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A causal relationship between chronic pancreatitis and cardiovascular disease: A two-sample Mendelian randomization analysis.

Current research suggests a link between chronic pancreatitis (CP) and cardiovascular disease (CVD), although the causality remains unclear. The aim of this study was therefore to conduct a 2-sample Mendelian randomization (MR) analysis to determine whether a causal relationship exists between CP and CVD. Summary-level data from publicly available genome-wide association studies of European populations were utilized for the MR analysis. Following quality control measures, independent single-nucleotide polymorphisms associated with CP and CVD were chosen as the genetic instruments. Four complementary MR methods were performed, namely the inverse variance weighted (IVW) method, weighted median, MR-Egger, and leave-one-out sensitivity. The IVW method revealed correlations between alcohol-induced CP and myocardial infarction (odds ratio [OR] = 1.001, 95% confidence interval [CI]: 1.000-1.002, P = .0010), as well as with large artery atherosclerosis stroke (OR = 1.067, 95% CI: 1.030-1.105, P = .0003). The IVW method also suggested that CP was significantly associated with stroke (OR = 1.040, 95% CI: 1.015-1.065, P = .0015) and with ischemic stroke (OR = 1.041, 95% CI: 1.005-1.078, P = .0024). These results remained robust and consistent in the sensitivity analysis. This MR study indicates a significant causal relationship between alcohol-induced CP and elevated risks of myocardial infarction and large artery atherosclerosis stroke, and a causal link between CP and stroke as well as ischemic stroke.

Mendelian Randomization Analysis↗

Causal relationship between occlusive lesions of the coronary artery and myocardial fibrosis in arteriosclerotic rabbits--differences between cholesterol-fed and heritable hyperlipidemic rabbits.

To investigate the causal relationship between lesions of either the proximal large or the distal small coronary arteries and myocardial fibrosis, the hearts and the aortas of 99 cholesterol-fed rabbits with either intermittent or continuous hyperlipidemia for 8 months or more, 44 Watanabe-heritable hyperlipidemic (WHHL) rabbits and 20 normal rabbits were studied histologically. The size and location of the myocardial fibrosis correlated closely with the almost completely occlusive distal small coronary artery which mainly consisted of macrophages, necrosis and calcification but did not correlate with the maximum % stenosis of the large proximal subepicardial coronary arteries in the cholesterol-fed-rabbits. Myocardial fibrosis and almost completely occlusive lesions of the distal small coronary arteries were very rare in the WHHL rabbits, and the maximum % stenosis of the proximal coronary artery and aortic lesions in the WHHL rabbits tended to be greater than those in the cholesterol-fed rabbits. Thus, we are still not certain as to whether or not, the organic stenosis of the subepicardial coronary artery is responsible for myocardial fibrosis in WHHL-rabbits. In conclusion, a causal relationship was observed between myocardial fibrosis and the occlusive lesions of the distal small coronary arteries in cholesterol-fed rabbits, while the arteriosclerotic lesions of the small coronary artery in cholesterol-fed rabbits completely differed from those observed in WHHL-rabbit.

Animals↗

Lipoma on the corpus callosum in a patient with schizophrenia-like episode: is there a causal relationship?

Disturbed interhemispheric communication has been proposed as responsible for schizophrenia. We present a case of a schizophrenia-like episode with no neurologic or other psychiatric symptoms. However, magnetic resonance imaging revealed a lipoma on the splenium of the corpus callosum. Neuropsychologic examination revealed normal interhemispheric transfer, but a slight dysfunction associated with right-hemispheric anterior regions. Rather than supporting the hypothesis of a causal relationship between callosal abnormality and schizophrenia-like symptoms, our findings argue against a direct causal relationship between lesion site and psychotic episode. We conclude that cerebral abnormality per se may represent a risk factor for neuropsychiatric symptoms.

Adult↗

The causal relationship between multiple cardiovascular diseases and glioblastoma: A Mendelian randomization study.

