Publications by authors named "Adam Butterworth"

Purpose: Bangladesh has experienced a rapid epidemiological transition from communicable to non-communicable diseases (NCDs) in recent decades. There is, however, limited evidence about multidimensional determinants of NCDs in this population. The BangladEsh Longitudinal Investigation of Emerging Vascular and nonvascular Events (BELIEVE) study is a household-based prospective cohort study established to investigate biological, behavioural, environmental and broader determinants of NCDs.

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Chronological age is a major risk factor for numerous diseases. However, chronological age does not capture the complex biological aging process. the difference between the chronological age and biologically driven aging could be more informative in reflecting health status.

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Background: Endothelial dysfunction and inflammation have been implicated in the pathophysiology of cerebral small vessel disease (SVD). However, whether they are causal, and if so which components of the pathways represent potential treatment targets, remains uncertain.

Methods: Two-sample Mendelian randomization (MR) was used to test the association between the circulating abundance of 996 proteins involved in endothelial dysfunction and inflammation and SVD.

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Background: South Asians may be particularly susceptible to premature myocardial infarction (MI) owing both to conventional cardiovascular risk factors and practices distinctive to South Asia. Identifying modifiable risk factors for MI in these populations could inform prevention strategies. We have, therefore, studied conventional risk factors and other characteristics in relation to occurrence of first MI in Bangladesh.

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Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported.

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Background: Myocardial infarction (MI) is a complex disease caused by both lifestyle and genetic factors. This study aims to investigate the predictive value of genetic risk, in addition to traditional cardiovascular risk factors, for recurrent events following early-onset MI.

Methods: The Italian Genetic Study of Early-Onset Myocardial Infarction is a cohort study enrolling patients with MI before 45 years.

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Understanding the cause of coronary heart diseases relies on the analysis of data from a range of techniques on an epidemiological scale. Lipidomics, the identification and quantification of lipid species in a system, is an omic approach increasingly used in epidemiology. The altered concentration of lipids in plasma is one of the recognised risk factors for these diseases.

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The G haplotype is a group of co-inherited single nucleotide variants in the F5 gene that reduce venous thromboembolism (VTE) risk. Although 7% of the population is homozygous for the G haplotype (F5-G/G), the underlying mechanism of VTE protection is poorly understood. Using RNA sequencing data from 4651 blood donors in the INTERVAL study, we detected a rare excision event at the factor V (FV)-short splice sites in 5% of F5-G/Gs carriers as compared with 2.

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Article Synopsis
  • The study investigated the links between saturated and unsaturated fatty acids and cardiovascular disease (CVD), focusing on conditions like coronary heart disease (CHD) and stroke in a large group of participants.
  • Results showed that higher levels of saturated fatty acids were linked to increased CVD risks, with specific subtypes having varying effects on CHD and stroke.
  • Conversely, higher concentrations of certain polyunsaturated fatty acids (both n-3 and n-6 types) were associated with lower risks of CHD and stroke, suggesting dietary fats play a significant role in cardiovascular health.
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Combining information from multiple GWASs for a disease and its risk factors has proven a powerful approach for development of polygenic risk scores (PRSs). This may be particularly useful for type 2 diabetes (T2D), a highly polygenic and heterogeneous disease where the additional predictive value of a PRS is unclear. Here, we use a meta-scoring approach to develop a metaPRS for T2D that incorporated genome-wide associations from both European and non-European genetic ancestries and T2D risk factors.

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Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioural traits and the disease aetiology of neuropsychiatric disorders. Here the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,000 individuals for 184 neuro-related proteins in human plasma. The analysis identified 125 cis-regulatory protein quantitative trait loci (cis-pQTL) and 164 trans-pQTL.

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Myocardial infarction is a leading cause of death globally but is notoriously difficult to predict. We aimed to identify biomarkers of an imminent first myocardial infarction and design relevant prediction models. Here, we constructed a new case-cohort consortium of 2,018 persons without prior cardiovascular disease from six European cohorts, among whom 420 developed a first myocardial infarction within 6 months after the baseline blood draw.

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Background: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited.

