Causal Role Research Articles

From metabolomics to therapeutics: identifying causal metabolites and potential drugs for the treatment of osteoarthritis.

Osteoarthritis (OA) is a common age-related disease that causes pain and impaired mobility. Various blood metabolites are reportedly associated with bone health; however, their impact on OA remains unclear. Therefore, we conducted a metabolome-wide Mendelian randomization (MR) study to identify causal metabolites and therapeutic targets in OA. Genetic associations of metabolites were derived from the largest genome-wide association study (GWAS) of the blood metabolome, which provided summary-level data on 1091 blood metabolites. Genetic associations with OA were obtained from four large-scale GWAS: McDonald's study (140,025 cases, 344,349 controls), Zengini's study (12,658 cases, 50,898 controls), Dönertaş's study (39,515 cases, 445,083 controls), and Tachmazidou's study (39,427 cases, 378,169 controls). MR and colocalization analyses were performed to validate the causal roles of the candidate metabolites. Further analyses were conducted using expression quantitative trait locus-based MR, single-cell sequencing data, protein-protein interaction networks, and druggability assessments. These analyses aimed to identify the differentially expressed genes and prioritize them as potential therapeutic targets. The genetically predicted levels of 10 metabolites were associated with OA. Elevated levels of five metabolites and reduced levels of another five metabolites were associated with an increased OA risk. Among these, five metabolites were prioritized based on the most compelling evidence. Seven genes were identified as potentially involved and could serve as novel therapeutic targets for OA. Several blood metabolites were associated with OA, providing new insights into the etiology of OA and highlighting promising therapeutic targets.

High mitochondrial DNA levels accelerate lung adenocarcinoma progression.

Lung adenocarcinoma is a common aggressive cancer and a leading cause of mortality worldwide. Here, we report an important in vivo role for mitochondrial DNA (mtDNA) copy number during lung adenocarcinoma progression in the mouse. We found that lung tumors induced by KRASG12D expression have increased mtDNA levels and enhanced mitochondrial respiration. To experimentally assess a possible causative role in tumor progression, we induced lung cancer in transgenic mice with a general increase in mtDNA copy number and found that they developed a larger tumor burden, whereas mtDNA depletion in tumor cells reduced tumor growth. Immune cell populations in the lung and cytokine levels in plasma were not affected by increased mtDNA levels. Analyses of large cancer databases indicate that mtDNA copy number is also important in human lung cancer. Our study thus reports experimental evidence for a tumor-intrinsic causative role for mtDNA in lung cancer progression, which could be exploited for development of future cancer therapies.

Fair Shares and Selective Attention

Attitudes toward fairness and redistribution differ along socioeconomic lines. To understand their formation, we conduct a large-scale experiment on attention to merit and luck and the effect of attention on fairness decisions. Randomly advantaged subjects pay less attention to information about true merit and retain more economic surplus, and this effect persists in subsequent impartial decisions. Attention also has a causal role: encouraging subjects to look at merit reduces the effect of an advantaged position on allocations. This suggests that attention-based policy interventions may be effective in reducing polarized views on inequality. (JEL C91, D63, D83)

Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion.

Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of microRNAs (miRNAs). However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improves insulin secretion and glucose intolerance in db/db mice. Supporting the function of EVs' miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs shows their distribution in mouse pancreatic islets. Tracing the injected AAV-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat results in upregulating miR-27a-5p in EVs and serum, and elicits mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targets L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduces insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolishes the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EVs' miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus.

The historical transformation of individual concepts into populational ones: an explanatory shift in the gestation of the modern synthesis.

