Mendelian Randomization Analysis of Systemic Iron Status and Risk of Different Types of Kidney Disease
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SUBMITTER: Zhou J
PROVIDER: S-EPMC11243746 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
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Project description:Objective: To assess the causal effect of systemic iron status by using four biomarkers (serum iron; transferrin saturation; ferritin; total iron-binding capacity) on knee osteoarthritis (OA), hip OA, total knee replacement, and total hip replacement using 2-sample Mendelian randomization (MR) design. Methods: Three instrument sets were used to construct the genetic instruments for the iron status: Liberal instruments (variants associated with one of the iron biomarkers), sensitivity instruments (liberal instruments exclude variants associated with potential confounders), and conservative instruments (variants associated with all four iron biomarkers). Summary-level data for four OA phenotypes, including knee OA, hip OA, total knee replacement, and total hip replacement were obtained from the largest genome-wide meta-analysis with 826,690 individuals. Inverse-variance weighted based on the random-effect model as the main approach was conducted. Weighted median, MR-Egger, and Mendelian randomization pleiotropy residual sum and outlier methods were used as sensitivity MR approaches. Results: Based on liberal instruments, genetically predicted serum iron and transferrin saturation were significantly associated with hip OA and total hip replacement, but not with knee OA and total knee replacement. Statistical evidence of heterogeneity across the MR estimates indicated that mutation rs1800562 was the SNP significantly associated with hip OA in serum iron (odds ratio, OR = 1.48), transferrin saturation (OR = 1.57), ferritin (OR = 2.24), and total-iron binding capacity (OR = 0.79), and hip replacement in serum iron (OR = 1.45), transferrin saturation (OR = 1.25), ferritin (OR = 1.37), and total-iron binding capacity (OR = 0.80). Conclusion: Our study suggests that high iron status might be a causal factor of hip OA and total hip replacement where rs1800562 is the main contributor.
| S-EPMC10060517 | biostudies-literature
Project description:BACKGROUND: Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. METHODS: Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. RESULTS: Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. CONCLUSION: Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.
| S-EPMC3584055 | biostudies-other
Project description:BackgroundThe relevance of iron status biomarkers for coronary artery disease (CAD), heart failure (HF), ischemic stroke (IS), and type 2 diabetes (T2D) is uncertain. We compared the observational and Mendelian randomization (MR) analyses of iron status biomarkers and hemoglobin with these diseases.Methods and resultsObservational analyses of hemoglobin were compared with genetically predicted hemoglobin with cardiovascular diseases and diabetes in the UK Biobank. Iron biomarkers included transferrin saturation, serum iron, ferritin, and total iron binding capacity. MR analyses assessed associations with CAD (CARDIOGRAMplusC4D [Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus The Coronary Artery Disease Genetics], n=181 522 cases), HF (HERMES [Heart Failure Molecular Epidemiology for Therapeutic Targets), n=115 150 cases), IS (GIGASTROKE, n=62 100 cases), and T2D (DIAMANTE [Diabetes Meta-Analysis of Trans-Ethnic Association Studies], n=80 154 cases) genome-wide consortia. Observational analyses demonstrated J-shaped associations of hemoglobin with CAD, HF, IS, and T2D. In contrast, MR analyses demonstrated linear positive associations of higher genetically predicted hemoglobin levels with 8% higher risk per 1 SD higher hemoglobin for CAD, 10% to 13% for diabetes, but not with IS or HF in UK Biobank. Bidirectional MR analyses confirmed the causal relevance of iron biomarkers for hemoglobin. Further MR analyses in global consortia demonstrated modest protective effects of iron biomarkers for CAD (7%-14% lower risk for 1 SD higher levels of iron biomarkers), adverse effects for T2D, but no associations with IS or HF.ConclusionsHigher levels of iron biomarkers were protective for CAD, had adverse effects on T2D, but had no effects on IS or HF. Randomized trials are now required to assess effects of iron supplements on risk of CAD in high-risk older people.
| S-EPMC11010009 | biostudies-literature
Project description:BackgroundObservational studies have previously suggested a link between iron status makers and back pain. We conducted a two-sample Mendelian randomization (MR) study to determine the putative causal relationship between systemic iron status and back pain.Materials and methodsIn this MR study, a genome-wide association study (GWAS) involving 48,972 individuals was used to identify genetic instruments highly associated with systemic iron status. The outcome data (back pain) were derived from the Neale Lab consortium's summary data from the UK Biobank (85,221 cases and 336,650 controls). With the inverse variance weighted (IVW) method as the main analysis, conservative analyses (selecting SNPs with concordant change of iron status biomarkers) and liberal analyses (selecting SNPs with genome-wide significant association with each iron status biomarker) were carried out. For sensitivity analyses, the MR-Egger, MR-Egger intercept, weighted median, weighted mode, and MR based on a Bayesian model averaging approaches were used. The Cochran's Q-test was used to detect heterogeneity.ResultsBack pain was associated with genetically instrumented serum iron (OR = 1.01; 95% CI = 1.00-1.02, p = 0.01), ferritin (OR = 1.02; 95% CI = 1.00-1.04, p = 0.02), and transferrin saturation (OR = 1.01; 95% CI = 1.00-1.01, p = 0.01). Furthermore, there was no evidence of a link between transferrin and the risk of back pain (OR = 0.99, 95% CI = 0.98-1.00, p = 0.08). The sensitivity analyses and Cochran's Q-test indicated that no pleiotropy or heterogeneity was detected (all p > 0.05).ConclusionWe provided potential genetic evidences for the causal associations of iron status with increased incidence of back pain. However, the evidences were weakened due to the low power. Further larger MR studies or RCTs are needed to investigate small effects.
