Jacques Fair

Bio: Jacques Fair is an academic researcher from St. Joseph's Hospital and Medical Center. The author has contributed to research in topics: Genome-wide association study & International HapMap Project. The author has an hindex of 2, co-authored 2 publications receiving 4 citations.

Genetics, its role in preventing the pandemic of coronary artery disease.

Abstract: Epidemiologists have claimed for decades that about 50% of predisposition for coronary artery disease (CAD) is genetic. Advances in technology made possible the discovery of hundreds of genetic risk variants predisposing to CAD. Multiple clinical trials have shown that cardiac events can be prevented by drugs to lower plasma low-density lipoprotein cholesterol (LDL-C). A major barrier to primary prevention is the lack of markers to identify those individuals at risk prior to the development of symptoms of the disease. Conventional risk factors are age-dependent, occurring mostly in the sixth or seventh decade, which is less than desirable for early primary prevention. A polygenic risk score, derived from the number of genetic risk variants predisposing to CAD inherited by an individual, has been evaluated in over 1 million individuals. The risk for CAD is stratified into high, intermediate, and low. Polygenic risk scores derived from retrospective genotyping of several clinical trials evaluating the effect of statin therapy or PCSK9 inhibitors show the genetic risk is reduced 40%-50% by decreasing plasma LDL-C. Prospective randomized placebo-controlled clinical trials document a 40%-50% reduction in cardiac events in individuals at high genetic risk associated with favorable lifestyle changes and increased physical activity. The polygenic risk score is not age-dependent and remains the same throughout life. Thus, the GRS is superior to conventional risk factors in identifying asymptomatic individuals at risk for CAD early in life for primary prevention. These results indicate clinical embracement of the GRS in primary prevention would be a paradigm shift in the treatment of the number one killer, CAD.

Clinical Application of Genetic Prediction in the Management of CAD

Abstract: Sequencing of the human genome followed by the HapMap project made possible the unbiased genome-wide association studies that led to the discovery of hundreds of genetic risk variants predisposing to CAD. The total genetic risk for CAD can be expressed in a single number based on the number of variants inherited. A GRS derived from genotyping with microarrays containing these risk variants has been evaluated in over 1 million individuals. Risk stratification for CAD based on the GRS was shown to be superior to conventional risk factors. Placebo-controlled clinical trials showed individuals with high genetic risk had a 40-50% reduction in cardiac events with a favorable lifestyle, and cholesterol-lowering drugs. The risk of CAD based on conventional risk factors such as hypertension are age-dependent, occurring primarily in the sixth or seventh decade which is too late for primary prevention. The GRS is independent of age and can be determined at birth if needed. Incorporation of the GRS into clinical practice would transform the primary prevention of CAD, the number one killer.

Uncovering Carpal Tunnel Syndrome Risk through Genetics: A Path to Early Prevention

Abstract: Carpal Tunnel Syndrome (CTS) is a common disorder that affects the hand, caused by compression of the median nerve at the wrist. Despite its prevalence and impact on individuals, the underlying biological mechanisms of CTS remain poorly understood. Moreover, there is a lack of strategies for identifying individuals at risk for CTS in order to prevent its development. In recent years, the use of genome sequencing, genetic analysis, and genome-wide association studies (GWAS) has revealed several genetic factors that may be associated with CTS, including specific genes and gene loci. A Genetic Risk Score (GRS) that incorporates these findings could potentially be used to predict the likelihood of developing CTS and enable earlier identification and prevention of the condition. GWAS has already demonstrated a correlation between CTS severity and a GRS composed of 13 susceptibility loci. Further research on the development of a more comprehensive GRS for CTS could potentially reduce the overall burden of this disorder.