In this paper, I will conduct three interrelated analyses. First, I will develop an analysis of various concepts in the history of biology that used to refer to individual-level phenomena but were then reinterpreted by the Modern Synthesis in terms of populations. Second, a similar situation can be found in contemporary evolutionary theory. While different approaches reflect on the causal role of developing organisms in evolution, proponents of the Modern Synthesis refrain from any substantial change by reinterpreting and explaining individual-level phenomena from a population perspective. Finally, I will approach these historical and contemporary debates by arguing for the statistical reading of natural selection, which holds that explanations by natural selection are statistical. My main conclusion is that the historical conceptual reinterpretations belong to a new explanatory strategy developed by the Modern Synthesis based on population thinking. Adopting the statistical point of view has three advantages for the issues discussed in this paper. First, understanding historical conceptual change as part of an explanatory shift fits with the emergence of population biology as a discipline that employs statistical methods. Second, concerning current debates in evolutionary biology, the statisticalist reading can validate the goal of both sides of the dispute. It ascribes an invaluable role to the population statistical explanation of the MS and also commends the study of developmental and organismal causes of adaptive evolution. Finally, the division of explanatory roles in evolutionary biology, embarrassed by statisticalism, can be related to the different interpretations that important biological concepts have undergone throughout history and contemporary biology, i.e., that the division of explanatory roles allows for a division of conceptual interpretations.

The Causal Role of Thyroid Hormones in Bipolar Disorders: A Two-Sample Mendelian Randomization Study.

Bipolar disorder is a complex psychiatric condition with distinctions between clinical subtypes including Type 1 and 2 disorders. Several studies have proposed that thyroid hormones may be involved in the aetiology of bipolar disorders. This study employed a two-sample Mendelian randomization (MR) approach to investigate the causal relationships between six thyroid hormone metrics (TSH, FT4, FT3, TT3, FT3/FT4 and TT3/FT4) and bipolar disorder and Type 1 and 2 disorders, separately. Genome-wide association (GWAS) data from the ThyroidOmics Consortium (up to 271,040 individuals of European ancestry) were used for thyroid function metrics. Bipolar disorder GWAS data included 41,917 cases and 371,549 controls (25,060 Type 1 and 6,781 Type 2 cases). We applied inverse variance weighted (IVW) methods for primary MR analysis, with MR Egger, weighted median and weighted mode for sensitivity. Additional tests assessed horizontal pleiotropy and heterogeneity. Higher FT4 levels showed a protective causal effect against bipolar disorder (OR: 0.92, 95% CI: 0.86-0.97, p = 4.58 × 10-3) and a suggestive effect on Type 1 disorders (OR: 0.92, 95% CI: 0.86-0.99, p = 3.21 × 10-2). Elevated FT3 (OR: 1.18, 95% CI: 1.03-1.35, p = 1.55 × 10-2) and FT3/FT4 ratio (OR: 1.97, 95% CI: 1.02-3.82, p = 4.46 × 10-2) had suggestive harmful effects on Type 1 disorders. Sensitivity analyses showed consistent effects, with no significant horizontal pleiotropy or heterogeneity. These findings highlight the protective role of FT4 and the potentially harmful effect of elevated FT3 in Type 1 bipolar disorder, highlighting the need for further research on thyroid hormone levels as a potential treatment strategy for Type 1 bipolar disorder.

Schistosome and malaria exposure and urban–rural differences in vaccine responses in Uganda: a causal mediation analysis using data from three linked randomised controlled trials

