The Homocysteine and Metabolic Syndrome: A Mendelian Randomization Study.
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ABSTRACT:
SUBMITTER: Lee HS
PROVIDER: S-EPMC8308555 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12-6.38; P = 2.7 × 10(-2)). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).
| S-EPMC4850434 | biostudies-other
Project description:BackgroundWhether a modestly elevated homocysteine level is causally associated with an increased risk of cardiovascular disease remains unestablished. We conducted a Mendelian randomization study to assess the associations of circulating total homocysteine (tHcy) and B vitamin levels with cardiovascular diseases in the general population.MethodsIndependent single nucleotide polymorphisms associated with tHcy (n = 14), folate (n = 2), vitamin B6 (n = 1), and vitamin B12 (n = 14) at the genome-wide significance level were selected as instrumental variables. Summary-level data for 12 cardiovascular endpoints were obtained from genetic consortia, the UK Biobank study, and the FinnGen consortium.ResultsHigher genetically predicted circulating tHcy levels were associated with an increased risk of stroke. For each one standard deviation (SD) increase in genetically predicted tHcy levels, the odds ratio (OR) was 1.11 (95% confidence interval (CI), 1.03, 1.21; p = 0.008) for any stroke, 1.26 (95% CI, 1.05, 1.51; p = 0.013) for subarachnoid hemorrhage, and 1.11 (95% CI, 1.03, 1.21; p = 0.011) for ischemic stroke. Higher genetically predicted folate levels were associated with decreased risk of coronary artery disease (ORSD, 0.88; 95% CI, 0.78, 1.00, p = 0.049) and any stroke (ORSD, 0.86; 95% CI, 0.76, 0.97, p = 0.012). Genetically predicted increased vitamin B6 levels were associated with a reduced risk of ischemic stroke (ORSD, 0.88; 95% CI, 0.81, 0.97, p = 0.009). None of these associations persisted after multiple testing correction. There was no association between genetically predicted vitamin B12 and cardiovascular disease.ConclusionsThis study reveals suggestive evidence that B vitamin therapy and lowering of tHcy may reduce the risk of stroke, particularly subarachnoid hemorrhage and ischemic stroke.
| S-EPMC8063383 | biostudies-literature
Project description:BackgroundObservational studies have previously demonstrated a significant relationship among both metabolic syndrome (Mets) and colorectal cancer (CRC). Whether there is a causal link remains controversial.ObjectiveTo clarify whether Mets and their components have a causal effect on colorectal cancer, we have carried out a bidirectional Mendelian randomization analysis (MR).MethodsThis study started from genome-wide association data for Mets and its 5 components (hypertension, waist circumference, fasting blood glucose, serum triglycerides, and serum high-density lipoprotein cholesterol) and colorectal cancer. Mendelian randomization (MR) techniques were used in the study to examine their associations.ResultsAfter Benjamini-Hochberg multiple corrections, genetically predicted significant causal link exists between WC (waist circumference) and CRC. The OR was 1.35 (95 % CI: 1.08-1.69; p = 0.0096). Other Mets components (HBP, FBG, TG, HDL), on the other hand, found no evidence of a genetic link between CRC and Mets. In addition, MR results showed that CRC was not causally related to either Mets or the components. We get the same result in the validated dataset.ConclusionAccording to the bidirectional MR investigation shows a significant causal relationship among obesity and CRC in the Mets component but no causal relationship in the opposite direction.
