Causal Mechanisms Of Disease Research Articles

Large-scale genetic and multi-omics analyses identify molecular pathways underlying dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) is a heart muscle disease that represents a major public health burden. While both common and rare genetic variants are known to affect DCM risk, previous genome-wide association studies (GWAS) have yielded only few loci and the molecular pathways underlying DCM remain largely unknown. Purpose We aimed to discover novel genetic loci for DCM by combining data from biobank and case-control studies, and by combining GWAS with multi-trait analyses. We also pursued multi-omics Mendelian randomization to nominate novel molecular pathways underlying DCM. Methods and results We first performed a GWAS of ICD-code defined DCM (N=1472 cases) from two large biobank datasets (UK Biobank and Mass General Brigham Biobank), and found good genetic correlation (rg=0.82, SE=0.22) and similar heritability estimates (h2=0.12, SE=0.03 vs. h2=0.14, SE=0.03) when compared with a previously published GWAS of recruited DCM cases. In a large meta-analysis across case-control and biobank datasets (N=4191 cases), we identified 10 loci significantly associated with DCM. We then integrated this novel meta-analysis into a multi-trait GWAS (MTAG) with MRI-derived left ventricular traits from the UK Biobank (LVEF and LVESV; N=36083), which yielded 44 lead variants at 36 significant loci. Novel loci overlap reported Mendelian cardiomyopathy genes (ACTN2, OBSCN, MYH7B), support previous mechanistic findings (HSPB8; heat shock protein family), and include genomic regions also arising from a recent GWAS of hypertrophic cardiomyopathy (notably, SVIL). We then performed Mendelian randomization analyses on the MTAG GWAS, using genetic instruments from published multi-omics datasets. Mendelian randomisation of the blood metabolome suggests potential causal roles for metabolites, notably those involved in the pentose phosphate pathway (ribitol; β=0.25, SE=0.04) and glycemic excursion (1,5-anhydroglucitol; β=0.08, SE=0.02). Analyses of the blood proteome suggest potential causal roles for several serum proteins, including proteins involved in redox balance (glutathione synthetase; β=-0.34, SE=0.05), mTORC1 signalling (LAMTOR3; β=0.08, SE=0.01), and the pentose phosphate pathway (G6PE; β=0.09, SE=0.02). Conclusion Our analyses link several new genomic regions with DCM, and implicate redox disbalance and alternative usage of (gluco)metabolic pathways as putative causal mechanisms of disease. Future functional studies could determine whether these represent actionable findings.

Considerations for animal models of blast-related traumatic brain injury and chronic traumatic encephalopathy.

The association of military blast exposure and brain injury was first appreciated in World War I as commotio cerebri, and later as shell shock. Similar injuries sustained in modern military conflicts are now classified as mild traumatic brain injury (TBI). Recent research has yielded new insights into the mechanisms by which blast exposure leads to acute brain injury and chronic sequelae, including postconcussive syndrome, post-traumatic stress disorder, post-traumatic headache, and chronic traumatic encephalopathy, a tau protein neurodegenerative disease. Impediments to delivery of effective medical care for individuals affected by blast-related TBI include: poor insight into the heterogeneity of neurological insults induced by blast exposure; limited understanding of the mechanisms by which blast exposure injures the brain and triggers sequelae; failure to appreciate interactive injuries that affect frontal lobe function, pituitary regulation, and neurovegetative homeostasis; unknown influence of genetic risk factors, prior trauma, and comorbidities; absence of validated diagnostic criteria and clinical nosology that differentiate clinical endophenotypes; and lack of empirical evidence to guide medical management and therapeutic intervention. While clinicopathological analysis can provide evidence of correlative association, experimental use of animal models remains the primary tool for establishing causal mechanisms of disease. However, the TBI field is confronted by a welter of animal models with varying clinical relevance, thereby impeding scientific coherence and hindering translational progress. Animal models of blast TBI will be far more translationally useful if experimental emphasis focuses on accurate reproduction of clinically relevant endpoints (output) rather than scaled replication of idealized blast shockwaves (input). The utility of an animal model is dependent on the degree to which the model recapitulates pathophysiological mechanisms, neuropathological features, and neurological sequelae observed in the corresponding human disorder. Understanding the purpose of an animal model and the criteria by which experimental results derived from the model are validated are critical components for useful animal modeling. Animal models that reliably demonstrate clinically relevant endpoints will expedite development of new treatments, diagnostics, preventive measures, and rehabilitative strategies for individuals affected by blast TBI and its aftermath.