Vaccine immunogenicity and effectiveness vary geographically. Chronic immunomodulating parasitic infections including schistosomes and malaria have been hypothesised to be mediators of geographical variations. We compared vaccine-specific immune responses between three Ugandan settings (schistosome-endemic rural, malaria-endemic rural, and urban) and did causal mediation analysis to assess the role of Schistosoma mansoni and malaria exposure in observed differences. We used data from the control groups of three linked randomised trials investigating the effects of intensive parasite treatment among schoolchildren. All participants received the BCG vaccine (week 0); yellow fever (YF-17D), oral typhoid (Ty21a), human papillomavirus (HPV; week 4); and HPV booster and tetanus-diphtheria (week 28). Primary outcomes were vaccine responses at week 8 and, for tetanus-diphtheria, week 52. We estimated the total effect (TE) of setting on vaccine responses and natural indirect effect (NIE) mediated through current or previous infection with S mansoni or malaria, and baseline vaccine-specific responses. We included 239 (43%) participants from the schistosomiasis-endemic setting, 171 (30%) from the malaria-endemic setting, and 151 (27%) from the urban setting. At week 8, vaccine responses were lower in rural settings: schistosomiasis-endemic versus urban settings (TE geometric mean ratio for YF-17D plaque reduction neutralisation at 50% (PRNT50) titres 0·58 [95% CI 0·37 to 0·91], for S Typhi O-lipopolysaccharide-specific IgG 0·61 [0·40 to 0·93], and for tetanus-specific IgG 0·33 [0·22 to 0·51]); malaria-endemic versus urban settings (YF-17D 0·70 [0·49 to 0·99], S Typhi O-lipopolysaccharide-specific IgG 0·29 [0·20 to 0·43], and tetanus-specific IgG 0·53 [-0·35 to 0·80]). However, we found higher BCG-specific IFNγ responses in the malaria-endemic versus urban setting (1·54 [1·20 to 1·98]). The estimated NIEs of setting on vaccine responses mediated through previous and current S mansoni and malaria were not statistically significant. For malaria-endemic versus urban settings, baseline vaccine-specific responses contributed to some but not all differences: S Typhi O-lipopolysaccharide-specific IgG at week 8 (57.9% mediated [38·6 to 77·2]) and week 52 (70·0% mediated [49·4 to 90·6]) and BCG at week 52 (46.4% mediated [-4·8 to 97·7]). We found significant variation in vaccine response between urban and rural settings but could not confirm a causal role for schistosome or malaria exposure. Other exposures require consideration. UK Medical Research Council.

Fat embolism: a systematic review to facilitate the development of standardised procedures in pathology.

Fat embolism (FE) is a historically recognised but still actively researched topic in forensic pathology. Several aspects remain not fully elucidated, such as its aetiopathogenesis, its causal role in death determination, the impact of interfering factors (e.g. cardiopulmonary resuscitation or other medical procedures) and both qualitative and quantitative diagnostic methodologies in clinical and forensic contexts. These issues are further underscored by the potential involvement of FE in the causal determination of non-traumatic deaths, which often raises questions of professional liability. The present study aims to provide a comprehensive and up-to-date overview of the most recent scientific evidence relevant to forensic pathology. Our systematic research has included 58 articles from 1990 to the present on the topic of FE and fat embolism syndrome (FES). From these articles, we identified 45 case reports, from which the authors' descriptions were extracted to provide information on individual cases and the operational methods of forensic pathologists. Additionally, 21 experimental studies were identified, and their key findings have been summarised narratively. It has emerged that both traumatic and non-traumatic cases are frequently reported in the forensic context, with orthopaedic and cosmetic surgery being among the highest-risk specialities. Experimental studies have re-evaluated the role of a patent foramen ovale in the pathogenesis of FE, as well as the impact of cardiopulmonary resuscitation in causing FE severe enough to result in death. Additionally, there are new findings regarding diagnostic techniques, including radiological and immunohistological methods; however, they have not yet fully bridged the reliability gap compared to an accurate autopsy-histological evaluation. The major critical points that emerged include the lack of complete and detailed information on premortem clinical conditions, the underutilisation of grading systems and the methodological heterogeneity applied, resulting in considerable variability regarding the organs studied histologically and the diagnostic techniques used. Despite the limitations associated with the analysis of case reports and the heterogeneity of included experimental studies, we believe that this study can provide a comprehensive overview of the FE topic. It furnishes pathologists with an updated overview useful for clinical practice and guiding future research trends, as well as facilitating the development of standardised procedures.