| S-EPMC10784169 | biostudies-literature
Project description:Metabolic syndrome exhibits associations with diverse neurological disorders, and its potential influence on the cerebral cortex may be one of the many potential factors contributing to these adverse outcomes. In this study, we aimed to investigate the causal relationship between metabolic syndrome and changes in cerebral cortex structure using Mendelian randomization analysis. Genome-wide association study data for the 5 components of metabolic syndrome were obtained from individuals of European descent in the UK Biobank. Genome-wide association study data for 34 known cortical functional regions were sourced from the ENIGMA Consortium. Data on Alzheimer's disease, major depression, and anxiety disorder were obtained from the IEU Open genome-wide association study database. The causal links between metabolic syndrome elements and cerebral cortex architecture were evaluated using inverse variance weighting, Mendelian randomization-Egger, and weighted median techniques, with inverse variance weighting as the primary method. Inverse variance weighting, Mendelian randomization Egger, weighted median, simple mode, and weighted mode methods were employed to assess the relationships between metabolic syndrome and neurological diseases (Alzheimer's disease, major depression, and anxiety disorder). Outliers, heterogeneity, and pleiotropy were assessed using Cochran's Q test, MR-PRESSO, leave-one-out analysis, and funnel plots. Globally, no causal link was found between metabolic syndrome and overall cortical thickness or surface area. However, regionally, metabolic syndrome may influence the surface area of specific regions, including the caudal anterior cingulate, postcentral, posterior cingulate, rostral anterior cingulate, isthmus cingulate, superior parietal, rostral middle frontal, middle temporal, insula, pars opercularis, cuneus, and inferior temporal. It may also affect the thickness of the medial orbitofrontal, caudal middle frontal, paracentral, superior frontal, superior parietal, and supramarginal regions. These findings were nominally significant and withstood sensitivity analyses, showing no substantial heterogeneity or pleiotropy. Furthermore, we found an association between metabolic syndrome and the risk of Alzheimer's disease, major depression, and anxiety disorder. This study suggests a potential association between metabolic syndrome and changes in cerebral cortex structure, which may underlie certain neurological disorders. Furthermore, we found an association between metabolic syndrome and the risk of Alzheimer's disease, major depression, and anxiety disorder. Early diagnosis of metabolic syndrome holds significance in preventing these neurological disorders.
| S-EPMC11349429 | biostudies-literature
Project description:Mendelian randomization (MR) of lipid traits in CAD has provided evidence for causal associations of LDL-C and TGs in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted and MR-Egger methods in large (n ≥ 300,000) GWAS datasets. We found that 30% of lipid trait genetic variants have effects on metabolic syndrome traits, including BMI, T2D, and systolic blood pressure (SBP). Nonetheless, in multivariable MR analysis, LDL-C, HDL-C, TGs, BMI, T2D, and SBP are independently associated with CAD, and each of these associations is robust to adjustment for directional pleiotropy. MR at loci linked to direct effects on HDL-C and TGs suggests locus- and mechanism-specific causal effects of these factors on CAD.
| S-EPMC7933489 | biostudies-literature
Project description: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 (>10 ?mol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 ?mol/L, Z?=?-5.29, P?<?0.01) and in healthy controls (median: 18.32 vs. 10.00 ?mol/L, Z?=?-8.76, P?<?0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 ?mol/L, Z?=?-1.32, P?=?0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, ??=?14.29, P?<?0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 ?mol/L, ??=?34.06, P?<?0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min·1.73 m, ??=?21.75, P?<?0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, ??=?2.97, P?=?0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, ??=?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%/28.00% vs. 14.81%/37.04%/48.15%, ??=?17.66, P?<?0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P?<?0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (??=?0.76, P?=?0.02), systolic blood pressure (??=?0.26, P?=?0.02), diastolic blood pressure (??=?0.20, P?=?0.01), and pathologic T lesion (??=?0.01, P?=?0.01) in IgAN. CONCLUSIONS:By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.
| S-EPMC7004620 | biostudies-literature
Project description:ObjectiveTrials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization.MethodsWe used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B6 (n = 1), and vitamin B12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases).ResultsGenetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 × 10-4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 × 10-4 ) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B12 levels were not associated with any stroke subtype.InterpretationThese findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501.