Ghrelin, Nitrite and Paraoxonase/Arylesterase Concentrations in Cement Plant Workers

Ghrelin, Nitrite and Paraoxonase/Arylesterase Concentrations in Cement Plant WorkersOccupational cement dust exposure has been associated with an increased risk of liver abnormalities, pulmonary disorders, and carcinogenesis. Decreased antioxidant capacity and increased plasma lipid peroxidation have been posed as possible causal mechanisms of disease. Accordingly, this study examined the serum paraoxonase (PON1) arylesterase (AE), ghrelin, HDL-C, LDL-C and serum nitrite (NOx) levels in cement dust exposed workers. Twenty-eight volunteer male cement plant workers and 30 volunteer control male workers, aged 29-54 years, participated. The concentrations of serum PON1, AE, NOx, ghrelin, and HDL-cholesterol and LDL-cholesterol were measured in both groups. PON-1, AE, ghrelin and HDL-cholesterol were lower in the cement plant workers than in controls. Serum nitrite (NOx), and LDL-C levels in cement plant workers were higher (p<0.05) than in the control group workers. No correlation was observed between the serum levels of HDL-cholesterol and PON1 and between HDL-cholesterol and ghrelin. A weak negative correlation was detected between the serum ghrelin and NOx. The study results strongly suggest that HDL-paraoxonase, AE, ghrelin, HDL-C, and high NOx, and LDL-C levels may have a role in disease involving oxidative damage. However, some studies are necessary to address the association between occupational dust exposure and respiratory symptoms.

Preventing Diet Induced Disease: Bioavailable Nutrient-Rich, Low-Energy-Dense Diets

What the World needs is an integrated and sustainable food policy that makes the best and most appropriate use of the technologies at our disposal to promote health and help prevent disease. Diet induced diseases account for the largest burden of chronic illnesses and health problems Worldwide. Historically a lack of knowledge about human nutritional requirements (including for the brain) helped promote diet induced disease. The scientific knowledge currently exists to help prevent many of the current deficiencies and imbalances in human diet. Primary prevention of cardiovascular disease and mental ill health starts, crucially, with maternal nutrition before the inception of pregnancy and continues throughout life of the new born and includes consuming more DHA and EPA omega-3 fats (and their cofactors) and other bioavailable brain nutrients and less high-energy-dense (>2 kcal g(-1)) foods (e.g. land-based cereal, chocolate, alcohol and refined sugar, fat and oil), so tissues synthesize less inflammatory mediators and to lower transient short-lived meal-induced oxidative stress, inflammation, proliferation and impaired nitric oxide (e.g. approximately 0.35-3.5 g DHA/ EPA day(-1) dependant on energy intake and noting the importance of cofactors). Micro- and nanotechnologies are already engineering nano foods for human (and livestock) consumption that may eventually (without excessive consumption) prevent the current diet induced disease epidemic, especially in future generations, by preventing the causal mechanisms of disease. Greater knowledge about the causal mechanisms of disease awaits to be discovered, which could further enhance the human desire to increase longevity in optimum health (creating more problems and challenges for society).

Commentary: Barriers and Opportunities to Changing the Research Agenda to Support Precaution and Primary Prevention

Conceptual research to define the Precautionary Principle and its rôle in science, science policy, and public health is making substantial progress. In September 2001, participants at the International Summit on Science and the Precautionary Principle developed a vision for science to address the complexity of contemporary health risks in a way that could lead to more precautionary, preventive decisions under uncertainty. Its components include: (1) a more effective linkage between research on hazards and research on primary prevention; (2) increased use of interdisciplinary approaches including better integration of qualitative and quantitative data; (3) innovative methods for analyzing cumulative and interactive effects, populations and systems and vulnerable sub-populations; (4) systems for continuous monitoring to avoid unintended consequences of actions and to identify early warnings of risks; (5) more comprehensive techniques for analyzing and communicating hazards and uncertainties; and (6) a more dynamic interface between science and policy. This article addresses barriers and opportunities to the practical application of this vision for science. Scientists in many fields have recognized the need for innovative approaches and tools to address increasingly complex, uncertain risks of a global scale. While opportunities to apply precautionary concepts in the research agenda exist, public health scientists must be cognizant of current and emerging barriers in the research agenda that balance the research focus on characterizing proximate causal mechanisms of disease, to the detriment of research and policy to support primary prevention.

Genetics of rheumatoid arthritis: is there a scientific explanation for the human leukocyte antigen association?

Human leukocyte antigen genes associated with rheumatoid arthritis are commonly found in the unaffected population, implying that causal mechanisms of disease involve interactions between these genes and other factors. A variety of approaches-genetic, structural, and immunologic-are used to explore possible molecular interactions that may contribute to understanding the basis for this disease association. The specific relation between human leukocyte antigen-DR4 alleles and rheumatoid arthritis remains one of the strongest and most thoroughly studied examples of human leukocyte antigen risk genes among human autoimmune disorders.