Linking Hierarchy Culture, Market Culture and Innovation Orientation: Moderating Roles of Causation and Effectuation

This paper aims to examine the influence of hierarchy and market cultures on firm’s innovation orientation. Also, it explores the moderating roles of the two decision-making logics, which are causation and effectuation on the relationship between hierarchy and market organizational cultures and innovation orientation. The current study extends past research on organizational culture and innovation, by being most likely the first study to examine the extent to which the relationship between hierarchical culture and SME innovation orientation is moderated by causal logic; and the extent to which effectual reasoning moderates the relationship between market culture and the innovation orientation of SMEs. The study utilizes survey data from 206 small and medium sized enterprises (SMEs) in the manufacturing and services sectors of the United Arab Emirates (UAE), that is analyzed using SmartPLS. The results of this study suggest that causation moderates the relationship between hierarchical culture and SME innovation orientation. Furthermore, market culture is only positively related to SME’s innovation orientation when effectuation moderates the relationship.

Correlation between gut microbiota and pancreatitis: a bidirectional Mendelian randomization.

The causative role of gut microbiota in pancreatitis remains unknown. This study aimed to investigate potential causal associations between gut microbiota and pancreatitis, using bidirectional Mendelian randomization (MR) analysis. We analyzed genome-wide association study (GWAS) summary statistics for gut microbiota (211 taxa from gut microbiota, n = 18 340) and two types of pancreatitis, namely acute pancreatitis (AP, 5509 cases and 301 383 controls) and chronic pancreatitis (CP, 3002 cases and 301 383 controls). A reverse MR analysis was also performed to assess the possibility of reverse causation. Nine features (one family + eight genera) showed a causal association with AP. According to inverse-variance weighted (IVW) estimates, phylum Firmicutes (P = 4.10 × 10-2), genus Erysipelatoclostridium (P = 4.80 × 10-2), genus Flavonifractor (P = 4.10 × 10-2), genus Methanobrevibacter (P = 3.40 × 10-2), and genus Prevotella9 (P = 4.60 × 10-2) were found to have a protective effect on AP. Additionally, genus Eubacteriumeligensgroup (P = 4.10 × 10-2), genus Eubacteriumfissicatenagroup (P = 4.00 × 10-3), genus Coprococcus3 (P = 4.10 × 10-2), and genus Haemophilus (P = 4.60 × 10-2) exhibited a positive correlation with AP. Four features (two families + two genera) were causally associated with CP. IVW results also confirmed that family Clostridiaceae1 (P = 3.30 × 10-2), genus LachnospiraceaeFCS020group (P = 4.60 × 10-2), and genus Prevotella9 (P = 1.90 × 10-2) were protective factors for CP, whereas the presence of family Victivallaceae (P = 2.60 × 10-2) correlated with CP risk. No causal effects of pancreatitis (AP or CP) on these gut microbiota taxa were found in the reverse MR analysis. This study confirms a potential causal relationship between gut microbiota and pancreatitis, highlighting the gut microbiota-pancreas axis in the pathogenesis of pancreatitis.

Effects of brain microRNAs in cognitive trajectory and Alzheimer’s disease

microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer’s disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes.

Flight power muscles have a coordinated, causal role in hawkmoth pitch turns.

Flying insects solve a daunting control problem of generating a patterned and precise motor program to stay airborne and generate agile maneuvers. In this motor program, each muscle encodes information about movement in precise spike timing down to the millisecond scale. Whereas individual muscles share information about movement, we do not know if they have separable effects on an animal's motion, or if muscles functionally interact such that the effects of any muscle's timing depend heavily on the state of the entire musculature. To answer these questions, we performed spike-resolution electromyography and electrical stimulation in the hawkmoth Manduca sexta during tethered flapping. We specifically explored how flight power muscles contribute to pitch control. Combining correlational study of visually-induced turns with causal manipulation of spike timing, we discovered likely coordination patterns for pitch turns, and investigated if these patterns can drive pitch control. We observed significant timing change of the main downstroke muscles, the dorsolongitudinal muscles (DLMs), associated with pitch turns. Causally inducing this timing change in the DLMs with electrical stimulation produced a consistent, mechanically relevant feature in pitch torque, establishing that power muscles in Manduca have a control role in pitch. Because changes were evoked in only the DLMs, however, these pitch torque features left large unexplained variation. We find this unexplained variation indicates significant functional overlap in pitch control such that precise timing of one power muscle does not produce a precise turn, demonstrating the importance of coordination across the entire motor program for flight.

