Usefulness of genome-wide association studies to identify novel genetic variants underlying the plasma lipoprotein metabolism as risk factors for CAD

AbstractCoronary artery disease (CAD) is a major killer across the world. The pathogenesis of CAD is a construct of multiple predisposing elements, including environmental, health and genetic factors. Traditional risk factors for CAD include age, hypertension, diabetes, smoking, and dyslipidaemia. Optimizing the lipid levels to within the normal range significantly and drastically reduces the risk of coronary atherosclerosis. Genome-wide association studies (GWASs) promise to accurately identifying the variants that increase or decrease the risks of multiple and complex disorders. In this review, we shed light on and discuss the recent GWASs of lipoprotein genetics and how such studies have provided new pathways and pharmacological targets that might enable the control the pathological plasma cholesterol levels

The 9p21.3 risk locus for coronary artery disease: A 10-year search for its mechanism

يعتبرالموضع الخطر للقطعة رقم پ21.3 على كروموسوم رقم ٩ أول موضع يوصف لارتباطه بزيادة خطر الإصابة بالحوادث ذات الصلة بأمراض الشرايين التاجية، وعدد من الظواهر الأخرى. تحتوي هذه القطعة على ٥٩ من النوكليوتيدات المنفردة المتعددة الأشكال في منطقة، مع العديد من المحفزات بعيدة المدى، ومناطق طويلة من الحمض النووي الريبي بلا رموز، التي تؤثر على التعبير عن الجينات القريبة، والسيكلين المعتمد على الكيناز 2أ و2ب والمطلوبة للتحكم في تنظيم الانقسام المتسارع، وشيخوخة الخلايا العضلية الملساء الموجودة في الأوعية الدموية. أجريت عدة دراسات لتحديد الآلية الصحيحة بدقة لكيفية ممارسة هذا الموضع تأثيره المرضي لزيادة خطر الإصابة بالحوادث ذات الصلة بأمراض الشرايين التاجية. في هذه المراجعة، سوف نقوم بتسليط الضوء على أبرز ما تم إنجازه، ومعرفته فيما يتعلق بارتباط النمط الجيني-المظهري على الصعيدين الميكانيكي والمظهري. نظرا إلى الخطر العالي على السكان الذي يعزى للموضع الخطر للقطعة رقم پ21.3 على كروموسوم رقم ٩، وآلية المعرفة التي حصلنا عليها حتى الآن، بالإضافة إلى الجهود المستمرة، قد تساعد في تصميم جزيئات علاجية جديدة لتقليل خطر أمراض الشرايين التاجية والحوادث ذات الصلة

Interferon-γ Activates Expression of p15 and p16 Regardless of 9p21.3 Coronary Artery Disease Risk Genotype

ObjectivesBecause post-transcriptional mechanisms modulate levels of p16 (encoded by CDKN2A) and p15 (encoded by CDKN2B), we tested whether interferon-γ regulates the expression of these proteins and the effect of the 9p21 genotype.BackgroundThe mechanism whereby the common variant at chromosome 9p21.3 confers risk for coronary artery disease (CAD) remains uncertain. A recent report proposed that 9p21.3 confers differential activation of adjacent genes in response to interferon-γ, and reported that mRNA levels of CDKN2B are reduced in response to interferon-γ.MethodsHuman umbilical vein endothelial cells (HUVECs), aortic smooth muscle cells, HeLa cells, HEK293 cells, and 16 human lymphoblastoid cell lines, all genotyped for the 9p21.3 locus, were treated with interferon-γ and analyzed by immunoblot.ResultsIn all cells tested—except HUVECs where expression was not modulated by interferon-γ—regardless of 9p21.3 genotype, interferon-γ increased the expression of p16 and p15. Northern blot analysis confirmed that interferon-γ has little effect on mRNA levels of CDKN2A and CDKN2B.ConclusionsThe 9p21.3 risk genotype does not affect the activation of cyclin-dependent kinase inhibitors p15 and p16 by interferon-γ. Thus, another mechanism is likely to account for the CAD risk associated with this locus

Recurrent variants in OTOF are significant contributors to prelingual nonsydromic hearing loss in Saudi patients

Purpose Hearing loss is more prevalent in the Saudi Arabian population than in other populations; however, the full range of genetic etiologies in this population is unknown. We report the genetic findings from 33 Saudi hearing-loss probands of tribal ancestry, with predominantly prelingual severe to profound hearing loss. Methods: Testing was performed over the course of 2012–2016, and involved initial GJB2 sequence and GJB6-D13S1830 deletion screening, with negative cases being reflexed to a next-generation sequencing panel with 70, 71, or 87 hearing-loss genes. Results: A “positive” result was reached in 63% of probands, with two recurrent OTOF variants (p.Glu57* and p.Arg1792His) accountable for a third of all “positive” cases. The next most common cause was pathogenic variants in MYO7A and SLC26A4, each responsible for three “positive” cases. Interestingly, only one “positive” diagnosis had a DFNB1-related cause, due to a homozygous GJB6-D13S1830 deletion, and no sequence variants in GJB2 were detected. Conclusion: Our findings implicate OTOF as a potential major contributor to hearing loss in the Saudi population, while highlighting the low contribution of GJB2, thus offering important considerations for clinical testing strategies for Saudi patients. Further screening of Saudi patients is needed to characterize the genetic spectrum in this population

