Systems epidemiology of metabolomics measures reveals new relationships between lipoproteins and other small molecules

Supplementary information included online at https://link.springer.com/article/10.1007/s11306-021-01856-6.Copyright © 2022 The Author. Introduction The study of lipoprotein metabolism at the population level can provide valuable information for the organisation of lipoprotein related processes in the body. To use this information towards interventional hypotheses generation and testing, we need to be able to identify the mechanistic connections among the large number of observed correlations between the measured components of the system. Objectives To use population level metabolomics information to gain insight on their biochemical networks and metabolism. Methods Genetic and metabolomics information for 230 metabolic measures, predominately lipoprotein related, from a targeted nuclear magnetic resonance approach, in two samples of an established European cohort, totalling more than 9400 individuals analysed using phenotypic and genetic correlations, as well as Mendelian Randomisation. Results More than 20,500 phenotypic correlations were identified in the data, with almost 2000 also showing evidence of strong genetic correlation. Mendelian randomisation, provided evidence for a causal effect between 9496 pairs of metabolic measures, mainly between lipoprotein traits. The results provide insights on the organisation of lipoproteins in three distinct classes, the heterogeneity between HDL particles, and the association, or lack of, between CLA, glycolysis markers, such as glucose and citrate, and glycoproteins with lipids subfractions. Two examples for the use of the approach in systems biology of lipoproteins are presented. Conclusions Genetic variation can be used to infer the underlying mechanisms for the associations between lipoproteins for hypothesis generation and confirmation, and, together with biological information, to map complex biological processes.BHF-Turing Cardiovascular Data Science Award (BHF-Turing-19/2/1008)

How close are we to implementing a genetic risk score for coronary heart disease?

Introduction: Genome-wide association meta-analysis have now identified more than 150 loci where common variants (SNPs) are significantly associated with coronary heart disease (CHD) and CHD end points. Areas covered: The authors review publications from their own laboratory and published recently where identified CHD risk SNPs are used in combination, and ‘scaled’ by their effect size, to create a ‘weighted’ Genetic risk Score (GRS), which, in combination with an individual’s classical CHD risk factors, can be used to identify those at overall low, intermediate and high future risk. Those at highest risk can be offered life-style and therapeutic options to reduce their risk and those at intermediate levels can be monitored. Expert commentary: The authors discuss the selection of the best variants to be included in the GRS, and the potential utility of such scores in different clinical settings. The limitations of the current data sets and the way forward in the next 5 years is discussed

Alcohol causes an increased risk of head and neck but not breast cancer in individuals from the UK Biobank study: A Mendelian randomisation analysis

This research has been conducted using the UK Biobank Resource under project 44566 (https://www.ukbiobank.ac.uk/2018/12/genetic-and-non-genetic-factors-able-to-predict-and-modify-the-risk-of-different-types-of-cancer/). All bona fide researchers can apply to use the UK Biobank resource for health related research that is in the public interest.Copyright © The Author(s)/Funder. Alcohol intake and the risk of various types of cancers have been previously correlated. Correlation though does not always mean that a causal relationship between the two is present. Excessive alcohol consumption is also correlated with other lifestyle factors and behaviours, such as smoking and increased adiposity, that also affect the risk of cancer and make the identification and estimation of the causal effect of alcohol on cancer difficult. Here, using individual level data for 322,193 individuals from the UK Biobank, we report the observational and causal effects of alcohol consumption on types of cancer previously suggested as correlated to alcohol. Alcohol was observationally associated with cancers of the lower digestive system, head and neck and breast cancer. No associations were observed when we considered those keeping alcohol consumption below the recommended threshold of 14 units/week. When Mendelian randomisation was used to assess the causal effect of alcohol on cancer, we found that increasing alcohol consumption, especially above the recommended level, was causal to head and neck cancers but not breast cancer. Our results where replicated using a two sample MR method and data from the much larger COGS genome wide analysis of breast cancer. We conclude that alcohol is causally related to head and neck cancers, especially cancer of larynx, but the observed association with breast cancer are likely due to confounding. The suggested threshold of 14 units/week appears suitable to manage the risk of cancer due to alcohol.PhD studentship from the College of Health and Life Sciences, Brunel University London

Variation at the Klotho gene locus does not affect cognitive function in up to 335,074 British Caucasians in the UK Biobank

Version 2 issued 19 November 2019.Copyright © The Author(s)/Funder. The proportion of older adults in Western populations is increasing and there is, therefore, a need to define factors affecting maintenance of physical and cognitive health in old age. Variations in the Klotho (KL) gene, and specifically the KL-VS haplotype, have been identified by several authors as potentially influencing cognitive function and decline. We have attempted to verify the reported associations between KL variants, including the KL-VS haplotype, and cognitive function in up to 335,074 British Caucasian participants aged 40-79 years from the UK Biobank. We do not find evidence that KL-VS affects cognitive function or its decline with increasing age. We examined a further 244 KL variants and found that rs117650866 was associated with Prospective Memory, but could not replicate this in follow-up samples. In conclusion, there is insufficient evidence in the UK Biobank to support the concept that KL variants affect cognitive function or its rate of decline.Calico LLC (South San Francisco, California, United States)