Observational studies suggest an association between glioblastoma (GBM) and cardiovascular diseases (CVDs), but a causal relationship remains unestablished. This study aimed to investigate the causal link between multiple CVDs and GBM risk. The inverse variance weighted method indicated that all 18 CVDs had significant causal associations with GBM (P&#x2005;<&#x2005;.05). Genetically predicted CVDs were uniformly associated with a lower risk of GBM (odds ratio&#x2005;<&#x2005;1), identifying them as potential protective factors. Sensitivity analyses confirmed the absence of significant heterogeneity or horizontal pleiotropy, and the MR-Steiger test validated the correct causal direction. This Mendelian randomization (MR) study provides evidence that a range of CVDs are causally associated with a decreased risk of developing GBM. These findings suggest shared biological pathways and offer new insights for understanding GBM etiology. We conducted a 2-sample MR analysis using publicly available genome-wide association study data. GBM was the outcome, and 18 cardiovascular-related traits (including coronary artery disease, myocardial infarction, and venous thromboembolism) were exposures. Instrumental variables were single-nucleotide polymorphisms significantly associated with exposures (P&#x2005;<&#x2005;5&#x2005;&#xd7;&#x2005;10-8). The primary analysis used the inverse variance weighted method, supplemented with MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including Cochran Q test, MR-Egger intercept test, leave-one-out analysis, and MR-Steiger directionality test, were performed to ensure robustness.

Causality↗

Detection of causal relationships between factors influencing adverse side-effects from anaesthesia and convalescence following surgery: a path analytical approach.

BACKGROUND AND OBJECTIVE: The anaesthesiologist's preoperative interview with the patient is important in preparing the patient for surgery. Its potential protective influence on adverse side-effects from anaesthesia and convalescence is rarely investigated within the context of other perioperative factors. Structural equation modelling allows detection and quantification of all causal relationships and mediator effects in multivariate models. Therefore, this method is presented as a tool and applied to discover the influence of the preoperative interview within socio-demographic variables and duration of surgery on complaints and recovery after anaesthesia. METHODS: The influence of individual satisfaction with the anaesthesiologist's preoperative interview on postoperative events such as nausea/vomiting, difficulties in recovering from anaesthesia, experience of postoperative pain, physical discomfort and satisfaction with convalescence expressed by the patient was analysed by means of structural equation modelling. The variables gender, age and duration of surgery were also included as predictors in the analyses. The model in the total sample of 710 patients was then analysed for structural differences between groups treated either with propofol (n = 204) or with isoflurane + nitrous oxide (n = 267) for maintenance of anaesthesia. RESULTS: The model revealed that the anaesthesiologist's preoperative interview in combination with associated mediating side-effects explains 45% of the variance of 'feeling physical discomfort' and 18% of the variance of 'satisfaction with convalescence'. The same model could be fitted in the propofol and the isoflurane + nitrous oxide group. Moreover, the structure and the strength of causal relations between variables were identical in the two groups. CONCLUSIONS: The anaesthesiologist's efforts to improve the interview with the patient by more reassuring and proper information will result in less side-effects from anaesthesia and better recovery from surgery. It could be demonstrated that structural equation modelling is a powerful tool for detection of causal relationships and mediator effects in perioperative medicine.

Adolescent↗

Women's caregiving and paid work: causal relationships in late midlife.

Care of an ill or disabled family member or friend is disproportionately done by women and typically is done in late midlife. Because this is-also a time in the life course when women's labor force participation peaks, many women faced with caregiving demands have to decide how to balance them with their employment. In this study we use the National Longitudinal Survey (NLS) of Mature Women to examine the causal relationship between employment and caring for an ill or disabled friend or relative over a three-year period. We find that employment does not affect whether or not women start caregiving, but that women who do start are more likely to reduce employment hours or stop work. Thus, the causal relationship between employment and caregiving in late midlife is largely unidirectional, with women reducing hours to meet caregiving demands.

Caregivers↗

Nuclear medical PET-study in the causal relationship between mastication and brain function in human evolutionary and developmental processes.

