Disease relevance of APOB

• Mutations in the genes encoding either LDLR or its ligand (APOB) cause severe hypercholesterolemia [1].
• When a discriminant analysis was performed, only APOB level was related to parental myocardial infarction [2].
• We conclude that part of the known relationship between parental history of myocardial infarction and coronary heart disease could be mediated by an increased APOB level [2].
• Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity [3].
• We performed a meta-analysis of the associations between the three most frequently investigated polymorphisms (XbaI, signal peptide insertion/deletion, EcoRI) in the apolipoprotein B (APOB) gene, lipid parameters, and the risk of ischemic heart disease (IHD) [4].

Psychiatry related information on APOB

• Furthermore, we investigated the impact of APOB and APOE polymorphisms on interindividual variation in total cholesterol level in the 2 Italian samples, which differ in dietary habits [5].
• The distribution of three DNA polymorphisms (XbaI, EcoRI, and I/D) of the apolipoprotein B (APOB) gene, and of the I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene was investigated in 53 patients with vascular dementia, in 80 patients with late-onset sporadic Alzheimer's disease, and in 153 age-matched control subjects [6].

High impact information on APOB

• Apo B-100 is made by the liver and is essential for the assembly of triglyceride-rich very low-density lipoproteins (VLDL) in the cisternae of the endoplasmic reticulum and for their secretion into the plasma [7].
• A family study confirmed that the unequal expression phenotype was inherited in an autosomal dominant manner and was linked to the apob gene locus [8].
• Products of the apob gene with high or low affinity for the MB-19 monoclonal antibody can be distinguished, and this antibody was used to identify heterozygotes with allele-specific differences in the amount of apoB in their plasma [8].
• A 43-year-old woman with severe coronary artery disease and hyperapobetalipoproteinemia was heterozygous for an abnormal Msp I apolipoprotein B (APOB) gene fragment because of the absence of the MspI site around codon 4046 in exon 29 of the APOB gene [9].
• Intestinal mRNA abundance of 2 candidate genes involved in lipid transport, mtp and apob, was unchanged, although serum levels of apolipoprotein A-IV were reduced [10].

Chemical compound and disease context of APOB

• The ratios of HDL/total cholesterol and APOA1/APOB were also lower in presence of parental myocardial infarction (p less than .001 and p less than .01, respectively) [2].

Biological context of APOB

• In 70 unrelated FH patients, 44 had LDLR mutations detected by EBESA, including missense, RNA splicing, nonsense, or small deletion mutations, and 5 had the APOB R3500Q mutation [11].
• APOB haplotypes explained 27% of the QTL effect observed for LDL-C on 2p24.1 and reduced the LOD-score by 0.82 [12].
• In Family 59, a point mutation (1941G>T) in APOB exon 13 converts glutamic acid to stop codon (E578X), specifying apoB-13 [13].
• APOB (PvuII) was strongly associated with apolipoprotein B levels (apoB) (P = 0.006) and the VNTR region of the APOB locus showed highly significant association between allele 7 and low triglyceride levels (P = 0.004) [14].
• Of the seven APO and LPL loci tested, only one locus, APOB XbaI, departed significantly from Hardy-Weinberg equilibrium, with an unexpected excess of observed heterozygotes [15].

Anatomical context of APOB

• Two forms of apoB are produced from the APOB gene by a unique posttranscriptional editing process: apoB-48, which is required for chylomicron production in the small intestine, and apoB-100, required for VLDL production in the liver [16].
• We now report the mapping of the human apoB gene (APOB) to the p23-p24 region of chromosome 2 by examination of human-mouse somatic cell hybrids and by in situ hybridization to human chromosomes [17].
• Transgenic mice that express human apolipoprotein (apo)B have been developed by microinjecting fertilized mouse oocytes with an 80 kb genomic DNA fragment that encompasses the entire human APOB gene [18].
• This is the first example showing differential transcriptional regulation of the apob gene by cytokines and dissimilar regulation of one gene in two different cell lines by TGF-beta [19].
• Hence, TGF-beta activates SMADs that bind to the 485-bp intestinal enhancer element in the apob gene and increase its transcription and secretion in Caco-2 cells [19].

Associations of APOB with chemical compounds

• In Family 56, a 5 bp deletion in APOB exon 7 (870_874del5) causes a frame shift, converting tyrosine to a stop codon (Y220X) and producing an apoB-5 truncation [13].
• In this study we investigated the relationship between plasma LDL-C concentrations and three genes with pivotal roles in LDL metabolism: the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and cholesterol 7alpha-hydroxylase (CYP7) [20].
• ACE (Ins/Del) and APOB (Ins/Del, XbaI, and EcoRI) and APOE (HhaI) polymorphisms were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses on agarose, and polyacrylamide gel electrophoresis [21].
• These data indicate that the ins/del and XbaI polymorphisms in the APOB gene affect interindividual variation in serum lipoprotein and lipid levels in African populations [22].
• Apo-B-100-containing lipoproteins present in the microsomal lumen were analyzed by ultracentrifugation in a sucrose gradient [23].

Physical interactions of APOB

• Mutations in apolipoprotein B (APOB) may reduce binding of low density lipoprotein (LDL) to the LDL receptor and cause hypercholesterolemia [24].

Other interactions of APOB

• Other loci, including APOA4, APOA1 and APOB have also been found to account for some of the variability in the fasting and fed states [25].
• After fine mapping, three maximum LOD scores mapped within 1 cM of major candidate genes, namely APOB (LOD=2.1), LDLR (LOD=1.9) and APOE (LOD=1.7) [12].
• We studied 29 individuals from eight families from this population for abnormal hemoglobins, G6PD deficiency, DNA haplotypes, and apolipoprotein B (APOB, gene) polymorphism [26].
• Like its homolog APOBEC1, which requires at least one additional factor to efficiently edit APOB RNA, other proteins are likely to be required for the proper targeting of AID to the immunoglobulin loci [27].
• Analysis of 150 nuclear families indicated statistically significant linkage between plasma LDL-C concentrations and CYP7, but not LDLR or APOB [20].

Analytical, diagnostic and therapeutic context of APOB

• METHODS: We developed a low-density oligonucleotide microarray to identify 118 DNA sequence variations (117 for the LDLR gene and 1 for the APOB gene) [28].
• This study extended that work by assessment of specificity of amplicons produced with non-human and human control DNAs for APOB, PAH and D1S80 under high and low stringency PCR conditions [29].
• METHODS: Genotypes of CYP7A, APOB, APOE and LDLR genes were determined in 105 patients with GSD diagnosed by B-mode ultrasonography and 274 control subjects [30].
• In this case-control study, we searched for an association between the insertion/deletion (I/D) polymorphism of the APOB gene and male infertility in 560 Slovene Caucasian men [31].
• The internal structure of APOB gene 3'VNTR alleles was also analyzed by the methods of SspI restriction mapping and DNA sequencing of the allele fragments [32].

References