Assessment of the clinical utility of adding common single nucleotide polymorphism genetic scores to classical risk factor algorithms in coronary heart disease risk prediction in UK men

UK Medical Research Council; British Heart Foundation

Using genetics to investigate the association between lanosterol and cataract

Data availability statement: The data analyzed in this study is subject to the following licenses/restrictions: UK Biobank data are available to all bona fide researchers for all types of health-related research which is in the public interest. Requests to access these datasets should be directed to https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access.Acknowledgements: The authors of the paper would like to thank the UKBB staff and participants who provide and facilitate access to their dataSupplementary material: The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgene.2024.1231521/full#supplementary-material .Background: Cataract is one of the most prevalent causes of blindness worldwide. Whilst surgery is the primary treatment for cataracts, it is not always an available option, particularly in developing countries. Non-surgical methods of treatment would increase treatment availability for more patients. Several studies have investigated how topical application of oxysterols, such as lanosterol, may break down aggregated proteins and restore lens transparency. However, the results are conflicting and inconclusive. Aim: In this study, we focus on combining genetic evidence for associations between lanosterol related genetic variation and cataract to explore whether lanosterol is a potentially suitable drug treatment option. Method: Using data from 45,449 available cataract cases from the UK Biobank, with participant ages ranging from 40–69, we conducted a genetic association study (GWAS) to assess the risk of cataract. Cataract cases were defined using diagnostic and operation codes. We focused on genetic variants in the lanosterol synthase gene region. We also compared our results with previously published genetic associations of phytosterol-to-lanosterol ratios. Finally, we performed a genetic risk score analysis to test the association between lanosterol within the cholesterol synthesis pathway and the risk of cataract. Results: No statistically significant single nucleotide polymorphisms (SNPs) associations with cataract were observed in the gene region of lanosterol synthase at a multiple testing adjusted significance threshold of p < 0.05/13. The comparison between cataract risk and genetic association of 8 phytosterol-to-lanosterol GWAS results also showed no evidence to support lanosterol’s protective properties for cataract risk. No statistically significant association was found between the lanosterol within the cholesterol synthesis pathway genetic risk score and cataract outcomes (OR = 1.002 p = 0.568). Conclusion: There was no evidence observed for genetic associations between lanosterol and cataract risk. Our results do not support lanosterol’s potential role in treating cataracts. Further research may be needed to address the effect of lanosterol on specific cataract subtypes

A systematic review of human evidence for the intergenerational effects of exposure to ionizing radiation

Supplemental material is available online at: https://www.tandfonline.com/doi/full/10.1080/09553002.2024.2306328#supplemental-material-section .Acknowledgements: The authors acknowledge Joanne Mcphie and Olwenn Martin for advising in the early stages of protocol development. The authors also thank Kirsty Lawrence and Ninoshka Barros for their support in elements of data extraction.Purpose: To provide a synthesis of the published evidence pertaining to the intergenerational health effects of parental preconceptional exposure to ionizing radiation in humans. Methods: The study populations are the descendants of those who were exposed to ionizing radiation prior to conception. A Boolean search identified publications for review in accordance with Office of Health Assessment and Translation guidelines. Initially, a risk of bias assessment was conducted for each published study and relevant data extracted. Information was organized into adverse health outcome groups and exposure situations. To make an assessment from the body of evidence within each group, an initial confidence rating was assigned, before factors including inconsistencies between studies, magnitude of effect, dose response and confounders were considered. From this, ‘an effect’, ‘no effect’ or whether the evidence remained ‘inadequate’ to determine either effect or no effect, was ascertained. This assessment was based primarily upon the author’s conclusions within that evidence-base and, by binomial probability testing of the direction of effect reported. Results: 2441 publications were identified for review which after screening was reduced to 127. For the majority of the adverse health groups, we find there to be inadequate evidence from which to determine whether the health effect was, or was not, associated with parental preconceptional radiation exposure. This was largely due to heterogeneity between individual study’s findings and conclusions within each group and, the limited number of studies within each group. We did observe one health grouping (congenital abnormalities) in occupationally exposed populations, where an increase in effect relative to their controls or large magnitude of effects, were reported, although it is noted that the authors of these studies interpreted their findings as most likely not to be associated with parental radiation exposure. Conclusions: We find there to be a lack of evidence to enable the formal assessment of radiation-related adverse effects in offspring of exposed humans. This is not the same as there being no clear evidence that effects may occur but does infer that if adverse health effects do arise in children of exposed parents, then these effects are small and difficult to reproducibly measure. Inconsistencies in designing studies are unavoidable, however we highlight the need for an element of standardization and, more sharing of primary datasets as part of open access initiatives, in order for future reviews to make reasonable conclusions. Overall, there is a need for future work to ensure comparable measures between studies where possible.This work was, in part, supported by the Nuclear Community Charity Fund (NCCF) through funds received by The Armed Forces Covenant Fund Trust under the Aged Veterans Fund Grant AVF16