The causal role of gastroesophageal reflux disease in endometriosis: a bidirectional Mendelian randomization study

Observational studies have reported an association between gastroesophageal reflux disease (GERD) and endometriosis. We conducted a two-sample and bidirectional Mendelian randomization analysis to determine whether those associations are causal. Two-sample and bidirectional MR analyses were performed using summary statistics from the European Individual Genome-Wide Association Study (GWAS). The inverse variance weighting (IVW) method is used as the main analysis method to evaluate causality. Sensitivity analyses were performed to assess heterogeneity, horizontal versatility, and stability. The results showed no significant causal association between GERD in women with endometriosis in the UK Bank database [ratio (OR) ≈ 0, 95% adjusted interval (CI) 1.0007∼1.0044, P = 0.006] and Finn databases [ratio (OR) = 1.29, 95% adjusted interval (CI) 0.99∼1.67, P = 0.06]. However, when studying the Finn database only for endometriosis, which is confined to the uterus, a significant increase in GERD was limited to the risk of endometriosis in the uterus [ratio (OR) = 1.47, 95% adjusted interval (CI) 1.00∼2.17, P = 0.05]. Sensitivity analysis showed that the results were robust and did not detect multi efficacy or heterogeneity. Meanwhile, reverse MR analysis showed that endometriosis did not increase the risk of GERD. This MR study supports a causal relationship between GERD and an increased risk of endometriosis confined to the uterus. Therefore, patients with gastric esophageal reflux should be treated with gynecological examination to avoid and prevent the development of endometriosis.

Causal role of immune cells in muscle atrophy: mendelian randomization study

Immune system and inflammation had a great influence on the progression of muscle atrophy. However, the causal relationship with specific immune cell traits remained uncertain. The aim of this study was to elucidate the genetic influences on these associations, providing insights into the underlying mechanisms of muscle atrophy. A bidirectional two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal relationship between immune cell phenotypes and muscle atrophy. Data on immune cell phenotypes were obtained from a research cohort containing data on 731 immune cell phenotypes and data on muscle atrophy were sourced from a Finnish database. MR analysis was performed using the MR-Egger method, weighted median, inverse variance weighting, heterogeneity testing, sensitivity analysis, and multiplicity analysis, with results subjected to false discovery rate(FDR) correction. Additionally, the UK Biobank cohort was utilized as an external validation. A total of 31 immune phenotypes with causal relationships with muscle atrophy were identified, including various phenotypes of conventional dendritic cells, myeloid cells, T cells/B cells/natural killer cells, regulatory cells, and T cell maturation stages. Among them, 12 immune phenotypes were identified as exhibiting a positive causal relationship with muscle atrophy, while 19 immune phenotypes were demonstrated to have a negative causal association, highlighting the complex interactions between immune cells and muscle health. The results of the reverse MR analysis indicated that a negative correlation between muscle atrophy and CD28 on secreting Treg (OR = 0.9038, 95%CI:0.8308 ~ 0.9832, P = 0.0186). A significant positive correlation was revealed by external datasets between the CD25 on IgD + CD38- immune phenotype and the risk of muscle atrophy, which was consistent with the trend observed in the training group (OR = 1.1041, 95% CI: 1.1005–1.1076, P = 0.0263). No evidence of pleiotropy was observed, and the reliability of these findings was demonstrated by the leave-one-out analysis. The findings highlight significant correlations between certain immune cell features and muscle atrophy, providing potential targets for further investigation of immunological mechanisms and therapeutic interventions for this condition.