The principal author (Kubote 1995, 1997, 1998, 1999, 2000 a, b) has proposed that chewing food well from infancy will lead to a clear-headed and robust person, following which the same concept has been presented to the general public by the mass media. Unfortunately, however, there does not yet seem to be any direct evidence to support this claim. It is thus necessary to review mastication from the standpoint of the new concept of evidence-based medicine (EBM) and to create a new direction in medicodental research and treatment from the viewpoint of human evolution, because the causal relationship between mastication and brain function has never been clarified either in fossil science research or in the modem scientific bibliography. To confirm the human historical fossil record in regard to the causal relationship between the development of mastication and brain function in human evolutionary processes, the effect of gum chewing on brain reaction was examined in humans by means of a positron-emission tomography (PET) camera (Momose et al. 1997) after an antecubital intravenous injection of H215O. Powerful activation of the cortical cells was demonstrated in multiple cortical areas involving the marginal areas of the bilateral central sulci of the cerebral cortex (Fig. 1), and the activated areas coincided with our previous results in region of interest (ROI) analysis (Momose et al. 1887). Three-dimensionally, numerous cortical cells were shown to form nuclei on relief maps (Fig. 2). As diets and feeding habits changed in a stepwise manner from frugivorous to omnivorous via herbivorous and carnivorous over the lengthy progress of evolution, the brain concomitantly grew and the cranial capacity gradually increased in volume from 500 cm3, food from plant sources to animal sources (700 cm3), and then to both (1500 cm3), during the human evolutionary and developmental processes. Gradual increases in the cranial capacity of human fossils during the developmental stage have been demonstrated also by PET images of the human brain acquired by means of a PET camera and an antecubital intravenous injection of H215O during mastication that showed powerful activation of cortical cells in multiple areas. It could be concluded that human fossils give us concrete information on how to feed our children in the modern human life style from infancy to adulthood, so that we should bring children up by adhering to images of the principal feeding habits discovered during this research on human evolutionary and developmental processes.

Brain↗

Mendelian randomization and FinnGen analysis of the causal relationship between 473 gut microbiota species and chronic sinusitis.

OBJECTIVE: To investigate the causal associations between Gut Microbiota (GM) and Chronic Sinusitis (CRS) using Mendelian Randomization (MR). METHODS: Genome-Wide Association Study (GWAS) summary statistics for 473&#x2009;GM taxa were obtained from MiBioGen consortium. CRS data (22,099 cases vs. 371,520 controls) were sourced from the FinnGen R12 cohort. Causal effects were estimated via Inverse Variance-Weighted (IVW), MR-Egger, weighted median, and Bayesian-weighted MR methods. Sensitivity analyses (heterogeneity and horizontal pleiotropy tests) were performed to validate robustness. RESULTS: IVW analysis identified 20&#x2009;GM taxa significantly associated with CRS risk (p&#x2009;<&#x2009;0.05). Of these, 7 taxa (e.g., Francisellales, Roseibacillus, Merdibacter massiliensis) exhibited risk-increasing effects, while 13 taxa (e.g., Firmicutes I, Succinivibrionaceae) showed protective effects. Sensitivity analyses confirmed the absence of significant heterogeneity (Cochran's Q p&#x2009;>&#x2009;0.05) or pleiotropy (MR-Egger intercept p&#x2009;>&#x2009;0.05). Bayesian-weighted MR validated 18 causal relationships (posterior probability > 95%), except for RUG420 sp900317985 and UBA7703 (non-significant). CONCLUSIONS: This MR study provides genetic evidence supporting causal roles of specific GM taxa in CRS pathogenesis. These findings highlight the gut-sinus axis as a potential therapeutic target and underscore the utility of large-scale biobanks (e.g., FinnGen) in advancing precision medicine. LEVEL OF EVIDENCE: Level 5. Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.

Humans↗

Cardiac abnormalities and nonimmune hydrops fetalis: a coincidental, not causal, relationship.

