Osteoarthritis and hypertension: observational and Mendelian randomization analyses
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ABSTRACT:
SUBMITTER: Yang Z
PROVIDER: S-EPMC11022320 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundHigh 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.MethodsFor 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.ResultsMajority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 μmol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 μmol/L, Z = -5.29, P < 0.01) and in healthy controls (median: 18.32 vs. 10.00 μmol/L, Z = -8.76, P < 0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 μmol/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%, χ = 14.29, P < 0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 μmol/L, χ = 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, χ = 21.75, P < 0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, χ = 2.97, P = 0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, χ = 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%, χ = 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 (β = 0.76, P = 0.02), systolic blood pressure (β = 0.26, P = 0.02), diastolic blood pressure (β = 0.20, P = 0.01), and pathologic T lesion (β = 0.01, P = 0.01) in IgAN.ConclusionsBy 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.
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Project description:BackgroundPrevious studies have demonstrated that asthma is closely associated with bronchiectasis, however, the causal relationship between asthma and bronchiectasis has not been investigated in depth. Therefore, this study aims to explore the causal relationship and to identify potential factors that mediate between these two diseases.MethodAll the necessary summarized information were obtained from publicly available genome-wide association study (GWAS). Two-sample Mendelian randomization (two-sample MR) was employed to explore the causal relationship between asthma and bronchiectasis, with an additional dataset used for validation. Heterogeneity and pleiotropy analyses were utilized to verify the robustness of the results. Subsequently, mediation MR analyses were performed to identify potential mediating factors. Lastly, a retrospective observational study was conducted to validate the findings.ResultPreliminary inverse-variance weighted (IVW) results indicated there was a causal effect of asthma on bronchiectasis (odds ratio [OR] = 1.228, 95% confidence interval [CI]: 1.077-1.400, P = 0.002). Repetition validation yielded a consistent result. Mediation MR analysis demonstrated that the presence of nasal polyps (OR = 1.063, 95% CI: 1.015-1.113, mediation ratio = 30.492%, P = 0.009), acute sinusitis (OR = 1.062, 95% CI: 1.009-1.118, mediation ratio = 30.157%, P = 0.018), chronic sinusitis (OR = 1.085, 95% CI: 1.024-1.150, mediation ratio = 40.677%, P = 0.005), and peripheral eosinophil counts (OR = 1.013, 95% CI: 1.000-1.026, mediation ratio = 6.514%, P = 0.042) served as significant mediators in the occurrence and development of bronchiectasis induced by asthma. Furthermore, a retrospective observational study observed that bronchiectasis patients with asthma had a higher prevalence of sinusitis (5.043% vs 2.971%, P < 0.001), nasal polyps (0.536% vs 0.152%, P < 0.001), and rhinitis (13.197% vs 1.860%, P < 0.001). The ratio (1.950 (0.500, 5.600) vs 1.500 (0.500, 2.600), P = 0.006) and counts (0.125 (0.040, 0.363) vs 0.090 (0.030, 0.160), P < 0.001) of peripheral blood eosinophils were also elevated in bronchiectasis patients with asthma.ConclusionThe MR analysis uncovered a notable genetic association between asthma and bronchiectasis, which was partially mediated by sinusitis, nasal polyps, and eosinophils. A subsequent retrospective study provided further evidence by demonstrating that bronchiectasis patients with asthma had a higher prevalence of sinusitis, nasal polyps, an elevated proportion of eosinophils, and higher eosinophil counts.
| S-EPMC11580211 | biostudies-literature
Project description:AimsDenture use may potentially increase the risk of cardiometabolic diseases (CMDs), but the casual relevance and strength of the associations are currently unknown.Methods and resultsA total of 495 938 participants from the UK Biobank were included in the observational analyses. Linkage disequilibrium score (LDSC) regression and Mendelian randomization analyses were employed to estimate genetic correlation and the associations between the genetic liability for denture use with coronary artery disease, myocardial infarction, heart failure (HF), any stroke (AS), ischaemic stroke, haemorrhagic stroke, type 2 diabetes (T2D), and related clinical risk factors. In observational analysis, denture use was associated with 14-25% higher risks of various CMDs. The LDSC analysis found that denture use showed a positive genetic correlation with CMDs (rg 0.21-0.38). Genetic liability for denture use was associated with an elevated risk of HF [odds ratio: 1.49 (1.20-1.83)] and T2D [1.11 (1.01-1.24)]. By integrating genetic summary data of denture use with the sum of decayed, missing, and filled tooth surfaces (DMFS), a clinical measure of dental caries obtained from an independent source, genetically determined denture use/DMFS was also associated with an elevated risk of AS [1.21 (1.04-1.40)]. Furthermore, genetically predicted denture use/DMFS was significantly associated with established cardiometabolic risk factors, including HDL cholesterol, triglycerides, waist circumference, waist-to-hip ratio, and height.ConclusionOur study supported potential causal associations between the genetic liability for denture use and risks for HF, AS, T2D, and related clinical risk factors. These findings may inform prevention and intervention strategies targeting dental diseases and CMDs.