Nexilin-related cardiomyopathy (NEXN-CMP) - an island's perspective

Abstract Introduction The phenotypic features of Nexilin related cardiomyopathies (NEXN-CMP) are poorly understood and under-reported. A better understanding of the genotype-phenotype association is paramount. Objectives The main objective of this study was to investigate the causative role and phenotypic expression of the NEXN gene in the Maltese Islands. Methodology Probands and relatives referred for a cardiac gene panel were evaluated. Subjects harbouring NEXN variants were identified. Those finally classified as having NEXN-CMP were evaluated for the purpose of this study. Results Out of 444 probands (confirmed or suspected cardiomyopathy), 12 probands were labelled with NEXN-CMP. This equates to a prevalence of 2.7% in the local cardiomyopathy pool, substantially higher to what has been previously reported. Genetic testing identified 19 individuals (probands [n=15] and relatives [n=4]) all harbouring the same novel frameshift variant: NEXN c.1589_1590del p.(Arg530LysfsTer3), classified as likely pathogenic according to ACMG criteria. Three (15.8%) harboured a second pathogenic variant (n=2 MYH7, n=1 TTN). Another 3 were not clinically affected (n=1 FH of SCD, n=2 first degree relatives of NEXN-CMP probands). These individuals were excluded from further analysis. The NEXN-CMP cohort (n=13) consisted of a dominant male (68.8%) population (54±22 years at presentation, 7.7% athletes, 12 families). Most were probands (n=12/13). DCM was the dominant phenotype (n=8, 61.5%) followed by HNDLVC (n=3, 23.1%) and HCM (n=2, 15.4%). One infantile DCM was homozygous for the NEXN variant. Symptoms were the most frequent method of presentation (n=6, 46.2%), followed by a FH of SCD and/or cardiomyopathy (n=3, 23.1%), abnormal echocardiogram (n=2 15.4%), OHCA (n=1, 7.7%) and inutero diagnosis (n=1, 7.7%). A FH of SCD was present in a third (n=4/12, 33.3%). The ECG was abnormal in the majority (n=10/11, 90.9%). Most patients had a LBBB (6/11, 54.5%) followed by inferolateral TWI (n=3, 27.3%), ventricular arrhythmias/high-grade AVB (n=1, 9.1% each). NEXN-CMP appears to be a left dominant cardiomyopathy. LV dilation and reduced LVEF were present in 84.6%. Non-ischaemic scar was present in 3/8 cases (37.5%), 2 had a ring-like pattern. RV morphology and function was normal in all cases. Tachyarrhythmias were frequently observed (n=4/6, 66.7%) during holter monitoring or exercise testing (n=2 NSVTs, n=1 VEs, n=1 SVEs). A fourth (n=3/11, 27.3%) were implanted with an electrophysiological device. No significant predictors for device implantation were identified at univariate analysis. One patient is on the transplant list (infantile DCM). Conclusion The prevalence of NEXN-CMP in Malta appears higher than previously reported (2.7%), possibly because of a founder mutation. DCM and HCM are the dominant presenting phenotypes, frequently associated with symptoms, an abnormal ECG, a FH of SCD and LV dilatation/dysfunction.

Proteome-wide associations of pulse pressure in the UK Biobank

Abstract Introduction Large artery stiffness (LAS) significantly contributes to the burden of cardiovascular morbidity and mortality, and is marked by an increased pulse pressure (PP)(1). Therapeutically targeting LAS may help in mitigating cardiovascular disease and other comorbidities. Purpose We aimed to investigate the proteomic associations of PP, and their putative causal role using Mendelian randomization (MR). Methods We first investigated associations between baseline circulating protein levels for 2,941 protein analytes measured using Olink technology, and PP in the UK Biobank (N=54,219). Regression analyses were adjusted for age, sex, mean arterial pressure, body mass index and stroke volume. Next, we conducted two-sample MR analyses to evaluate associations between genetically-predicted plasma protein levels and PP, for 1,820 proteins with available genetic instruments. We conducted inverse-variance weighted MR as our main analysis, and genetic colocalization analyses as sensitivity. We used a 5% false discovery rate (FDR) threshold to account for multiple comparisons. Results After correction for multiple comparisons, measured levels of 61 out of 2,923 proteins were significantly associated with PP (Figure 1). Genetically-predicted levels for 58 proteins were significantly associated with PP after FDR correction (Figure 2). At nominal significance, 31 proteins were concordantly associated with PP in both analyses, and 19 had consistent directions of effect, including natriuretic peptide B (NPPB, βobservational=0.04, Standard Error (SE)=0.009, PFDR<0.001), thrombospondin-2 (THBS2, βobservational=0.05, SE=0.009, PFDR<0.001), paraoxonase-2 (PON2, βobservational=-0.03, SE=0.008, PFDR<0.001), and sclerostin (SOST, βobservational=-0.03, SE=0.009, PFDR<0.001). NPPB was concordant in direction of effect and met an FDR-corrected significance threshold. Conclusions Our study identifies multiple novel proteins with a putative causal effect on PP. Our findings identify NPPB with a high level of statistical confidence, which could have important implications given the current availability of FDA-approved medications to boost NPPB effects. Our findings will lead to further investigations regarding the biology and clinical role of the identified candidate therapeutic targets.