Methods: In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry.

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Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. Despite its known pathological consequences in specific rare diseases, we have a limited understanding of its wider prevalence and mechanisms in humans. To address this, we analyzed gene misexpression in 4,568 whole-blood bulk RNA sequencing samples from INTERVAL study blood donors.

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Article Synopsis
  • Restless legs syndrome (RLS) affects nearly 10% of older adults, but many face delays in diagnosis and treatment.
  • A large-scale genetic study identified 164 risk loci for RLS, enhancing our understanding of its genetic basis and showing similarities in genetic predispositions between sexes.
  • Findings suggest potential drug targets, a relationship between RLS and diabetes, and highlight the effectiveness of machine learning in predicting RLS risk using genetic and other data.
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  • * The research showed that individuals with high polygenic risk scores have significantly higher blood pressure (almost 17 mmHg more) and over seven times the risk of developing hypertension compared to those with low scores.
  • * Incorporating these genetic risk scores into hypertension prediction models improved their accuracy, and excitingly, similar genetic associations were found in a large African-American sample, underscoring the potential of these findings for precision health initiatives.
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  • * Our research uncovered 40 proteins linked to cancer risks, including PLAUR for breast cancer and CTRB1 for pancreatic cancer, while also noting possible negative side effects like hypertension from altering these proteins.
  • * We found 18 proteins that are associated with cancer risk and linked to existing drugs, plus 15 proteins not yet being studied for clinical use, enhancing our understanding of cancer causes and the implications of targeting these proteins for prevention.
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Unlabelled: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk.

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  • Epidemiological studies suggest that the link between dietary protein intake and cardiovascular disease (CVD) might depend on whether the protein is plant- or animal-based, but previous research has been inconclusive.
  • The analysis involved over 16,000 CVD cases and aimed to assess how different protein sources impact the risk of CVD, ischemic heart disease (IHD), and stroke using various statistical methods.
  • Findings revealed that plant-derived protein intake was associated with a lower incidence of total stroke in never smokers, especially when replacing red and processed meat proteins, but overall, neither protein source showed a significant association with CVD, IHD, or stroke risk.
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  • - This study conducted a genome-wide association analysis on metabolic traits in over 136,000 participants, revealing over 400 genetic loci that influence human metabolism and complex diseases.
  • - Researchers used advanced techniques like nuclear magnetic resonance spectroscopy to link specific genetic variants with how they affect lipoprotein metabolism and other metabolic processes.
  • - The findings highlight the genetic connections between metabolism and conditions such as hypertension, providing valuable data for further research on metabolic-related diseases.
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  • Type 2 diabetes (T2D) is a complex disease influenced by various genetic factors and molecular mechanisms that vary by cell type and ancestry.
  • In a large study involving over 2.5 million individuals, researchers identified 1,289 significant genetic associations linked to T2D, including 145 new loci not previously reported.
  • The study categorized T2D signals into eight distinct clusters based on their connections to cardiometabolic traits and showed that these genetic profiles are linked to vascular complications, emphasizing the role of obesity-related processes across different ancestry groups.
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Background: Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer's disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets.

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  • Hypertensive disorders of pregnancy (HDPs), such as gestational hypertension and preeclampsia, significantly increase risks of maternal health issues and long-term cardiovascular disease across the globe.
  • The study aimed to link specific proteins in the blood to HDPs using genetic data, employing two-sample mendelian randomization for analysis.
  • Findings involved a broad dataset, including over 393,000 women for gestational hypertension and nearly 607,000 for preeclampsia, uncovering associations between 90 candidate cardiovascular-related proteins and these hypertensive disorders.
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Large-scale genome-wide association studies conducted over the last decade have uncovered numerous genetic variants associated with cardiometabolic traits and risk factors. These discoveries have enabled the Mendelian randomization (MR) design, which uses genetic variation as a natural experiment to improve causal inferences from observational data. By analogy with the random assignment of treatment in randomized controlled trials, the random segregation of genetic alleles when DNA is transmitted from parents to offspring at gamete formation is expected to reduce confounding in genetic associations.

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