| S-EPMC6594149 | biostudies-literature
Project description:Background: Homocysteine (Hcy) is a toxic amino acid and hyperhomocysteinemia (HHcy) was reported to be associated with both cerebrovascular disease and neurodegenerative disease. Our aim was to assess the causal link between plasma Hcy level and cerebrovascular and neurodegenerative diseases through a Mendelian randomization (MR) study. Methods: A two-sample MR study was performed to infer the causal link. We extracted the genetic variants (SNPs) associated with plasma Hcy level from a large genome-wide association study (GWAS) meta-analysis. The main MR analysis was performed using the inverse variance-weighted method. Additional analyses were further performed using MR-Egger intercept and Cochran's Q statistic to detect the heterogeneity or pleiotropy of our findings. Results: Thirteen Hcy-associated SNPs were selected as instrumental variables. The results showed evidence of a causal link between plasma Hcy level and ischemic stroke (IS) caused by small artery occlusion (SAS, OR = 1.329, 95% CI 1.047-1.612, p = 0.048). Meanwhile, there was no evidence of association between plasma Hcy level and other types of IS, transient ischemic attack (TIA), or neurodegenerative disease. The MR-Egger intercept test indicated no evidence of directional pleiotropy. Results of additional MR analysis indicated that blood pressure (BP) and type 2 diabetes mellitus (T2DM) serve as influencers in the association. Conclusion: The MR study found a little causal link between plasma Hcy level and SAS. The link is likely to be influenced by other risk factors like BP and T2DM.
| S-EPMC8047106 | biostudies-literature
Project description:Background: Since the association of homocysteine and clinical results of observational studies are controversial on non-alcoholic fatty liver related disease, we compute the two-sample Mendelian Randomization (MR) study. Objective: To evaluate whether the plasma level of homocysteine has an effect on the risk of Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and Cirrhosis after its progress, we investigated the causal relationships between plasma homocysteine and the three non-alcoholic fatty liver related diseases mentioned above. Design and methods: Summary estimates were elicited from the inverse-variance weighted (IVW) method through 12 single nucleotide polymorphisms (SNPs) which related to the plasma homocysteine, the SNPs were obtained from a large genome-wide association studies (GWAS) of 44,147 European participants. And the summary statistics for the latest and largest GWAS datasets for NAFLD (307576 in total and 1,578 cases), NASH (309055 in total and 99 cases) and Cirrhosis (306145 in total and 826 cases) were collected from Ristey FinnGen website where the association of genetic variations with blood metabolite levels was conducted using comprehensive metabolite profiling. The study was performed through two-sample MR method. Results: The result indicated that the plasma homocysteine is not significantly associated with NAFLD, and its progression, NASH and Cirrhosis. Conclusion: The evidence in this study is quite deficient to support the causal association of the individual plasma homocysteine with NAFLD, NASH and Cirrhosis, the putative of associations is not exist.
| S-EPMC9763576 | biostudies-literature
Project description:BackgroundThe onset and progression of chronic kidney disease (CKD) has been linked to metabolic syndrome (MetS), with the results of recent observational studies supporting a potential link between renal failure and MetS. The causal nature of this relationship, however, remains uncertain. This study thus leveraged a Mendelian Randomization (MR) approach to probe the causal link of MetS with renal failure.MethodsA genetic database was initially used to identify SNPs associated with MetS and components thereof, after which causality was evaluated through the inverse variance weighted (IVW), MR-Egger regression, and weighted media techniques. Results were subsequently validated through sensitivity analyses.ResultsIVW (OR = 1.48, 95% CI = 1.21-1.82, P =1.60E-04) and weighted median (OR = 1.58, 95% CI =1.15-2.17, P = 4.64E-03) analyses revealed that MetS was linked to an elevated risk of renal failure. When evaluating the specific components of MetS, waist circumference was found to be causally related to renal failure using the IVW (OR= 1.58, 95% CI = 1.39-1.81, P = 1.74e-11), MR-Egger (OR= 1.54, 95% CI = 1.03-2.29, P = 0.036), and weighted median (OR= 1.82, 95% CI = 1.48-2.24, P = 1.17e-8). The IVW method also revealed a causal association of hypertension with renal failure (OR= 1.95, 95% CI = 1.34-2.86, P = 5.42e-04), while renal failure was not causally related to fasting blood glucose, triglyceride levels, or HDL-C levels.ConclusionThese data offer further support for the existence of a causal association of MetS with kidney failure. It is thus vital that MetS be effectively managed in patients with CKD in clinical settings, particularly for patients with hypertension or a high waist circumference who are obese. Adequate interventions in these patient populations have the potential to prevent or delay the development of renal failure.
| S-EPMC11190295 | biostudies-literature