Few conditions associated with nonimmune hydrops fetalis have had a demonstrable causal relationship. Congenital heart disease is often said to be a cause of nonimmune hydrops fetalis and antenatal closure of the foramen ovale is the cardiac abnormality most frequently reported in association with hydrops. In order to examine the role of congenital heart disease in hydrops, and, in particular, that of antenatal closure of the foramen ovale, we reviewed all autopsy cases with hydrops fetalis over an 11 year period and compared cardiac anomalies with those of nonhydropic controls. The incidence of various congenital heart malformations was not significantly different among these groups, suggesting that factors in addition to cardiac anomalies must be considered in the pathogenesis of nonimmune hydrops fetalis.

Abnormalities, Multiple↗

Mendelian randomization reveals causal relationships between cytokines and male reproductive diseases.

This study aims to explore the causal links between cytokines and four male reproductive disorders, namely abnormal spermatozoa (AS), male infertility, erectile dysfunction (ED), and hyperplasia of prostate (HP), employing a two-sample Mendelian randomization (MR) approach. Genetic associations with male reproductive diseases were derived from the IEU OpenGWAS project, with cytokine data from two GWASs focused on the human proteome and cytokines. Estimations were derived using inverse variance weighting, MR-Egger regression, weighted median, weighted model, and simple mode. Furthermore, the robustness of the findings was evaluated through Cochran's Q-test, MR-Egger regression, and leave-one-out sensitivity analysis. Fifteen unique cytokines were identified as having causal relationships with the risk of four male reproductive disorders. Specifically, for AS, interleukin-22 (IL-22), IL-12, and macrophage migration inhibitory factor were negatively correlated with AS, while tumor necrosis factor &#x3b2; levels were positively correlated with AS. In the context of male infertility, IL-2 receptor antagonist levels, IL-34, and granulocyte-colony stimulating factor levels were positively linked to male infertility, whereas IL-21 showed a negative relationship. Regarding ED, IL-19, IL-1&#x3b2;, and eotaxin levels were negatively associated with ED risk, while macrophage inflammatory protein 1&#x3b2; (MIP-1&#x3b2;) levels and interferon gamma-induced protein 10 levels were positively associated. As for HP, stromal-cell-derived factor 1&#x3b1; levels and MIP-1&#x3b1; levels revealed negative associations with HP. In conclusion, this MR analysis revealed that several cytokines were causally associated with male reproductive diseases and could be valuable in offering new insights for further mechanistic and clinical investigations of cytokines-associated male reproductive diseases.

Male↗

New insights into causal relationship between serum lipids, obesity, and asthma: a Mendelian randomization study.

OBJECTIVE: To identify causal risk factors for asthma using a Mendelian randomization (MR) approach. METHODS: Genetic variants associated with the exposures at the genome-wide significance level (p&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;10&#x2009;-&#x2009;8) were obtained from corresponding genome-wide association studies. Summary-level statistical data for asthma were obtained from the UK Biobank (UKB) and the FinnGen Consortia. Univariate and multivariate MR analyses were performed to clarify causal relationships among obesity, serum lipids, and asthma. Meta-analyses were performed to combine UKB and FinnGen results using a fixed-effects model. RESULTS: In FinnGen, the odds for asthma increased for every 1-SD increase in body mass index (BMI; odds ratio [OR] 1.292, p&#x2009;=&#x2009;1.34&#x2009;&#xd7;&#x2009;10-7), together with body fat percentage (BF%; OR 1.449, p&#x2009;=&#x2009;4.90&#xd7;10-3), and total cholesterol level (OR = 0.949, p&#x2009;=&#x2009;0.027). However, higher BMI and BF% were found to increase the risk for asthma in the multivariate MR analysis. In the UKB, the BMI results were replicated. Meta-analysis revealed that high-density lipoprotein cholesterol could also increase the risk for asthma, although there were no associations with other risk factors included in this study. CONCLUSION: This MR study found that genetically predicted higher BF% and BMI could increase the risk for asthma and corroborated some risk factors for asthma from previous MR studies. Moreover, the results suggest that higher BMI and BF% could serve as independent risk factors for asthma.

