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Journal Highlights February - technology in molecular genetics

27 February 2018   (0 Comments)
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Volume 269 Issue February 2018

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

This issue of Atherosclerosis contains several articles, which exemplarily illustrate how the advance of technology in molecular genetics helps deepen insights into the pathogenesis and clinical manifestation of classical monogenic dyslipidemias, unravels novel genetic determinants of atherosclerotic vascular disease, or opens avenues to novel mechanisms of regulation.


Issue highlights



    Highlighted articles


    Molecular and functional characterization of familial chylomicronemia syndrome

    Familial chylomicronemia syndrome is a rare autosomal recessive disorder due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative genes and mutations. In this study, Teramoto and colleagues performed comprehensive genotyping and investigated the phenotypes of eight patients with familial hyperchylomicronemia.

    They evaluated the clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next-generation sequencing on a panel of 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency <1% and in silico annotation prediction, the authors used three types of variant filtering to identify causative mutations: homozygous mutations in known familial hyperchylomicronemia-associated genes, homozygous mutations with high-damaging scores in novel genes, and deleterious mutations within 37 genes known to be associated with HTG.

    A total of 1810 variants (out of the 73,389 identified with 94.3% mean coverage (×20)) were rare and non-synonymous. Among these, four pathogenic or likely pathogenic mutations in the LPL gene were detected, including one novel mutation and a variant of uncertain significance. Patients harboring LPL gene mutations showed no severe atherosclerotic changes in coronary arteries, but recurrent pancreatitis with long-term exposure to HTG was observed.

    These results confirm that the LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis.


    In their editorial, Fogacci and Cicero emphasize how this extremely rare disease (estimated prevalence in the population of 1:1,000,000) has well-recognized major effects on both physical and mental health. Beyond the dietary management and usual pharmacologic therapies, some new genetic treatments are emerging to directly target the driver mutations of the disease. This new approach is certainly promising, but extremely expensive and lacking long-term safety data.

    By providing the genetic background of the disease, Teramoto and collaborators show the potential effectiveness of these innovative drugs and their pharmacological mechanism of action.

    Spectrum of mutations in index patients with familial hypercholesterolemia in Singapore: Single center study

    Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by the presence of high plasma low-density lipoproteins cholesterol (LDL-c). Patients with FH, with mutations detected, are at increased risk of premature cardiovascular disease compared to those without identified mutations. Pek et al. aimed at assessing the mutation spectrum in patients in Singapore in whom FH was diagnosed by clinical criteria.

    Ninety-six probands with untreated/highest on-treatment LDL-c >4.9 mmol/l were recruited. Anthropometric, biochemical indices, blood and family history were collected. DNA was extracted and Next Generation Sequencing (NGS) was performed in 26 lipid-related genes, including LDLR, APOB and PCSK9, and validated using Sanger sequencing. Multiplex-ligation probe analyses for LDLR were performed to identify large deletions or insertions. LDLR mutations were classified as “null” (nonsense, frameshift, large rearrangements) and “defective” (pathogenic point mutations).

    52.1% of patients had mutations in LDLR including 15 novel mutations, and 4.2% had mutations in APOB. Patients with mutations in LDLR had more pronounced hypercholesterolemia than those with mutations in APOB or no mutations. Patients with null alleles had higher cholesterol levels than those with defective variants.

    This is the first report of mutation detection in patients with clinically suspected FH in Singapore. While the percentage of mutations is similar to other countries, the spectrum locally differs. The most common mutation in this cohort was LDLR exon 12 (c.1747C > T).

    Autosomal recessive hypercholesterolemia in Spain

    Autosomal recessive hypercholesterolemia (ARH) is a very rare disease, caused by mutations in the gene encoding LDL protein receptor adaptor 1 (LDLRAP1), which is involved in the uptake of the LDL receptor (LDLr) and clearance of LDL particles. ARH is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature cardiovascular disease. Sánchez-Hernández and collaborators aimed at estimating the prevalence, phenotype variability, genotype-phenotype correlation and response to lipid-lowering treatment of ARH in Spain.

    Data were collected from the Dyslipidemia Registry of the Spanish Atherosclerosis Society. A literature search was performed up to June 2017, and all diagnostic genetic studies for familial hypercholesterolemia in Spain were reviewed.

    Seven patients with ARH were identified, six homozygotes and one compound heterozygote with a novel mutation. The studied cohort presented high genetic heterogeneity. The compound heterozygous subject presented a milder phenotype, with much lower baseline LDL-C concentrations and later diagnosis than most homozygotes. Cardiovascular disease was present in 14% of the cases. LDL-C treated with lipid-lowing therapy was above 185 mg/dl, implying the need of new treatments to achieve the recommended LDL-C goals. A heterogeneous reduction of LDL-C levels response to PCSK9 inhibitor was observed. Finally, the estimated prevalence in Spain was estimated to be one case per 6.5 million people.

