after surgical treatment, they were significantly lower than in patients with PHLF B and C. In particular, in patients with class B and C PNF, there is a significant trend towards an increase in homocysteine levels after surgery. Hyperhomocysteinemia may be a risk factor for the development of acute liver failure after surgical treatment for focal liver disease. Possibly, its adverse effect on the function and restoration of the liver parenchyma, which requires further targeted study.

Flaxseed Increases Animal Lifespan and Reduces Ovarian Cancer Severity by Toxically Augmenting One-Carbon Metabolism

We used an LC-MS/MS metabolomics approach to investigate one-carbon metabolism in the plasma of flaxseed-fed White Leghorn laying hens (aged 3.5 years). In our study, dietary flaxseed (via the activity of a vitamin B6 antagonist known as “1-amino d-proline”) induced at least 15-fold elevated plasma cystathionine. Surprisingly, plasma homocysteine (Hcy) was stable in flaxseed-fed hens despite such highly elevated cystathionine. To explain stable Hcy, our data suggest accelerated Hcy remethylation via BHMT and MS-B12. Also supporting accelerated Hcy remethylation, we observed elevated S-adenosylmethionine (SAM), an elevated SAM:SAH ratio, and elevated methylthioadenosine (MTA), in flaxseed-fed hens. These results suggest that flaxseed increases SAM biosynthesis and possibly increases polyamine biosynthesis. The following endpoint phenotypes were observed in hens consuming flaxseed: decreased physiological aging, increased empirical lifespan, 9–14% reduced body mass, and improved liver function. Overall, we suggest that flaxseed can protect women from ovarian tumor metastasis by decreasing omental adiposity. We also propose that flaxseed protects cancer patients from cancer-associated cachexia by enhancing liver function.

The Impact of Homocysteine on the Risk of Hormone-Related Cancers: A Mendelian Randomization Study

Background: Aberrant homocysteine level is associated with metabolic disorders and DNA damage, which may be involved in the carcinogenesis of hormone-related cancers, but clinical results of observational studies are controversial. In this study, we investigated the causal relationships between plasma homocysteine and breast cancer (BRCA), prostate cancer (PrCa), and renal cell carcinoma (RCC) using Mendelian randomization (MR) analyses.Design and Methods: To investigate the putative causal associations between homocysteine and the aforementioned three types of cancers, a two-sample MR study was employed for the study. The primary strategy for summary data analyses was the inverse-variance-weighted (IVW) approach. In our study, the single-nucleotide polymorphisms (SNPs) excluded confounding factors through Linkage Disequilibrium (LD). Phenoscanner tests were the instrumental variants (IVs), homocysteine was the exposure, and BRCA, PrCa, and RCC were the outcomes. Single-nucleotide polymorphisms associated with homocysteine were extracted from a large genome-wide association study (GWAS) meta-analysis of European participants (n = 44,147). Summary Statistics of BRCA were obtained from the latest and largest GWAS meta-analysis comprising of 82 studies from Breast Cancer Association Consortium (BCAC) studies, including women of European ancestry (133,384 cases and 113,789 controls); we obtained summary-level data from the GWAS meta-analysis of PrCa comprising 79,148 cases and 61,106 controls of European ancestry, and the dataset of RCC was a sex-specific GWAS meta-analysis comprising of two kidney cancer genome-wide scans for men (3,227 cases and 4,916 controls) and women (1,992 cases and 3,095 controls) of European ancestry. The MR-Egger and weight median analyses were applied for the pleiotropy test.Results: The results showed null associations between plasma homocysteine levels and overall BRCA (effect = 0.97, 95% CI: 0.90–1.06, P = 0.543), overall PrCa (effect = 1.01, 95% CI: 0.93–1.11, P = 0.774), RCC in men (effect = 0.99, 95% CI: 0.73–1.34, P = 0.929), and RCC in women (effect = 0.89, 95% CI: 0.61–1.31, P = 0.563).Conclusions: We found no putative causal associations between homocysteine and risk of BRCA, PrCa, and RCC.