| S-EPMC10767255 | biostudies-literature
Project description:AimsWe conducted observational and Mendelian randomization (MR) analyses to explore the associations between blood proteins and risk of peripheral artery disease (PAD).Methods and resultsThe observational cohort analyses included data on 257 proteins estimated in fasting blood samples from 12 136 Swedish adults aged 55-94 years who were followed up for incident PAD via the Swedish Patient Register. Mendelian randomization analyses were undertaken using cis-genetic variants strongly associated with the proteins as instrumental variables and genetic association summary statistic data for PAD from the FinnGen study (11 924 cases and 288 638 controls) and the Million Veteran Program (31 307 cases and 211 753 controls). The observational analysis, including 86 individuals diagnosed with incident PAD during a median follow-up of 6.6-year, identified 13 proteins [trefoil factor two, matrix metalloproteinase-12 (MMP-12), growth differentiation factor 15, V-set and immunoglobulin domain-containing protein two, N-terminal prohormone brain natriuretic peptide, renin, natriuretic peptides B, phosphoprotein associated with glycosphingolipid-enriched microdomains one, C-C motif chemokine 15, P-selectin, urokinase plasminogen activator surface receptor, angiopoietin-2, and C-type lectin domain family five member A] associated with the risk of PAD after multiple testing correction. Mendelian randomization analysis found associations of T-cell surface glycoprotein CD4, MMP-12, secretoglobin family 3A member 2, and ADM with PAD risk. The observational and MR associations for T-cell surface glycoprotein CD4 and MMP-12 were in opposite directions.ConclusionThis study identified many circulating proteins in relation to the development of incident PAD. Future studies are needed to verify our findings and assess the predictive and therapeutic values of these proteins in PAD.
| S-EPMC10267302 | biostudies-literature
Project description:BackgroundRecent insights suggest that remnant cholesterol (RC) plays a role in cellular senescence, yet its specific contribution to frailty remains indeterminate. Through the integration of observational and mendelian randomization (MR) studies, this research explores the impact of elevated serum RC levels on frailty susceptibility.MethodsA dual-method approach, combining an observational study with an MR study, was employed to investigate the connection between RC and frailty. The observational study included 11,838 participants from the National Health and Nutrition Examination Survey. Multivariable logistic regression and propensity score matching were employed to control for potential confounders. The non-linear relationship was assessed using restricted cubic splines. To circumvent observational study limitations, a two-sample MR analysis was conducted using the inverse-variance weighted method, leveraging genome-wide association studies (GWAS) data.ResultsAfter adjusting for potential confounding variables, the observational study identified a significant association between high serum RC levels and frailty in middle-aged and older adults (odds ratio [OR] = 1.67, 95% confidence interval [CI] = 1.20 to 2.33, P = 0.003), exhibiting a non-linear dose-response correlation (non-linear P = 0.011). This association persisted after propensity score matching (OR = 1.53, 95% CI = 1.14 to 2.06, P = 0.005). The MR study echoed these results, demonstrating a causal association of RC with the frailty index (β = 0.059, 95% CI = 0.033 to 0.085, P = 1.05E-05), consistent with the observational findings (β = 0.017, 95% CI = 0.008 to 0.026, P = 4.51E-04).ConclusionThis study provides evidence that higher RC levels amplify frailty risk in middle-aged and older adults, implying that the reduction of RC levels may present a promising strategy for frailty prevention and management.
| S-EPMC10399004 | biostudies-literature
Project description:BackgroundEnd-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.MethodsObservational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.ResultsThere were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.ConclusionsIn people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
| S-EPMC9662821 | biostudies-literature
Project description:Identifying metabolic biomarkers of frailty, an age-related state of physiological decline, is important for understanding its metabolic underpinnings and developing preventive strategies. Here, we systematically examined 168 nuclear magnetic resonance-based metabolomic biomarkers and 32 clinical biomarkers for their associations with frailty. In up to 90,573 UK Biobank participants, we identified 59 biomarkers robustly and independently associated with the frailty index (FI). Of these, 34 associations were replicated in the Swedish TwinGene study (n = 11,025) and the Finnish Health 2000 Survey (n = 6073). Using two-sample Mendelian randomization, we showed that the genetically predicted level of glycoprotein acetyls, an inflammatory marker, was statistically significantly associated with an increased FI (β per SD increase = 0.37%, 95% confidence interval: 0.12-0.61). Creatinine and several lipoprotein lipids were also associated with increased FI, yet their effects were mostly driven by kidney and cardiometabolic diseases, respectively. Our findings provide new insights into the causal effects of metabolites on frailty and highlight the role of chronic inflammation underlying frailty development.