| S-EPMC9399786 | biostudies-literature
Project description:BackgroundMental disorders account for an enormous global burden of disease, and has been associated with disturbed iron metabolism in observational studies. However, such associations are inconsistent and may be attributable to confounding from environmental factors. This study uses a two-sample Mendelian randomization (MR) analysis to investigate whether there is any causal effect of systemic iron status on risk of 24 specific mental disorders.MethodsGenetic variants with concordant relations to 4 biomarkers of iron status (serum iron, ferritin, transferrin saturation, and transferrin) were obtained from a genome-wide association study performed by the Genetics of Iron Status (GIS) consortium. Summary-level data for mental disorders were obtained from the UK Biobank. An inverse-variance weighted (IVW) approach was used for the main analysis, and the simple median, weighted median and MR-Egger methods were used in sensitivity analyses.ResultsGenetically predicted serum iron, ferritin, and transferrin saturation were positively associated with depression and psychogenic disorder, and inversely associated with gender identity disorders. A higher transferrin, indicative of lower iron status, was also associated with increased risk of gender identity disorders and decreased risk of psychogenic disorder. Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy.ConclusionOur findings offer a novel insight into mental health, highlighting a detrimental effect of higher iron status on depression and psychogenic disorder as well as a potential protective role on risk of gender identity disorders. Further studies regarding the underlying mechanisms are warranted for updating preventative strategies.
| S-EPMC9797506 | biostudies-literature
Project description:We conducted a two-sample Mendelian randomization study to explore the associations of iron status with overall cancer and 22 site-specific cancers. Single-nucleotide polymorphisms for iron status were obtained from a genome-wide association study of 48,972 European-descent individuals. Summary-level data for breast and other cancers were obtained from the Breast Cancer Association Consortium and UK Biobank. Genetically predicted iron status was positively associated with liver cancer and inversely associated with brain cancer but not associated with overall cancer or the other 20 studied cancer sites at p < 0.05. The odds ratios of liver cancer were 2.45 (95% CI, 0.81, 7.45; p = 0.11), 2.11 (1.16, 3.83; p = 0.02), 10.89 (2.44, 48.59; p = 0.002) and 0.30 (0.17, 0.53; p = 2 × 10-5) for one standard deviation increment of serum iron, transferrin saturation, ferritin and transferrin levels, respectively. For brain cancer, the corresponding odds ratios were 0.69 (0.48, 1.00; p = 0.05), 0.75 (0.59, 0.97; p = 0.03), 0.41 (0.20, 0.88; p = 0.02) and 1.49 (1.04, 2.14; p = 0.03). Genetically high iron status was positively associated with liver cancer and inversely associated with brain cancer.
| S-EPMC7071358 | biostudies-literature
Project description:BackgroundSerum iron status has been reported as associated with primary liver cancer (PLC) risk. However, whether iron status plays a role in the development of PLC remains inconclusive.MethodsGenetic summary statistics of the four biomarkers (serum iron, ferritin, transferrin saturation, and transferrin) of iron status and PLC were retrieved from two independent genome-wide association studies (GWAS) that had been performed in European populations. Two-sample univariate and multivariate Mendelian randomization (MR) analyses were conducted to determine the causal link between iron status and PLC risk.ResultsNo significant horizontal pleiotropy was detected for the four biomarkers according to the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test. No evidence of between-single nucleotide polymorphism (SNP) heterogeneity and directional pleiotropy was detected by the Cochran's Q test and MR-Egger regression for serum iron, ferritin, and transferrin. For transferrin saturation, although no heterogeneity was detected, the directional pleiotropy was significant (P value for intercept of MR-Egger regression =0.033). Univariate MR estimates based on inverse variance weighting (IVW) method suggested that there was no causal link between serum iron [odds ratio (OR) =0.71, 95% confidence interval (CI): 0.45 to 1.11], ferritin (OR =0.56, 95% CI: 0.16 to 2.04), and transferrin (OR =0.91, 95% CI: 0.72 to 1.15) and PLC risk. We found a significant causal relationship between transferrin saturation and PLC risk (OR =0.45, 95% CI: 0.22 to 0.90), although this link was non-significant in multivariate MR analysis.ConclusionsThere might be no causal relationship between iron status and PLC risk. However, data from larger sample size and people with different ethnic background were needed to further validate our findings.
