Novel protein-truncating variant in the APOB gene may protect from coronary artery disease and adverse cardiovascular events

Background and aims: Genetic testing is still rarely used for the diagnosis of dyslipidemia, even though gene variants determining plasma lipids levels are not uncommon.Methods: Starting from a a pilot-analysis of targeted Next Generation Sequencing (NGS) of 5 genes related to familial hypercholesterolemia (LDLR, APOB, PCSK9, HMGCR, APOE) within a cardiovascular cohort in subjects with extreme plasma concentrations of low-density lipoprotein (LDL) cholesterol, we discovered and characterized a novel point mutation in the APOB gene, which was associated with very low levels of apolipoprotein B (ApoB) and LDL cholesterol.Results: APOB c.6943 G > T induces a premature stop codon at the level of exon 26 in the APOB gene and generates a protein which has the 51% of the mass of the wild type ApoB-10 0 (ApoB-51), with a trun-cation at the level of residue 2315. The premature stop codon occurs after the one needed for the synthesis of ApoB-4 8, allowing chylomicron production at intestinal level and thus avoiding potential nutritional impairments. The heterozygous carrier of APOB c.6943G > T, despite a very high-risk profile encompassing all the traditional risk factors except for dyslipidemia, had normal coronary arteries by angiography and did not report any major adverse cardiovascular event during a 20-years follow-up, thereby obtaining advantage from the gene variant as regards protection against atherosclerosis, apparently without any metabolic retaliation.Conclusions: Our data support the use of targeted NGS in well-characterized clinical settings, as well as they indicate that.a partial block of ApoB production may be well tolerated and improve cardiovascular outcomes. (C) 2022 The Authors. Published by Elsevier B.V

Detection of urinary exosomal HSD11B2 mRNA expression: a useful novel tool for the diagnostic approach of dysfunctional 11β-HSD2-related hypertension

Apparent mineralocorticoid excess (AME) is an autosomal recessive disorder caused by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme deficiency, traditionally assessed by measuring either the urinary cortisol metabolites ratio (tetrahydrocortisol+allotetrahydrocortisol/tetrahydrocortisone, THF+5αTHF/THE) or the urinary cortisol/cortisone (F/E) ratio. Exosomal mRNA is an emerging diagnostic tool due to its stability in body fluids and its biological regulatory function. It is unknown whether urinary exosomal HSD11B2 mRNA is related to steroid ratio or the HSD11B2 662 C>G genotype (corresponding to a 221 A>G substitution) in patients with AME and essential hypertension (EH)

One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation

Several polymorphic gene variants within one-carbon metabolism, an essential pathway for nucleotide synthesis and methylation reactions, are related to cancer risk. An aberrant DNA methylation is a common feature in cancer but whether the link between one-carbon metabolism variants and cancer occurs through an altered DNA methylation is yet unclear. Aims of the study were to evaluate the frequency of one-carbon metabolism gene variants in hepatocellular-carcinoma, cholangiocarcinoma and colon cancer, and their relationship to cancer risk together with global DNA methylation status. Genotyping for BHMT 716A>G, DHFR 19bp ins/del, MTHFD1 1958G>A, MTHFR 677C>T, MTR 2756A>G, MTRR 66A>G, RFC1 80G>A, SHMT1 1420C>T, TCII 776C>G and TS 2rpt-3rpt was performed in 102 cancer patients and 363 cancer-free subjects. Methylcytosine (mCyt) content was measured by LC/MS/MS in peripheral blood mononuclear cells (PBMCs) DNA. The MTHFD1 1958AA genotype was significantly less frequent among cancer patients as compared to controls (p = 0.007) and related to 63% reduction of overall cancer risk (p = 0.003) and 75% of colon cancer risk (p = 0.006). When considering PBMCs mCyt content, carriers of the MTHFD1 1958GG genotype showed a lower DNA methylation as compared to carriers of the A allele (p = 0.048). No differences were highlighted by evaluating a possible relationship between the other polymorphisms analyzed with cancer risk and DNA methylation. The MTHFD1 1958AA genotype is linked to a significantly reduced cancer risk. The 1958GG genotype is associated to PBMCs DNA hypomethylation as compared to the A allele carriership that may exert a protective effect for cancer risk by preserving from DNA hypomethylation

Alcohol and DNA methylation

Alcohol is an environmental toxicant that is associated with several major human diseases because it has harmful effects on many different tissues and organs. Alcohol effects cellular toxicity by several mechanisms, mainly through acetaldehyde, the first metabolite produced during ethanol degradation, and through the formation of reactive oxygen species. Acetaldehyde interferes with DNA synthesis and repair mechanisms and is well recognized as playing a role in cancer of upper and lower gastrointestinal tract. Meanwhile, the hazardous effects of alcohol on the liver are more likely to be mediated by oxidative stress. Several studies have also demonstrated that alcohol impairs one-carbon metabolism leading to an aberrant methyl group transfer, and it is believed that this molecular event may play a role in the develop- ment of cancer and other alcohol-related diseases. In this chapter, we focused on the effects of alcohol on one-carbon metabolism and its influence on DNA methylation, which could be one of the mechanisms involved in the epigenetic effects of alcohol

