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HapMap and mapping genes for cardiovascular disease.

ABSTRACT: A key goal of biomedical science is to understand why individuals differ in their susceptibility to disease. Family history is among the established risk factors for most forms of cardiovascular disease, in part because inherited DNA sequence variants play a causal role in disease susceptibility. Consequently, the search for these variants has intensified over the past decade. One class of DNA sequence variants takes the form of single nucleotide changes(single nucleotide polymorphisms, or SNPs), usually with two variants or alleles for each SNP. SNPs are scattered throughout the 23 pairs of chromosomes of the human genome, and roughly 11 million common polymorphisms (ie,those > 1% frequency) are estimated to exist. A combination of SNP alleles along a chromosome is termed a haplotype. The International Haplotype Map Project was designed to create a public genome-wide database of common SNPs and, consequently, enable systematic studies of most common SNPs for their potential role in human disease. We review the following: (1) the concept of linkage disequilibrium orallelic association, (2) the HapMap project, and (3) several examples of the utility of HapMap data in genetic mapping for cardiovascular disease phenotypes.

SUBMITTER: Musunuru K

PROVIDER: S-EPMC3073405 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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HapMap and mapping genes for cardiovascular disease.

Musunuru Kiran K Kathiresan Sekar S

Circulation. Cardiovascular genetics 20081001 1

A key goal of biomedical science is to understand why individuals differ in their susceptibility to disease. Family history is among the established risk factors for most forms of cardiovascular disease, in part because inherited DNA sequence variants play a causal role in disease susceptibility. Consequently, the search for these variants has intensified over the past decade. One class of DNA sequence variants takes the form of single nucleotide changes(single nucleotide polymorphisms, or SNPs) ...[more]

PMID: 20031544

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Project description:Background: Hepatic knockdown of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or the angiopoietin-like 3 (ANGPTL3) gene has been demonstrated to reduce blood low-density lipoprotein cholesterol (LDL-C) levels, and hepatic knockdown of the angiotensinogen (AGT) gene has been demonstrated to reduce blood pressure. Genome editing can productively target each of these three genes in hepatocytes in the liver, offering the possibility of durable “one-and-done” therapies for hypercholesterolemia and hypertension. However, concerns around making permanent gene sequence changes via DNA strand breaks might hinder acceptance of these therapies. Epigenome editing offers an alternative approach to gene inactivation, via silencing of gene expression by methylation of the promoter region, but the long-term durability of epigenome editing remains to be established. Objectives and Results: We assessed the ability of epigenome editing to durably reduce the expression of the human PCSK9, ANGPTL3, and AGT genes in HuH-7 hepatoma cells. Cells treated with the CRISPRoff epigenome editor and PCSK9 guide RNAs were maintained for up to 124 cell doublings and demonstrated durable knockdown of gene expression and increased CpG dinucleotide methylation in the promoter, exon 1, and intron 1 regions. In contrast, cells treated with CRISPRoff and ANGPTL3 guide RNAs experienced only transient knockdown of gene expression. Cells treated with CRISPRoff and AGT guide RNAs also experienced transient knockdown of gene expression; although initially there was increased CpG methylation throughout the early part of the gene, this methylation was geographically heterogeneous—transient in the promoter, and stable in intron 1.Conclusions: This work demonstrates precise and durable gene regulation via methylation, supporting a new therapeutic approach for protection against cardiovascular disease via knockdown of genes such as PCSK9. However, the durability of knockdown with methylation changes is not generalizable across target genes, likely limiting the therapeutic potential of epigenome editing compared to other modalities.

Dataset Information

HapMap and mapping genes for cardiovascular disease.

Publications

HapMap and mapping genes for cardiovascular disease.

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