| S-EPMC8576647 | biostudies-literature
Project description:BackgroundAlzheimer's disease (AD) has become a common illness affecting the elderly, adding to society's social and financial burden. We used two-sample Mendelian randomization (MR) in this study to determine the association between working status and AD.MethodsWe performed a two-sample MR analysis. The genetic associations were derived from the UK Biobank (n = 263,615) and the International Genomics of Alzheimer's Project (n = 63,926). Inverse variance weighted (IVW), MR-Egger, and weighted median were used in the MR analysis. The funnel plot, Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis were used in sensitivity analyses. Further risk factor analyses were carried out to look into the potential mediators.ResultsJobs involve heavy manual or physical work (OR = 2.13, 95%CI 1.36-3.36; p = .0011), job involves mainly walking or standing (OR = 1.74, 95%CI 1.19-2.54; p = .004), and job involves shift work (OR = 2.78, 95%CI 1.14-6.80; p = .02) increased the risk of AD in the IVW analysis. There was no heterogeneity and no horizontal pleiotropy in the sensitivity analysis. Risk factor analysis suggested that each of the above association may be mediated by different risk factors.ConclusionOur study adds to the evidence that the development of AD is associated with the working status (job involves heavy manual or physical work, job involves mainly walking or standing, and job involves shift work) by using extensive human genetic data.
| S-EPMC9847601 | biostudies-literature
Project description:Background Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this study was to investigate the effect of genetically determined iron status on carotid intima-media thickness, carotid plaque, and venous thromboembolism using Mendelian randomization. Methods and Results Genetic instrumental variables for iron status were selected from a genome-wide meta-analysis of 48 972 subjects. Genetic association estimates for carotid intima-media thickness and carotid plaque were obtained using data from 71 128 and 48 434 participants, respectively, and estimates for venous thromboembolism were obtained using data from a study incorporating 7507 cases and 52 632 controls. Conventional 2-sample summary data Mendelian randomization was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of venous thromboembolism. Odds ratios per SD increase in biomarker levels were 1.37 (95% CI 1.14-1.66) for serum iron, 1.25 (1.09-1.43) for transferrin saturation, 1.92 (1.28-2.88) for ferritin, and 0.76 (0.63-0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding odds ratios were 0.85 (0.73-0.99) for serum iron and 0.89 (0.80-1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no Mendelian randomization evidence of an effect of iron status on carotid intima-media thickness. Conclusions These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease but increases the risk of thrombosis related to stasis of blood.
| S-EPMC6761644 | biostudies-literature
Project description:Although the associations between serum lipid levels and aneurysms have been investigated in epidemiological studies, causality remains unknown. Thus, this study aimed to investigate the causal relationships of serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels on five types of aneurysms, using genetic variants associated with four lipid traits as instrumental variables in a Mendelian randomization (MR) analysis. We performed two-sample Mendelian randomization (MR) analyses to evaluate the associations of HDL-C, LDL-C, TC, and TG levels with risks for five types of aneurysms and those of LDL-C- (HMGCR, NPC1L1, PCSK9, CETP, and LDLR) and TG-lowering targets (ANGPTL3 and LPL) with aneurysms. The sample sizes of the included studies ranged from nearly 80,000 to 410,000. We found inverse associations between genetically predicted HDL-C levels and aortic (OR = 0.74, 95% CI = 0.65-0.85) and abdominal aortic aneurysms (0.58, 0.45-0.75). A 1-SD increase in LDL-C and TC levels was associated with increased risks for aortic (1.41, 1.26-1.58 and 1.36, 1.18-1.56, respectively) and abdominal aortic aneurysms (1.82, 1.48-2.22 and 1.55, 1.25-1.93, respectively). TG levels were significantly associated with aortic (1.36, 1.18-1.56) and lower extremity artery aneurysms (2.76, 1.48-5.14), but limited to cerebral aneurysm (1.23, 1.06-1.42). Secondary analyses revealed a relationship between genetically proxied LDL-C-lowering targets and all types of aneurysms; however, the drug targets remained heterogeneous. We found a weak association between TG-lowering therapies and aortic (ANGPTL3, 0.51, 0.29-0.89) and abdominal aortic aneurysms (LPL, 0.64, 0.44-0.94). According to genetic evidence, lipid dysfunction is a causal risk factor for aneurysms. Lipid-lowering drugs may be a potential effective strategy in preventing and managing aneurysms.
| S-EPMC8621501 | biostudies-literature