Plasma PCSK9 levels are elevated with acute myocardial infarction in two independent retrospective angiographic studies.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein (LDL) receptor. Mutations that block PCSK9 secretion reduce LDL-cholesterol and the incidence of myocardial infarction (MI). However, it remains unclear whether elevated plasma PCSK9 associates with coronary atherosclerosis (CAD) or more directly with rupture of the plaque causing MI. METHODS AND RESULTS: Plasma PCSK9 was measured by ELISA in 645 angiographically defined controls (<30% coronary stenosis) and 3,273 cases of CAD (>50% stenosis in a major coronary artery) from the Ottawa Heart Genomics Study. Because lipid lowering medications elevated plasma PCSK9, confounding association with disease, only individuals not taking a lipid lowering medication were considered (279 controls and 492 with CAD). Replication was sought in 357 controls and 465 with CAD from the Emory Cardiology Biobank study. PCSK9 levels were not associated with CAD in Ottawa, but were elevated with CAD in Emory. Plasma PCSK9 levels were elevated in 45 cases with acute MI (363.5±140.0 ng/ml) compared to 398 CAD cases without MI (302.0±91.3 ng/ml, p = 0.004) in Ottawa. This finding was replicated in the Emory study in 74 cases of acute MI (445.0±171.7 ng/ml) compared to 273 CAD cases without MI (369.9±139.1 ng/ml, p = 3.7×10(-4)). Since PCSK9 levels were similar in CAD patients with or without a prior (non-acute) MI, our finding suggests that plasma PCSK9 is elevated either immediately prior to or at the time of MI. CONCLUSION: Plasma PCSK9 levels are increased with acute MI

Mean PCSK9 levels do not differ with atherosclerosis burden.

<p>A Tukey's boxplot displaying PCSK9 levels in OHGS CAD controls (0 diseased vessels) and cases (1, 2 or 3 diseased vessels) in individuals not taking statins. The median is the line in the box, the 1^st and 3^rd quartiles are the upper and lower edges of the boxes and 1.5 interquartile range (IQR) is displayed as whiskers. Outliers have been removed. (0 vessel disease, N = 280; 1-vessel disease, N = 126; 2-vessel disease, N = 102; 3-vessel disease, N = 104).</p

Logistic regression analysis of the association of PCSK9 with acute MI in the OHGS cohort, stratified by statin use.

<p>Results given as beta for continuous variables and odds ratio (OR) for categorical variables. Abbreviations: BMI, body mass index; HTN, anithypertensive medication; Total-C, total-cholesterol; LDL-C, Low density lipoprotein-cholesterol; HDL-C, high density lipoprotein-cholesterol; TG, triglycerides. On statin, N = 1,568; Not taking statin, N = 287.</p><p>Logistic regression analysis of the association of PCSK9 with acute MI in the OHGS cohort, stratified by statin use.</p

Linear regression analysis of the relationships between explanatory variables and the level of PCSK9 in the OHGS.

<p>Abbreviations: BMI, body mass index; HTN, anithypertensive medication. N = 3,918.</p><p>Linear regression analysis of the relationships between explanatory variables and the level of PCSK9 in the OHGS.</p

Logistic regression analysis of the association of PCSK9 with CAD in the OHGS cohort, stratified by statin use.

<p>Results given as beta for continuous variables and odds ratio (OR) for categorical variables. Abbreviations: BMI, body mass index; HTN, anithypertensive medication; Total-C, total-cholesterol; LDL-C, Low density lipoprotein-cholesterol; HDL-C, high density lipoprotein-cholesterol; TG, triglycerides. On statin, N = 2,396; Not taking statin, N = 478. Samples with missing values for variables were excluded.</p><p>Logistic regression analysis of the association of PCSK9 with CAD in the OHGS cohort, stratified by statin use.</p

Logistic regression analysis of the association of PCSK9 with CAD in the EmCB sub-study.

<p>All EmCB samples were from non-diabetic individuals not taking a statin at the time of recruitment. Results given as beta for continuous variables and odds ratio (OR) for categorical variables. Abbreviations: BMI, body mass index; HTN, anithypertensive medication; Total-C, total-cholesterol; LDL-C, Low density lipoprotein-cholesterol; HDL-C, high density lipoprotein-cholesterol; TG, triglycerides. N = 677.</p><p>Logistic regression analysis of the association of PCSK9 with CAD in the EmCB sub-study.</p