Genetic Risk Stratification and the Primary Prevention of Coronary Artery Disease

Abstract: Coronary artery disease (CAD) is the number cause of death in the world. It is estimated that 50% of Americans will experience a cardiac event in their lifetime. The underlying pathology leading to coronary artery disease and its clinical manifestations, such as angina, myocardial infarction, and sudden death is coronary atherosclerosis. While the disease is not usually manifested clinically until the sixth or seventh decade, the underlying pathology is initiated as early as the second or third decade. Numerous randomized clinical trials have shown cardiac morbidity and mortality can be prevented by lowering the risk of known conventional risk factors for CAD such as decreasing plasma cholesterol or controlling hypertension. Secondary prevention of these conventional risk factors has been very effective; however, primary prevention has been shown to be even more effective. A major barrier to primary prevention is the lack of markers to detect among young asymptomatic individuals those at risk for CAD. The conventional risk factors are often not present until the sixth or seventh decade which could be late for primary prevention. Genetic predisposition accounts for 50% of the risk for CAD. Recently over 200 genetic risk variants predisposing to CAD have been discovered. Based on these variants, one can express the genetic risk for CAD in a single number referred to as the Polygenic Risk Score (PRS). The PRS has been evaluated in over one million individuals and shown that those with high genetic risk have the highest incidence of heart disease and can be reduced by 40-50%, utilizing drugs (statins and PCSK9 inhibitors) or lifestyle changes (favorable diet and increased exercise). The genetic risk for CAD is determined at conception and thus can be predicted anytime from birth onward. The PRS detection of young asymptomatic individuals based on the PRS enables one to implement early primary prevention. Adoption of the PRS to risk stratify for CAD could represent a paradigm shift in the prevention of this pandemic disease.

Genetics, its role in preventing the pandemic of coronary artery disease.

Abstract: Epidemiologists have claimed for decades that about 50% of predisposition for coronary artery disease (CAD) is genetic. Advances in technology made possible the discovery of hundreds of genetic risk variants predisposing to CAD. Multiple clinical trials have shown that cardiac events can be prevented by drugs to lower plasma low-density lipoprotein cholesterol (LDL-C). A major barrier to primary prevention is the lack of markers to identify those individuals at risk prior to the development of symptoms of the disease. Conventional risk factors are age-dependent, occurring mostly in the sixth or seventh decade, which is less than desirable for early primary prevention. A polygenic risk score, derived from the number of genetic risk variants predisposing to CAD inherited by an individual, has been evaluated in over 1 million individuals. The risk for CAD is stratified into high, intermediate, and low. Polygenic risk scores derived from retrospective genotyping of several clinical trials evaluating the effect of statin therapy or PCSK9 inhibitors show the genetic risk is reduced 40%-50% by decreasing plasma LDL-C. Prospective randomized placebo-controlled clinical trials document a 40%-50% reduction in cardiac events in individuals at high genetic risk associated with favorable lifestyle changes and increased physical activity. The polygenic risk score is not age-dependent and remains the same throughout life. Thus, the GRS is superior to conventional risk factors in identifying asymptomatic individuals at risk for CAD early in life for primary prevention. These results indicate clinical embracement of the GRS in primary prevention would be a paradigm shift in the treatment of the number one killer, CAD.

Integrating a Polygenic Risk Score for Coronary Artery Disease as a Risk Enhancing Factor in the Pooled Cohort Equation is Cost-effective in a US Health System