| S-EPMC10410014 | biostudies-literature
Project description:BackgroundHypertension and non-alcoholic fatty liver disease (NAFLD) share several pathophysiologic risk factors, and the exact relationship between the two remains unclear. Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and Mendelian randomization (MR) analyses.MethodsWeighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018. Subsequently, a two-sample MR study was performed using the genome-wide association study (GWAS) summary statistics to identify the causal association between hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and NAFLD. The primary inverse variance weighted (IVW) and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD. Sensitivity analyses were adopted to confirm the robustness of the results.ResultsA total of 3144 participants were enrolled for our observational study in NHANES. Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk (odds ratio [OR] = 1.677; 95% confidence interval [CI], 1.159-2.423). SBP ≥130 mmHg and DBP ≥80 mmHg were also significantly positively correlated with NAFLD. Moreover, hypertension was independently connected with liver steatosis ( β = 7.836 [95% CI, 2.334-13.338]). The results of MR analysis also supported a causal association between hypertension (OR = 7.203 [95% CI, 2.297-22.587]) and NAFLD. Similar results were observed for the causal exploration between SBP (OR = 1.024 [95% CI, 1.003-1.046]), DBP (OR = 1.047 [95% CI, 1.005-1.090]), and NAFLD. The sensitive analysis further confirmed the robustness and reliability of these findings (all P >0.05).ConclusionHypertension was associated with an increased risk of NAFLD.
| S-EPMC10876227 | biostudies-literature
Project description:BackgroundIt is hypothesized that uric acid acts as an antioxidant and may prevent cancer. However, observational studies regarding the relationship between serum urate levels, gout, and breast cancer have provided discrepant evidence. Therefore, the objective of our study was to investigate the potential causal relationship between them.MethodsThis study included 12,451 participants from the National Health and Nutrition Examination Survey (NHANES) 2009-2018. Associations between urate levels, gout, and breast cancer were examined using multivariate logistic regression analysis. In addition, to assess the causal link among them, Mendelian randomization (MR) analysis was conducted, primarily using the inverse variance weighted (IVW) approach, supplemented by MR Egger and weighted median approaches, and a set of sensitivity analyses to test the robustness of the results, and finally, multivariate MR was used to adjust for confounders.ResultsIn cross-sectional studies, urate levels [odds ratio (OR) 0.99, 95% confidence interval (CI): 0.89-1.09, P=0.80] and gout (OR 0.96, 95% CI: 0.53-1.76, P=0.90) were negatively associated with breast cancer risk after controlling for multiple confounders, although the P value was not significant. Two-sample MR analysis showed that serum urate levels were negatively associated with the estrogen receptor-negative (ER-) breast cancer (IVW, OR 0.916, 95% CI: 0.848-0.989, P=0.03) risk, but not significantly associated with overall and the estrogen receptor-positive (ER+) breast cancer (IVW, both P>0.05). In addition, gout was negatively associated with overall (IVW, OR 0.07, 95% CI: 0.008-0.594, P=0.02), ER+ (IVW, OR 0.062, 95% CI: 0.005-0.742, P=0.03), and ER- breast cancer (IVW, OR 0.041, 95% CI: 0.004-0.472, P=0.01) risk. These associations persisted after multivariate MR adjustment for smoking status, alcohol intake frequency, and body mass index (BMI).ConclusionsOur study elucidated the relationship between uric acid, gout and breast cancer, and further studies are still needed in the future to clarify the mechanisms involved.
| S-EPMC11833399 | biostudies-literature
Project description:IntroductionAs ageing accelerates, frailty increasingly impacts public health. Cough, sputum, wheezing and dyspnea are common respiratory symptoms, and the relationship to frailty is unclear. We aimed to analyze the relationship between respiratory symptoms and frailty.MethodsCross-sectional and Mendelian randomization (MR) studies were used. Cross-sectional data involved 14,021 participants from the National Health and Nutrition Examination Survey (NHANES). Logistic and linear regression were used to analyze the relationship between respiratory symptoms (cough, sputum, wheezing, dyspnea) and frailty. We adjusted for multiple variables and used propensity score matching (PSM). Mediation analysis was used to explore the role of inflammatory markers and age in the relationship between the two. We analyzed the relationship using a two-sample MR approach with data from genome-wide association studies (GWAS) to enhance causal inference.ResultsObservational studies have shown that cough (OR 1.74, 95 CI% 1.44, 2.09), sputum (OR 1.87, 95 CI% 1.57, 2.22), wheezing (OR 2.01, 95 CI% 1.68, 2.40), and dyspnea (OR 2.60, 95 CI% 2.28, 2.97) are associated with an elevated risk of frailty. The PSM results were stable. Mediation analyses indicated that elevated inflammatory markers and advancing age were mediators between respiratory symptoms and frailty. The results of the MR study showed that sputum and wheezing were associated with an elevated frailty index; and in the study of FI on respiratory symptoms, all respiratory symptoms were elevated with elevated FI.ConclusionsOur study identified a potential association between frailty and respiratory symptoms. Inflammation and ageing may be essential factors mediating this association.
| S-EPMC11685262 | biostudies-literature