Humans↗

The causal relationships and potential pathways between birth weight and cardiovascular diseases: A human genomics study.

The causal relationships and potential pathways between birth weight (BW) and various cardiovascular diseases (CVDs) remain unclear, particularly when discriminating maternal and fetal contributions of BW to CVDs. Leveraging the genome-wide association studies (GWASs) of BW (N&#x2005;=&#x2005;321,223) and a range of CVDs (ncases&#x2005;=&#x2005;43,676-181,522), we performed a 2-sample Mendelian randomization (MR) analysis to estimate the causal effect of BW, fetal-specific BW, and maternal-specific BW on coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), atrial fibrillation (AF), and stroke. Furthermore, we applied a stepwise MR analysis approach to assess the potential involvement of childhood body mass index (CBMI) and age at menarche (AAM) in the causal pathways from BW to CVDs, while considering adult BMI. Finally, we performed colocalization analyses to justify the different biological mechanisms of maternal-specific and fetal-specific BW. The 2-sample MR analysis revealed that genetically predicted higher BW per standard deviation (SD) was associated with a decreased risk of CAD (odds ratio [OR]&#x2005;=&#x2005;0.804, 95% confidence interval [CI]: 0.731-0.883), MI (OR&#x2005;=&#x2005;0.720, 95% CI: 0.638-0.814), and stroke (OR&#x2005;=&#x2005;0.900, 95% CI: 0.823-0.985), but an increased risk of AF (OR&#x2005;=&#x2005;1.279, 95% CI: 1.160-1.410). Similar associations were observed for fetal-specific/maternal-specific BW. The stepwise MR analysis indicated that CBMI and AAM could serve as factors linking BW/fetal-specific BW and CVDs, albeit in different roles, by displaying an indirect causal effect through adult BMI. However, for maternal-specific BW, our results failed to support a causal effect on CBMI or AAM. Colocalization analyses supported the distinct biological mechanisms for maternal-specific and fetal-specific BW by showing different causal genes. The study suggested that both fetal genotype and intrauterine environmental exposure contribute to the causal associations. Additionally, AAM and CBMI may play a role in the pathways linking BW and CVDs, though the effect was only observed for fetal-specific BW.

Humans↗

Development of a structural equation model for causal relationships among arteriosclerosis risk factors.

The purpose of this study was to clarify the dynamic causal relationships among arteriosclerotic risk factors, including age, smoking, alcoholic consumption, exercise, hypercholesterolemia, hypertriglyceridemia, and hypertension. Data were collected from the medical records of 400 male clients who visited a university hospital located in Inchon, Korea, from May 1996 to December 1996 for physical examinations. The Lineal Structural Relationships 8 program was used to verify the fitness of the hypothetical model to data. All of the fit statistics, except the Chi-square value, showed that the hypothetical model was well fitted to the data. Seven percent of obesity was explained by the variables of age, smoking, alcohol consumption, and exercise. Sixty percent of hyperlipidemia could be explained by the variables of age, smoking, exercise, and obesity. And 22% of hypertension was explained by the variables of age, smoking, alcohol consumption, exercise, and hyperlipidemia. Our results showed that these risk factors were directly and indirectly interrelated, and lifestyle variables (smoking, alcohol consumption, and exercise) influence almost all of arteriosclerotic risk factors.

Arteriosclerosis↗

A longitudinal causal relationship among cardiovascular risk factors in the employees of the government savings bank.

A longitudinal structural causal model was generated to examine the causal relationship among determinants which were composed of four personal factors, stress, four health behaviors, and BMI on five physiological risks for cardiovascular disease: SBP, DBP, FBS, TC and HDL-C in 1,019 bank employees, within a five-year interval. A fourteen-item food frequency questionnaire for assessing eating habits and the Health Opinion Survey for the stress test were included in the self-administered questionnaires. Weight, height and blood pressure were measured and blood samples were collected for blood chemical analysis. Data analysis by LISREL showed that the determinants in the proposed model explained as much as 96 per cent variation in physiological risks for CVD (R2 = 0.96, relative chi-square = 1.92, RMSEA = 0.03, GFI = 0.96 and AGFI = 0.95). The findings also indicated that current physiological status was affected by their status of age, education, health behaviors, BMI and physiological status 5 years ago.