Vitamins and epigenetics

This chapter focuses on the role of vitamins with a recognized function in modulating epigenetic mechanisms. Epigenetics refers to the complex of somatically heritable states that regulate gene expression resulting from modifications in DNA and chromatin structure that occur without alterations in the DNA sequence. Epigenetic phenomena include DNA methylation, posttranslational histone modifications, chromatin remodeling mechanisms, and the role of small noncoding RNA. Folate, namely vitamin B9, is a major player in the link between vitamins and epigenetics because it is responsible for the transport of methyl groups for the methylation of DNA, one of the most significant epigenetic phenomena. While pathologic conditions are associated with severe vitamin deficiency, it is now known that even mild vitamin deficiencies, especially of the hydrosoluble B group, are related to the impairment of epigenetic features of DNA. Vitamin A status is also associated with the modification of DNA methylation and other epigenetic phenomena at histone tails sites

One-carbon metabolism and epigenetics

The function of one-carbon metabolism is that of regulating the provision of methyl groups for biological methylation reactions including that of DNA and histone proteins. Methylation at specific sites into the DNA sequence and at histone tails are among the major epigenetic feature of mammalian genome for the regulation of gene expression. The enzymes within one-carbon metabolism are dependent from a number of vitamins or nutrients that serve either as co-factors or methyl acceptors or donors among which folate, vitamin B12, vitamin B6, betaine, choline and methionine have a major role. Several evidences show that there is a strict inter-relationship between one-carbon metabolism nutrients and epigenetic phenomena. Epigenetics is closely involved in gene transcriptional regulation through modifications super-imposed to the nucleotide sequence of DNA, such as DNA methylation, through chromatin remodeling systems that involves post-translational modifications of histones or through non-coding RNAs-based mechanisms. The epigenetic features of the genome are potentially modifiable by the action of several environmental factors among which nutrients cover a special place and interest considering their potential of influencing regulatory pathways at a molecular level by specific nutritional intervention and eventually influence disease prevention and outcomes. The present review will focus on the link between one-carbon nutrients and epigenetic phenomena based on the current knowledge from findings in cell culture, animal models and human studies

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DNA methylation and DNA hydrocymethylation from peripheral blood mononuclear cels are valida biomarkers for survival rate in human primary liver cancer

Cardiovascular epigenetics: from DNA methylation to microRNAs

Epigenetic phenomena define heritable mechanisms that establish and maintain mitotically stable patterns of gene expression regulation that occur without modifying the base sequence of DNA. The major epigenetic features of mammalian cells enclose DNA methylation, post-translational histone modifications and RNA-based mechanisms including those controlled by small non-coding RNAs (miRNAs). Their impact in cardiovascular pathophysiology is now emerging as a major interface between genotype to phenotype variability with strict implications on disease development and progression, opening up to possible novel preventive strategies. Epigenetic mechanisms are potentially reversible and may be influenced by nutritional-environmental factors as well as through gene-environment interactions, all of which have an important role in complex, multifactorial diseases such as those affecting the cardiovascular system. Gene expression regulation through the interplay of DNA methylation and histone modifications is well-established, although the knowledge about the function of epigenetic signatures in cardiovascular disease is still largely unexplored. The study of epigenetic markers is, therefore, an emerging and very promising frontier of science which may help for a deeper understanding of molecular mechanisms underlying the modulation of gene expression in cardiovascular disease-linked biomolecular pathways. This review will focus on up-to-date knowledge pertaining to the role of epigenetics, from DNA methylation to miRNAs, in major cardiovascular diseases such as ischemic heart disease, hypertension, heart failure and stroke

Reply to Li, Zhi et al Hypomethylation and hypohydroxymethylation of DNA in hepatocellular carcinoma and cholangiocarcinoma

DNA methylation and DNA hydrocymethylation from peripheral blood mononuclear cels are valida biomarkers for survival rate in human primary liver cancer

High ferritin and low folate increases PBMCs genomic DNA methylation in association with SHMT1-1420TT variant.

Nutrient-gene interactions within one-carbon metabolism modulate DNA methylation, the major potentially reversible epigenetic modification in eukaryotic cells. The cytosolic serine hydroxymethyltransferase (SHMT1) regulates the metabolic balance between nucleotide synthesis and methylation in one-carbon pathway. The SHMT1-1420T allele has been associated with a reduced enzyme activity and a decreased risk of cancer. By enhancing SHMT1 expression, ferritin affects folate-mediated one-carbon metabolism. Aim of this study was to analyze how the interaction among ferritin, folate and SHMT1-1420C>T polymorphism may affect peripheral blood mononuclear cells (PBMCs) DNA methylation (LC/ESI/MS method) in 537 subjects enrolled in the Verona Heart Studyto identify a possible biomarker for cancer. Results showed that SHMT1-TT carriers, under a high ferritin/low folate condition, show significantly increased PBMCs genomic DNA methylation than SHMT1-CC subjects (P=0.01). Since cancer is usually associated with genomic hypomethylation, the increased genomic methylation in SHMT1-1420TT genotypes in presence of high ferritin/low folate, could be potentially protective for cancer risk