Causal link between thyroid function and schizophrenia: a two-sample Mendelian randomization study

Schizophrenia is a chronic psychiatric disorder with inconsistent behavioral and cognitive abnormalities with profound effects on the individual and the society. Individuals with schizophrenia have altered thyroid function, but results from observational studies are conflicting. To date, it remains unclear whether and in which direction there is a causal relationship between thyroid function and schizophrenia. To investigate causal paths, a bidirectional two-sample Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies including up to 330,132 Europeans. Thyroid function was described by the normal-range thyroid-stimulating hormone (TSH) and free thyroxine levels as well as an increased and decreased TSH status. The iterative radial inverse-variance weighted approach with modified second order weights was used as the main method. Based on a discovery and replication sample for schizophrenia, pooled effect estimates were derived using a fixed-effect meta-analysis. Robustness of results was assessed using both a range of pleiotropy robust methods and a network analysis that clustered genetic instruments potentially responsible for horizontal pleiotropy. Genetic liability for hypothyroidism was inversely associated with schizophrenia (β=−0.06; 95% CI: (-0.10; -0.02); P=0.004). No notable associations were observed between other thyroid parameters and schizophrenia. Furthermore, no associations could be detected in the reverse direction. Our results suggest that an elevated level of TSH reduce the risk for schizophrenia. The role of thyroid function and the hypothalamic-pituitary-thyroid axis in the development of schizophrenia should be subject of further research

Association between inflammatory bowel disease and Parkinson's disease: a Mendelian randomization study

Emerging evidence from observational studies suggests an increased risk of Parkinson’s disease (PD) in patients with inflammatory bowel disease (IBD). However, to date it is not clear whether a causal relationship exists. To investigate whether IBD is causally related to PD, a two-sample Mendelian randomization study was carried out. Independent genetic instruments from the largest available genome-wide association study (GWAS) for IBD (7045 cases, 456,327 controls) including European participants were used to investigate the association with PD (56,306 cases; 1.4 million controls). The results were validated by using a second IBD sample (12,882 cases; 21,770 controls) including the main subtypes ulcerative colitis (UC; 6968 cases; 20,464 controls) and Crohn’s disease (CD; 5956 cases; 14,927 controls). The radial inverse-variance weighted (IVW) approach was used in the primary analysis, and the robustness of the findings were confirmed in a number of sensitivity analyses. Finally, the recently proposed CAUSE approach was performed. There was no evidence of an association between IBD and PD (OR(IVW) = 0.98; 95% CI: [0.93; 1.04]; P = 0.48). This finding could be validated using a second sample of IBD cases (OR(IVW) = 0.98; 95% CI: [0.95; 1.02]; P = 0.36). Furthermore, MR analyses did not support a causal effect of CD (OR(IVW) = 1.00; 95% CI: [0.98; 1.03]; P = 0.96) or UC (OR(IVW) = 1.02; 95% CI: [0.98; 1.06]; P = 0.45) on PD. The present study suggests that neither IBD nor its subtypes CD and UC causally affect Parkinson’s disease in the European population. Further research is necessary to investigate whether intestinal inflammation impacts the development of PD

Asthma and the risk of gastrointestinal disorders: a Mendelian randomization study

BACKGROUND: The question of whether asthma is causally related to gastrointestinal disorders remained unanswered so far. Thus, this study investigated whether there is such a relation and whether the time of onset of asthma plays a role in the occurrence of the following gastrointestinal disorders: peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD) including the distinction between Crohn’s disease (CD) and ulcerative colitis (UC). METHODS: Using summary data of genome-wide association studies (GWASs), we ran Mendelian randomization analyses based on up to 456,327 European participants. Outlier assessment, a series of sensitivity analyses and validation of IBD results in a second GWAS were performed to confirm the results. RESULTS: Presented ORs represent the average change in the outcome per 2.72-fold increase in the prevalence of the exposure. Genetically predicted childhood-onset asthma was positively associated with PUD, GORD, and IBS with similar odds ratios near 1.003 and adjusted P-values from 0.007 (GORD) to 0.047 (PUD). Furthermore, it was inversely related to IBD (OR = 0.992, 95% CI: 0.986, 0.998, adjusted P = 0.023) and suggestively associated with its UC subtype (OR = 0.990, 95% CI: 0.982, 0.998, adjusted P = 0.059). There were no associations between genetically predicted adult-onset asthma and the mentioned gastrointestinal disorders. CONCLUSIONS: This study provides evidence that the presence of asthma onset in childhood increases the risk for GORD, PUD, and IBS but decreases the risk for IBD in adults. The lower risk for IBD may be attributed to a lower risk primarily for UC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02283-7

Causal relationship between dietary macronutrient composition and anthropometric measures: a bidirectional two-sample Mendelian randomization analysis

