Beyond genome wide discovery : an exploration of novel genetic variants for coronary heart disease

Recent developments spurred on by the Human Genome Project have for the first time permitted genome wide association studies leading to identification of multiple novel variants for complex diseases. This thesis consists of a series of studies exploring recent genetic findings for coronary heart disease (CHD) within the broader context of the promises of the genomic era that new findings would ultimately lead to 1) Identification of new disease mechanisms 2) Permit genotype based risk prediction and 3) Promote development of novel and targeted therapies based on genotype. We sought to address these questions, using the Emory Genebank, a collection of angiographically phenotyped subjects with stored blood samples and long-term follow up. We first refined the phenotype for CHD to help understand underlying mechanism and demonstrated differential associations between 8 novel risk variants including 9p21, and sub-phenotypes of CHD and thereby proposed differing mechanisms of risk for these loci. With two non-CHD cohorts we then demonstrated further association between one particular risk variant at 6p24 and the intermediate phenotype of arterial elasticity and related this to a potential novel mechanism of risk. Despite significant association with first events in population cohorts, we showed that these risk variants including 9p21 have limited value in secondary risk prediction, failing to demonstrate any association with prospective events in our cohort as single markers or when combined into a cumulative genetic risk score. Finally in subjects carrying leukotriene pathway CHD risk variants, we administered an oral leukotriene synthesis inhibitor and after just 4 week of therapy observed significant improvement in their endothelial function. In summary, these studies demonstrate the value of refining the phenotype to understand potential mechanisms, the complexities of genetic risk prediction and the feasibility and benefit of targeting therapy based on risk genotype.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Beyond genome wide discovery: an exploration of novel genetic variants for coronary heart disease

Recent developments spurred on by the Human Genome Project have for the first time permitted genome wide association studies leading to identification of multiple novel variants for complex diseases. This thesis consists of a series of studies exploring recent genetic findings for coronary heart disease (CHD) within the broader context of the promises of the genomic era that new findings would ultimately lead to 1) Identification of new disease mechanisms 2) Permit genotype based risk prediction and 3) Promote development of novel and targeted therapies based on genotype. We sought to address these questions, using the Emory Genebank, a collection of angiographically phenotyped subjects with stored blood samples and long-term follow up. We first refined the phenotype for CHD to help understand underlying mechanism and demonstrated differential associations between 8 novel risk variants including 9p21, and sub-phenotypes of CHD and thereby proposed differing mechanisms of risk for these loci. With two non-CHD cohorts we then demonstrated further association between one particular risk variant at 6p24 and the intermediate phenotype of arterial elasticity and related this to a potential novel mechanism of risk. Despite significant association with first events in population cohorts, we showed that these risk variants including 9p21 have limited value in secondary risk prediction, failing to demonstrate any association with prospective events in our cohort as single markers or when combined into a cumulative genetic risk score. Finally in subjects carrying leukotriene pathway CHD risk variants, we administered an oral leukotriene synthesis inhibitor and after just 4 week of therapy observed significant improvement in their endothelial function. In summary, these studies demonstrate the value of refining the phenotype to understand potential mechanisms, the complexities of genetic risk prediction and the feasibility and benefit of targeting therapy based on risk genotype

The Impact of Long-Term Conditions and Comorbidity Patterns on COVID-19 Infection and Hospitalisation: A Cohort Study

INTRODUCTION: Older adults are more vulnerable to COVID-19 infections; however, little is known about which comorbidity patterns are related to a higher risk of COVID-19 infection. This study investigated the role of long-term conditions or comorbidity patterns on COVID-19 infection and related hospitalisations. METHODS: This study included 4,428 individuals from Waves 8 (2016-2017) and 9 (2018-2019) of the English Longitudinal Study of Ageing (ELSA) who also participated in the ELSA COVID-19 Substudy in 2020. Comorbidity patterns were identified using an agglomerative hierarchical clustering method. The relationships between comorbidity patterns or long-term conditions and COVID-19-related outcomes were examined using multivariable logistic regression. RESULTS: Among a representative sample of community-dwelling older adults in England, those with cardiovascular disease (CVD) and complex comorbidities had an almost double risk of COVID-19 infection (OR = 1.87, 95% CI = 1.42-2.46) but not of COVID-19-related hospitalisation. A similar pattern was observed for the heterogeneous comorbidities cluster (OR = 1.56, 95% CI = 1.24-1.96). The individual investigations of long-term conditions with COVID-19 infection highlighted primary associations with CVD (OR = 1.46, 95% CI = 1.23-1.74), lung diseases (OR = 1.40, 95% CI = 1.17-1.69), psychiatric conditions (OR = 1.40, 95% CI = 1.16-1.68), retinopathy/eye diseases (OR = 1.39, 95% CI = 1.18-1.64), and arthritis (OR = 1.27, 95% CI = 1.09-1.48). In contrast, metabolic disorders and diagnosed diabetes were not associated with any COVID-19 outcomes. CONCLUSION: This study provides novel insights into the comorbidity patterns that are more vulnerable to COVID-19 infections and hospitalisations, highlighting the vulnerability of those with CVD and other complex comorbidities. These findings facilitate crucial new evidence that should be considered for appropriate screening measures and tailored interventions for older adults in the ongoing global outbreak