Abstract: ImportanceThe pooled cohort equation (PCE) is used to determine an individuals 10-year risk (low, borderline, intermediate, or high) of atherosclerotic cardiovascular disease (ASCVD) but it fails to identify all individuals at high risk. Those with borderline or intermediate risk require additional risk enhancing factors to guide preventive therapy decisions. Including a polygenic risk score (PRS) for coronary artery disease as a risk enhancing factor improves precision in determining the risk of ASCVD and informs decisions for prevention therapy. ObjectiveTo assess the cost-effectiveness of integrating PRS for coronary artery disease with the PCE to determine an individuals 10-year risk for ASCVD compared to the PCE-alone. Design, setting, and populationA Markov model was developed on a hypothetical cohort of 40-year-old individuals in the US with borderline or intermediate PCE 10-year risk for ASCVD who fall in the top quintile of the PRS distribution and are not on preventive therapy (e.g., statins). Model transition probabilities and economic costs came from existing literature with costs reflecting a payer perspective and inflation-adjusted to 2019 US$. InterventionsThe modeled strategies were: (1) the PCE-alone and (2) the PCE with PRS for coronary artery disease as a risk enhancing factor. Analyses were performed at 5 year, 10 year, and lifetime time horizons. Main outcomes and measuresQuality-adjusted life-years (QALYs) gained, acute coronary syndromes and ischemic stroke events prevented, mean costs, and incremental cost-effectiveness ratios (ICER) were measured. One-way, two-way, and probabilistic sensitivity analyses were used to assess uncertainty in parameter estimates. Future costs and health benefits were discounted at an annual rate of 3%. ResultsCompared to the PCE-alone, PCE+PRS was cost-saving, effective and cost-effective (dominant). A health system would save more than $500, $2,300, and $9,000 per additional high-risk individual identified using PCE+PRS and prevent 27, 47 and 83 acute CAD or ischemic stroke events per 1,000 persons in 5 year, 10 year, and lifetime time horizons, respectively. Conclusions and relevanceImplementing PRS as a risk enhancing factor for CAD among individuals with borderline or intermediate 10-year risk reclassifies individuals as high-risk who would otherwise remain unidentified, prevents future acute CAD and ischemic stroke events, and both saves money and is cost-effective for health systems. Key PointsO_ST_ABSQuestionC_ST_ABSIs it cost-effective to use polygenic risk scores (PRS) for coronary artery disease (CAD) among individuals with borderline or intermediate risk of atherosclerotic cardiovascular disease (ASCVD) to inform preventive therapy decisions? FindingsWe modeled a hypothetical cohort of individuals with borderline or intermediate risk of ASCVD who fall in the top quintile of the CAD-PRS distribution but not on preventive therapy. Integrating CAD-PRS in the pooled cohort equation improved quality-adjusted life-years, saved money and was cost-effective. MeaningIntegrating PRS as an enhancing factor in the pooled cohort equation risk assessment for ASCVD used in current clinical practice was cost-effective.

Genetic risk stratification, pivotal to precluding the CAD pandemic

Abstract: © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Association of APOE (rs429358 and rs7412) and PON1 (Q192R and L55M) Variants with Myocardial Infarction in the Pashtun Ethnic Population of Khyber Pakhtunkhwa, Pakistan

Abstract: Coronary Artery Diseases (CAD) remains the top among Non-communicable Diseases (NCDs). Variations in Apolipoprotein E (APOE) and Paroxonase 1 (PON1) have been associated with Myocardial Infarction (MI) in several populations. However, despite the high prevalence of CAD, no such study has been reported in the Pashtun ethnic population of Pakistan. We have conducted a two-stage (i.e., screening and validation) case-control study in which 200 cases and 100 control subjects have been recruited. In the first stage, Whole Exome Sequencing (WES) was used to screen for pathogenic variants of Myocardial Infarction (MI). In the second stage, selected variants of both APOE and PON1 genes (rs7412, rs429358, rs854560, and rs662) were analyzed through MassARRAY genotyping. Risk Allele Frequencies (RAFs) distribution and association of the selected SNPs with MI were determined using the Chi-square test and logistic regression analysis. WES identified a total of 12 sequence variants in APOE and 16 in PON1. Genotyping results revealed that APOE variant rs429358 (ɛ4 allele and ɛ3/ɛ4 genotype) showed significant association in MI patients (OR = 2.11, p value = 0.03; 95% CI = 1.25–2.43); whereas no significant difference (p˃ 0.05) was observed for rs7412. Similarly, the R allele of PON1 Q192R (rs662) was significantly associated with cases (OR = 1.353, p value = 0.048; 95% CI = 0.959–1.91), with particular mention of RR genotype (OR = 1.523, p value = 0.006; 95% CI = 1.087–2.132). Multiple logistic regression analysis showed that rs429358 (C allele) and rs662 (R allele) have a significantly higher risk of MI after adjustment for the conventional risk factors. Our study findings suggested that the rs429358 variant of APOE and PON1 Q192R are associated with MI susceptibility in the Pashtun ethnic population of Pakistan.