Background: The question whether the proportion of energy provided by fat and carbohydrates in the diet is associated with body mass index (BMI) and waist circumference (WC) is an important public health issue, but determining causality is difficult in epidemiological studies. Objectives: Using a two-sample bidirectional Mendelian randomization (MR) in both a univariable and multivariable setting, we aimed to determine whether the relative proportion of different macronutrients in the diet (in % of total energy intake (E%)) is causally related to BMI and WC and vice versa. Methods: All analyses were based on genome-wide association studies including 268,922 Europeans with dietary data (SSGAC Consortium) and at least 232,101 with anthropometric measures (GIANT Consortium). An inverse-variance weighted approach using modified second-order weights within the radial regression framework was performed. Radial MR-Egger, weighted median and mode, Robust Adjusted Profile Score (RAPS), and Pleiotropy RESidual Sum and Outlier (PRESSO) methods were used in sensitivity analyses to verify MR assumptions. Additionally, multivariable MR was conducted to account for inter correlation between macronutrient intakes. All estimates represent the standard deviation (SD) change in each outcome per one SD change in the respective exposure. Results: We found that genetically predicted relative carbohydrate intake (E%) reduced BMI (β = −0.529; 95% CI: −0.745, −0.312; P-value = 2⋅10−6) and WC (β = −0.459; 95% CI: −0.656, −0.262; P-value = 5⋅10−6). Both effects were also supported by the multivariable approach: β = −0.441 (95% CI: −0.772, −0.109; P-value = 0.009) for BMI and β = −0.410 (95% CI: −0.667, −0.154; P-value = 0.002) for WC. Genetically predicted dietary intake of fat (E%) was weaker and positively related to both anthropometric measures. We obtained evidence that a higher BMI and WC increased the relative dietary intake of fat and protein (E%). For example, each SD higher BMI increased protein intake (E%) by 0.114 SD (95% CI: 0.081, 0.147; P-value = 9⋅10−12) and each SD higher WC increased protein intake (E%) by 0.078 SD (95% CI: 0.035, 0.121; P-value = 4⋅10−4). Sensitivity analyses confirmed these findings revealing consistent effect estimates. Conclusions: Using genetic information to improve causal inference we found evidence, that a low relative carbohydrate proportion (E%) and a high proportion of fat (E%) in the diet is causally related to a higher BMI and a higher WC. Further research considering carbohydrate, fat, and protein quality and possible consequences on micronutrient intake is needed to define the implications for dietary intake recommendations

Associations between serum cholesterol and immuno-phenotypical characteristics of circulatory B cells and Tregs

Blood lipids play a major role in the manifestation of cardiovascular diseases. Recent research suggested that there are connections between cholesterol levels and immunological alterations. We investigated whether there is an association between serum cholesterol levels (total, HDL, LDL) and immune cells (B cell and regulatory T cells [Tregs]). The analysis was based on data from 231 participants of the MEGA study in Augsburg, Germany, recruited between 2018 and 2021. Most participants was examined two different times within a time period of 9 months. At every visit, fasting venous blood samples were taken. Immune cells were analyzed immediately afterwards using flow cytometry. Using multivariable-adjusted linear regression models, the associations between blood cholesterol concentrations and the relative quantity of several B cell and Treg subsets were analyzed. We found that particularly HDL cholesterol concentrations were significantly associated to some immune cell subpopulations: HDL cholesterol showed significant positive associations with the relative frequency of CD25++ Tregs (as proportion of all CD4+CD25++ T cells) and conventional Tregs (defined as the proportion of CD25+CD127- cells on all CD45RA- CD4+ T cells). Regarding B cells, HDL cholesterol values were inversely associated with the cell surface expression of IgD and with naïve B cells (CD27- IgD+ B cells). In conclusion, HDL cholesterol levels were associated with modifications in the composition of B cell and Tregs subsets demonstrating an important interconnection between lipid metabolism and immune system. Knowing that this association exists might be crucial for a deeper and more comprehensive understanding of the pathophysiology of atherosclerosis

Association between inflammatory markers and serum paraoxonase and arylesterase activities in the general population: a cross-sectional study

Background: Recent studies focused on modulating factors of paraoxonase-1 (PON1) activity. In some studies the association between pro-inflammatory markers and PON1 activity was examined, but so far no population-based investigations on this issue have been conducted. The present study investigated the relationships between the pro-inflammatory markers tumor necrosis factor (TNF)-α, leptin, interleukin (IL)-6, and high-sensitive C-reactive protein (hs-CRP) and paraoxonase and arylesterase, two hydrolytic activities of PON1, in the population-based Bavarian Food Consumption Survey II. Methods: Based on 504 participants (217 men, 287 women), the relationship between the pro-inflammatory markers and the outcomes paraoxonase and arylesterase activities were investigated using multivariable linear models. Results: Circulating plasma levels of leptin (P-value 75th percentile) the activities reached a plateau or even decreased somewhat. After Bonferroni-Holm correction, only leptin remained non-linearly but significantly associated with arylesterase activity (adjusted overall P-value < 0.0001). Neither age nor sex nor obesity modified the associations. No association was found between TNF-α and paraoxonase or arylesterase activity. Conclusions: The present findings suggest that in persons with very high levels of inflammation, PON1 activity may be impaired, a fact that might subsequently be accompanied by a higher risk for cardiometabolic diseases. Whether or not the measurement of PON1 activity in combination with a lipid profile and certain inflammatory markers could improve the prediction of cardiometabolic diseases in middle-aged individuals from the general population should be evaluated in clinical studies. Keywords: Arylesterase activity; Inflammation; Oxidative stress; PON1; Paraoxonase activity. © 2021. The Author(s)