Adult↗

Disentangling the causal relationships between work-home interference and employee health.

OBJECTIVES: The present study was designed to investigate the causal relationships between (time- and strain-based) work-home interference and employee health. The effort-recovery theory provided the theoretical basis for this study. METHODS: Two-phase longitudinal data (with a 1-year time lag) were gathered from 730 Dutch police officers to test the following hypotheses with structural equation modeling: (i) work-home interference predicts health deterioration, (ii) health complaints precede increased levels of such interference, and (iii) both processes operate. The relationship between stable and changed levels of work-home interference across time and their relationships with the course of health were tested with a group-by-time analysis of variance. Four subgroups were created that differed in starting point and the development of work-home interference across time. RESULTS: The normal causal model, in which strain-based (but not time-based) work-home interference was longitudinally related to increased health complaints 1 year later, fit the data well and significantly better than the reversed causal model. Although the reciprocal model also provided a good fit, it was less parsimonious than the normal causal model. In addition, both an increment in (strain-based) work-home interference across time and a long-lasting experience of high (strain-based) work-home interference were associated with a deterioration in health. CONCLUSIONS: It was concluded that (strain-based) work-home interference acts as a precursor of health impairment and that different patterns of (strain-based) work-home interference across time are related to different health courses. Particularly long-term experience of (strain-based) work-home interference seems responsible for an accumulation of health complaints.

Adult↗

["Karoshi" and causal relationships].

This paper aims to introduce a measure for use by physicians for stating the degree of probable causal relationship for "Karoshi", ie, a sudden death from cerebrovascular diseases or ischemic heart diseases under occupational stresses, as well as to give a brief description for legal procedures associated with worker's compensation and civil trial in Japan. It is a well-used measure in epidemiology, "attributable risk percent (AR%)", which can be applied to describe the extent of contribution to "Karoshi" of the excess occupational burdens the deceased worker was forced to bear. Although several standards such as average occupational burdens for the worker, average occupational burdens for an ordinary worker, burdens in a nonoccupational life, and a complete rest, might be considered for the AR% estimation, the average occupational burdens for an ordinary worker should normally be utilized as a standard for worker's compensation. The adoption of AR% could be helpful for courts to make a consistent judgement whether "Karoshi" cases are compensatable or not.

Death, Sudden, Cardiac↗

Causal relationship between educational attainment and the occurrence of venous thromboembolism.

BACKGROUND: The association between educational attainment (EA) and arterial thrombotic disease has been reported, but the causal relationship between EA and venous thromboembolism (VTE) is not clear. We aimed to assess the causal effect of EA on VTE using the two-sample mendelian randomization (MR) method. METHODS: Data mining was conducted on the genome wide association studies (GWAS), with exposure factor EA and outcome factor VTE. Two-sample Mendelian Randomization (TSMR) analysis was conducted, with the results obtained from the random effects inverse variance weighted method (IVW). Use the MR-Egger method for pleiotropy analysis and leave one method for sensitivity analysis to verify the reliability of the data. RESULTS: Genetically predicted decreased EA was associated with a decreased risk of VTE in both the FinnGen consortium and UK Biobank (FinnGen-VTE: OR&#x2009;=&#x2009;0.848; 95% CI 0.776-0.927; P&#x2009;=&#x2009;2.84&#x2009;&#xd7;&#x2009;10-4; UKB-VTE OR&#x2009;=&#x2009;0.996; 95% CI 0.994-0.999; P&#x2009;=&#x2009;0.008) under a multiplicative random-effects IVW model. Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. CONCLUSIONS: The MR technique instructed a potential inverse causative relationship between EA and occurrence of VTE. Therefore, patients with low EA should be more vigilant about the occurrence of VTE.

Venous Thromboembolism↗