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

Functional analysis of germline <em>VANGL2</em> variants using rescue assays of <em>vangl2</em> knockout zebrafish

\ua9 The Author(s) 2023. Published by Oxford University Press. Developmental studies have shown that the evolutionarily conserved Wnt Planar Cell Polarity (PCP) pathway is essential for the development of a diverse range of tissues and organs including the brain, spinal cord, heart and sensory organs, as well as establishment of the left-right body axis. Germline mutations in the highly conserved PCP gene VANGL2 in humans have only been associated with central nervous system malformations, and functional testing to understand variant impact has not been performed. Here we report three new families with missense variants in VANGL2 associated with heterotaxy and congenital heart disease p.(Arg169His), non-syndromic hearing loss p.(Glu465Ala) and congenital heart disease with brain defects p.(Arg135Trp). To test the in vivo impact of these and previously described variants, we have established clinically-relevant assays using mRNA rescue of the vangl2 mutant zebrafish. We show that all variants disrupt Vangl2 function, although to different extents and depending on the developmental process. We also begin to identify that different VANGL2 missense variants may be haploinsufficient and discuss evidence in support of pathogenicity. Together, this study demonstrates that zebrafish present a suitable pipeline to investigate variants of unknown significance and suggests new avenues for investigation of the different developmental contexts of VANGL2 function that are clinically meaningful

NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration

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

An assessment of the role of vinculin (VCL) loss of function variants in inherited cardiomyopathy.

The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin gene (VCL) illustrates these challenges. Model organism data provides evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case-control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy (OR= 9.01; CI=4.93-16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance

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