Body mass index and waist circumference as determinants of hemostatic factors in participants of a population-based study

Background: In contrast to studies in patients, an association between obesity and blood coagulation factors has not been established in the population. If confirmed it could become a target for primary prevention. Objective: To investigate the relationship between Body Mass Index (BMI) and waist circumference (WC) with plasma concentrations of antithrombin III, D-dimers, fibrinogen D, protein S, factor VIII, activated partial thromboplastin time (aPTT), quick value, and international normalized ratio (INR) in the general population. Materials and Methods: Participants of the Cooperative Health Research in the Region of Augsburg (KORA) S4 study who took part in the KORA Fit follow-up (2018–2019, aged 54–74 years) examination were eligible. Citrate plasma samples were collected in fasted participants. After the exclusion of participants with anticoagulative treatment, 776 participants (420 women and 356 men) with analytic data on hemostatic factors were included in the present analysis. Linear regression models were used to explore the association between BMI or WC with hemostatic markers, adjusted for sex, age, alcohol consumption, education, smoking status, and physical activity. In a second model, additional adjustments were made for the prevalence of stroke, hypertension, myocardial infarction, serum non-HDL cholesterol, and serum triglycerides. Results: In the multivariable models (with or without health conditions), significant positive associations with BMI were obtained for plasma concentrations of D-dimers, factor VIII, fibrinogen D, protein S, and quick value, while INR and antithrombin III were inversely associated. Similar to BMI, WC was significantly associated with all hemostatic factors, except for aPTT. Conclusion: In this population-based study, both increasing BMI and WC affect the blood coagulation system. Thus, modification of a prothrombotic coagulation profile emerged as a potential target for primary prevention in obese subjects

Inflammation biomarkers in acute ischemic stroke according to different etiologies

Background: High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross-sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood-based proteins. Methods: We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel, ICAM-1 set and VCAM-1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio-Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in σ-standardized cytokine levels on the log2 -scale. Results: Stromal-cell-derived-factor 1 alpha (SDF-1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (β = 0.48; 95% CI 0.22; 0.75; Padj = 0.036). Significantly lower levels of interleukin-6 (IL-6) (β = -0.53; 95% CI -0.84; -0.23; Padj = 0.036) and macrophage migration inhibitory factor (MIF) (β = -0.52; 95% CI -0.84; -0.21; Padj = 0.043) were found in the small vessel versus large vessel stroke subtype. Conclusions: Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes

Prognostic value of stress hyperglycemia ratio on short- and long-term mortality after acute myocardial infarction

Aims: Prior studies demonstrated an association between hospital admission blood glucose and mortality in acute myocardial infarction (AMI). Because stress hyperglycemia ratio (SHR) has been suggested as a more reliable marker of stress hyperglycemia this study investigated to what extent SHR in comparison with admission blood glucose is associated with short- and long-term mortality in diabetic and non-diabetic AMI patients. Methods: The analysis was based on 2,311 AMI patients aged 25–84&nbsp;years from the population-based Myocardial Infarction Registry Augsburg (median follow-up time 6.5&nbsp;years [IQR: 4.9–8.1]). The SHR was calculated as admission glucose (mg/dl)/(28.7 × HbA1c (%)—46.7). Using logistic and COX regression analyses the associations between SHR and admission glucose and mortality were investigated. Result: Higher admission glucose and higher SHR were significantly and nonlinearly associated with higher 28-day mortality in AMI patients with and without diabetes. In patients without diabetes, the AUC for SHR was significantly lower than for admission glucose (SHR: 0.6912 [95%CI 0.6317–0.7496], admission glucose: 0.716 [95%CI 0.6572–0.7736], p-value: 0.0351). In patients with diabetes the AUCs were similar for SHR and admission glucose. Increasing admission glucose and SHR were significantly nonlinearly associated with higher 5-year all-cause mortality in AMI patients with diabetes but not in non-diabetic patients. AUC values indicated a comparable prediction of 5-year mortality for both measures in diabetic and non-diabetic patients. Conclusions: Stress hyperglycemia in AMI patients plays a significant role mainly with regard to short-term prognosis, but barely so for long-term prognosis, underlining the assumption that it is a transient dynamic disorder that occurs to varying degrees during the acute event, thereby affecting prognosis