A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases. To identify novel genetic causes of HSP. Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family. We found a homoplasmic MT-TV (mitochondrial tRNAVal) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP. Fourth-generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number. Upregulation of mitochondrial autophagy genes in these patients suggested that MT-TV mutations could lead to reduced mtDNA copy number. Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria. The rare MT-TV m.1661A > G mutation is associated with HSP. Variations in mtDNA copy number may play a causal role in differences among clinical phenotypes. © 2024 International Parkinson and Movement Disorder Society.

Prognostic role of remnant cholesterol and traditional cardiovascular risk factors in young adults: results of long-term follow-up of a cohort of 30-year-old norwegians

Abstract Background There are limited data on the prevalence and impact of traditional cardiovascular (CV) risk factors among young adults. In addition, more knowledge on novel CV risk factors is needed to explain the residual risk beyond that of the traditional risk factors. Increasing evidence suggest a causal role of remnant cholesterol (RC) in the development of atherosclerotic cardiovascular disease (CVD) and subsequent clinical events. However, the role of RC in young adults is unresolved. Purpose We aimed to evaluate the prevalence of traditional risk factors and the respective sex-differences in young adults, as well as their association with long-term CV events. Further, we hypothesized that higher RC concentrations are associated with impaired CV prognosis. Methods In year 2000, all 30-year-old inhabitants of our city were invited to a cross-sectional study including assessment of health status, anthropometric measurements, and non-fasting blood samples. RC was calculated as total cholesterol minus (LDL-C + HDL-C). Long-term clinical follow-up was performed through linkage with mandatory national registries, 22 years after inclusion. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalization for unstable angina and coronary revascularization. Results A total of 5950 individuals were included (56% women). At baseline, men displayed significantly higher systolic and diastolic blood pressure, total cholesterol, LDL-C and triglycerides, as compared with women (Table 1). Also, men had higher levels of RC (Table 1). During a mean follow-up time of 22 years, 108 events (1.8%) occurred. In multivariable Cox regression analysis, non-West-European ancestry (adjusted [a] HR 1.76, 95% confidence interval [CI] 1.03-2.99), diabetes mellitus (aHR 6.39, 95% CI 2.52-16.2), systolic blood pressure (aHR 1.03, 95% CI 1.01-1.04), and LDL-cholesterol (aHR 1.37, 95% CI 1.11-1.68) were associated with an increased risk of CV events during long-term follow-up. Female gender was associated with a reduced risk of CV events (aHR 0.38, 95% CI 0.23-0.64), whereas smoking status did not show any significant association. RC was identified as a significant predictor of CV events (aHR 1.55, 95% CI 1.11-2.18, per 1.0 mmol/L increase). The highest RC quartile (mean RC: 1.1 mmol/L), had the highest event rate (Figure 1, p<0.001 with log-rank test). Conclusion This study uncovers significant sex-differences in modifiable CV risk factors among young adults at the age of 30, which are associated with increased risk for long-term CV events. Interestingly, increasing concentrations of RC at the age of 30 were strongly associated with impaired long-term CV outcome and should be accounted for in early risk prediction.Baseline characteristics.Remnant cholesterol and CVD events.