    ARH is a very rare disease in Spain, showing high genetic heterogeneity, similarly high LDL-C concentrations, but lower incidence of atherosclerotic cardiovascular disease than homozygous familial hypercholesterolemia (HoFH). Nevertheless, the small number of patients limits conclusions that can be drawn from the results on genotype-phenotype correlation and response to therapy.

    The natural history of phytosterolemia: Observations on its homeostasis

    Phytosterolemia is a rare genetic disease caused by mutations in the ABCG5/8 genes, characterized by tendon xanthomas, high levels of plasma plant sterols (predominantly sitosterol), accelerated atherosclerosis, and coronary heart disease. In this study, Mymin et al. assessed the natural history and homeostasis of phytosterolemia.

    The authors analyzed a Hutterite kindred consisting of 21 homozygotes with phytosterolemia, all carrying the ABCG8 S107X mutation and treated with ezetimibe. The Hutterite community is an Anabaptist religious sect living in the north-central plains of Canada and the United States. Hutterites live on communal farms, which they refer to as colonies, and are endogamous. This facilitates the process of cascade screening.

    Most of these subjects were asymptomatic and devoid of clinical stigmata, suggesting that, relative to its true prevalence, phytosterolemia is a condition of low morbidity. All subjects responded well to ezetimibe treatment. Initial (pre-treatment) and post-ezetimibe levels of cholesterol and sitosterol were measured and percentage changes on ezetimibe were calculated. The initial levels and percentage responses to ezetimibe therapy were inversely correlated to the subjects' age. There was also a direct correlation between initial levels and percentage responses to ezetimibe. Hence, on-treatment levels were very uniform.

    The evidence of a link with age lead the authors to suggest that an age-related change in cholesterol and sterol homeostasis occurs at puberty in phytosterolemia and that the change is due to high sterol and/or stanol levels causing feedback inhibition of sterol regulatory element-binding protein (SREBP-2) processing. They further speculated that this would explain the well-documented phenomenon of depressed cholesterol synthesis in phytosterolemia. It is also well-known that LDL-receptor activity is increased, and this explains reduced LDL levels and consequent reduction of plasma cholesterol and sitosterol levels. Downregulated SREBP-2 processing would be expected to also lower proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and this would explain high LDL-receptor activity. The above state could be termed disrupted homeostasis and the alternative, seen mostly in children and characterized by hypercholesterolemia and hypersterolemia, simple homeostasis.

    Genetic variants in PPARGC1B and CNTN4 are associated with thromboxane A2 formation and with cardiovascular event free survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

    Thromboxane A2 (TxA2) is a potent platelet agonist formed during platelet activation, contributing to the risk of arterial thrombosis. Elevated urinary 11-dehydro thromboxane B2 (TxB2), a measure of TxA2 formation in vivo and predicts future atherothrombotic events. McCarthy et al. conducted the first genome wide association study to investigate the genetic determinants of 11-dehydro TxB2 and their associations with cardiovascular morbidity.

    Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants.

    Five single nucleotide polymorphisms (SNPs) in two genes, PPARGC1B and CNTN4, were associated with elevated 11-dehydro TxB2 formation in 806 ASCOT participants. Haplotypes of 11-dehydro TxB2 increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB2, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events. Two risk alleles associated with increased urinary 11-dehydro TxB2 were individually associated with greater incidences of cardiovascular events; effect sizes were larger in subjects not taking aspirin.
    PPARGC1B and CNTN4 genotypes are associated with elevated TxB2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. These results suggest specific protection of aspirin for people with certain PPARGC1B and CNTN4 genotypes. If confirmed, PPARGC1B and CNTN4 genotyping could potentially provide guidance in the use of aspirin in primary prevention.

    Genetic polymorphisms offer insight into the causal role of microRNA in coronary artery disease

    MicroRNAs (miRNAs), a class of short and highly conserved non-coding RNA molecules (∼22 nucleotides), are dysregulated in many human diseases. There is growing interest in the potential of circulating miRNAs as diagnostic and/or prognostic biomarkers in CAD. Despite this promising role, there are still widespread inconsistencies among studies, and important obstacles must be overcome before miRNAs can enter clinical practice. This review by Borghini and Andreassi aims to provide a general overview of the studies that have investigated the association of miRNA gene polymorphisms with the susceptibility to CAD development and progression, and to highlight potential future research perspectives. The study of single nucleotide polymorphisms (SNPs) in the miRNA regulatory network could help to shed light on the causality of associations as well as validate the value of cardiovascular miRNAs. SNPs in miRNA biogenesis or miRNA targetome genes may affect miRNA expression and resulting circulating levels or the fidelity of the miRNA-mRNA interaction, influencing susceptibility to atherosclerotic vascular disease.

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