MicroRNA Expression Profile in CAD Patients and the Impact of ACEI/ARB

Coronary artery disease (CAD) is the largest killer of males and females in the United States. There is a need to develop innovative diagnostic markers for this disease. MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in important cellular processes, and we hypothesized that the miRNA expression profile would be altered in whole blood samples of patients with CAD. We performed a microarray analysis on RNA from the blood of 5 male subjects with CAD and 5 healthy subjects (mean age 53 years). Subsequently, we performed qRT-PCR analysis of miRNA expression in whole blood of another 10 patients with CAD and 15 healthy subjects. We identified 11 miRNAs that were significantly downregulated in CAD subjects (P < .05). Furthermore, we found an association between ACEI/ARB use and downregulation of several miRNAs that was independent of the presence of significant CAD. In conclusion, we have identified a distinct miRNA signature in whole blood that discriminates CAD patients from healthy subjects. Importantly, medication use may significantly alter miRNA expression. These findings may have significant implications for identifying and managing individuals that either have CAD or are at risk of developing the disease

Elevated plasma triglyceride concentration and risk of adverse clinical outcomes in 1.5 million people: a CALIBER linked electronic health record study

BACKGROUND: Assessing the spectrum of disease risk associated with hypertriglyceridemia is needed to inform potential benefits from emerging triglyceride lowering treatments. We sought to examine the associations between a full range of plasma triglyceride concentration with five clinical outcomes. METHODS: We used linked data from primary and secondary care for 15 M people, to explore the association between triglyceride concentration and risk of acute pancreatitis, chronic pancreatitis, new onset diabetes, myocardial infarction and all-cause mortality, over a median of 6-7 years follow up. RESULTS: Triglyceride concentration was available for 1,530,411 individuals (mean age 56·6 ± 15·6 years, 51·4% female), with a median of 1·3 mmol/L (IQR: 0.9.to 1.9). Severe hypertriglyceridemia, defined as > 10 mmol/L, was identified in 3289 (0·21%) individuals including 620 with > 20 mmol/L. In multivariable analyses, a triglyceride concentration > 20 mmol/L was associated with very high risk for acute pancreatitis (Hazard ratio (HR) 13·55 (95% CI 9·15-20·06)); chronic pancreatitis (HR 25·19 (14·91-42·55)); and high risk for diabetes (HR 5·28 (4·51-6·18)) and all-cause mortality (HR 3·62 (2·82-4·65)) when compared to the reference category of ≤ 1·7 mmol/L. An association with myocardial infarction, however, was only observed for more moderate hypertriglyceridaemia between 1.7 and 10 mmol/L. We found a risk interaction with age, with higher risks for all outcomes including mortality among those ≤ 40 years compared to > 40 years. CONCLUSIONS: We highlight an exponential association between severe hypertriglyceridaemia and risk of incident acute and chronic pancreatitis, new diabetes, and mortality, especially at younger ages, but not for myocardial infarction for which only moderate hypertriglyceridemia conferred risk

Galvanic Vestibular Stimulation Induces a Spatial Bias in Whole-body Position Estimates

Letter to the Edito

Modelling a two-stage adult population screen for autosomal dominant familial hypercholesterolaemia: cross-sectional analysis within the UK Biobank

Background: Most people with autosomal dominant familial hypercholesterolaemia (FH) remain undetected, which represents a missed opportunity for coronary heart disease prevention. Objective: To evaluate the performance of two-stage adult population screening for FH. Design: Using data from UK Biobank, we estimated the screening performance of different low-density lipoprotein cholesterol (LDL-C) cut-offs (stage 1) to select adults for DNA sequencing (stage 2) to identify individuals with FH-causing variants inLDLR, APOB, PCSK9andAPOE. We estimated the number of additional FH cases detected by cascade testing of first-degree relatives of index cases and compared the overall approach with screening in childhood. Setting: UK Biobank. Participants: 140 439 unrelated participants of European ancestry from UK Biobank with information on circulating LDL-C concentration and exome sequence. Main outcome measures: For different LDL-C cut-offs, we estimated the detection and false-positive rate, the proportion of individuals who would be referred for DNA sequencing (stage 1 screen positive rate), and the number of FH cases identified by population screening followed by cascade testing. Results: We identified 488 individuals with an FH-causing variant and 139 951 without (prevalence 1 in 288). An LDL-C cut-off of &gt;4.8 mmol/L had a stage 1 detection rate (sensitivity) of 40% (95% CI 36 to 44%) for a false-positive rate of 10% (95% CI 10 to 11%). Detection rate increased at lower LDL-C cut-offs but at the expense of higher false-positive and screen positive rates, and vice versa. Two-stage screening of 100 000 adults using an LDL-C cut-off of 4.8 mmol/L would generate 10 398 stage 1 screen positives for sequencing, detect 138 FH cases and miss 209. Up to 207 additional cases could be detected throughtwo-generationcascade testing of first-degree relatives. By comparison, based on previously published data, childhood screening followed by cascade testing was estimated to detect nearly three times as many affected individuals for around half the sequencing burden. Conclusions: Two-stage adult population screening for FH could help achieve the 25% FH case detection target set in the National Health Service Long Term Plan, but less efficiently than childhood screening and with a greater sequencing requirement