Unlocking adolescent dietary behaviours: the causal role of social contexts

Abstract Background Using a causal inference framework, our study aimed to extend previous work in providing a comprehensive understanding of the role various social contexts across different levels can play in predicting adolescent dietary behaviours. Methods Data came from the 2017/18 Health Behaviour in School-aged Children (HBSC) survey in Flanders (Belgium). The sample included representative data from 8,702 adolescents in 165 schools. Social factors at individual-level (family meals, family, peer, student and teacher support) and at contextual-level (school culture of student and teacher support and school-level socioeconomic status [SES]) were considered. Multilevel logistic regression analyses were performed. Results At individual-level, family meals and family and student support were positively associated with fruit and vegetable consumption, family meals with sweet consumption too. Student and teacher support showed positive associations solely with fruit consumption. At contextual-level, adolescents attending schools with a lower school-SES demonstrated lower vegetable consumption. Culture of teacher support was negatively associated with sweets but also vegetable consumption. For culture of student support no associations were found. Conclusions The study mainly provide cues for strengthening family social ties as dietary health promotion initiatives, with some evidence supporting the role of beneficial peer and school social factors. Mixed results for contextual school-level social factors warrant further research to identify additional school-related influences on adolescent dietary behaviours to advance current understandings. Key messages • Family meals and support promote healthy eating in adolescents, emphasising the health promoting role of family social ties in dietary habits. • Mixed findings on school-level social factors call for more research on school health policies.

Role of Galectin-3 in resident macrophages and effects on atherosclerosis

Abstract Background Arterial macrophages play an important role in atherosclerosis, exhibiting heterogeneity in their origins as either resident or inflammatory monocyte-derived macrophages. Resident macrophages originate predominantly from the yolk sac, and they are endowed with homeostatic functions and can have anti-inflammatory properties under inflammation [1]. Resident macrophages pre-existing within the tissue differentiate into foamy macrophages before monocytes appear in early atherosclerotic lesions [2]. Galectin-3 (Gal-3) encoded by the gene Lgals3, is a crucial effector molecule that is prominently expressed by macrophages [3]. Studies have provided conflicting evidence regarding the role of Gal-3 in atherosclerosis by affecting macrophage functions and monocyte recruitment [4,5]. Purpose This study aims to investigate the role of Gal-3 in arterial resident macrophages for atherosclerosis and reveal the underlying mechanisms. Methods General Lgals3 knockout (Lgals3-/-) and resident macrophage specific knockout (Lgals3-/-Rank-Cretg) mice on the Apoe-deficient background were generated and atherosclerotic lesion development (8 weeks of western diet) was compared. Results Our study revealed that Lgals3-/- mice exhibited increased numbers of monocytes and neutrophils in the blood, which was associated with the development of larger atherosclerotic plaques. Plasma Gal-3 concentration from Lgals3-/-Rank-Cretg mice was decreased by 60%, indicating that the majority of circulating Gal-3 is derived from resident macrophages. Surprisingly, Lgals3-/-Rank-Cretg mice did not show the observed increase in blood monocytes and neutrophils, suggesting that this effect was independent of circulating Gal-3. Consistent with a causal role of monocytosis and leukocytosis in atherogenesis, plaque formation in Lgals3-/-Rank-Cretg was not significantly affected. Additionally, Gal-3 deficiency promoted M1 polarization and reduced efferocytosis, phagocytosis and chemokine receptor expression in BMDMs, and the addition of exogenous Gal-3 restored the effect on phagocytosis and blocked CXCL12 and CCL5-induced leukocyte migration. Conclusion This study reveals a prominent protective role of Gal-3, primarily through inflammatory macrophages rather than resident macrophages for the development of atherosclerotic lesions. This protective effect is attributed to its homeostatic effects on monocyte and neutrophil numbers, as well as its influence on macrophage functions.