A physical map of the apolipoprotein gene cluster on human chromosome 19

Myklebost, Ola; Rogne, Sissel

doi:10.1007/bf00291670

Cited by 62 publications

(22 citation statements)

References 27 publications

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“…Our preliminary results indicate that peritoneal macrophages from 198.KK transgenic mice express human and mouse apoE. 2 Therefore, the trace amounts of human apoE and apoC-I mRNA detected in the livers of 198ϪHCR.1&2.KK mice may be due to apolipoprotein synthesis by monocyte-derived Kü pffer cells of the liver; these particular cells have been shown to produce apoE in the rat (40). It is noteworthy that the downstream human apoC-IV and apoC-II transgenes were not expressed at unusually high levels in the five extrahepatic tissues of 198ϪHCR.1&2.KK mice.…”

Section: Transgenic Mice Generated With Genomic Fragments Containing mentioning

confidence: 95%

“…The human apolipoprotein (apo) 1 E, apoC-I, apoC-IV, and apoC-II genes are located in the same transcriptional orientation within a 44-kb cluster on chromosome 19 (1)(2)(3). These genes share many structural and sequence characteristics (3)(4)(5), suggesting that they evolved from a common ancestral gene; and they are evolutionarily related to the apoA-I, apoA-IV, and apoC-III genes located in an 18-kb cluster on chromosome 11 (5)(6)(7).…”

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confidence: 99%

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Two Hepatic Enhancers, HCR.1 and HCR.2, Coordinate the Liver Expression of the Entire Human Apolipoprotein E/C-I/C-IV/C-II Gene Cluster

Allan

Taylor

1997

Journal of Biological Chemistry

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We show that the liver-specific expression of all four genes in the human apolipoprotein (apo) E/C-I/C-IV/C-II gene cluster in transgenic mice is determined by the coordinate action of two distinct hepatic control regions (HCR). These enhancers are positioned 15 kilobases (kb) (HCR.1) and 26 kb (HCR.2) downstream of the apoE gene. To investigate the action of each HCR, transgenic mice were generated with a 70-kb human genomic fragment that contained the complete apoE gene cluster or with this fragment modified by the specific deletion of HCR.1, HCR.2, or both HCR domains. Hepatic expression of all four apolipoprotein genes was observed in transgenic mice in which either HCR.1 or HCR.2 was deleted, but no transgene expression was found in the liver in the absence of both HCR domains. The overall patterns of transgene expression suggested that HCR.2 was the dominant element for apoC-IV and apoC-II expression and that HCR.1 was dominant for the apoE/C-I expression. No liver-specific transcriptional activity was identified for the proximal promoter of any gene in the cluster; all liver-specific activity was associated with HCR.1 and HCR.2. Thus, the HCRs of the apoE gene cluster constitute unique regulatory domains for determining the requirements for apolipoprotein gene expression in the liver.

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Section: Transgenic Mice Generated With Genomic Fragments Containing mentioning

confidence: 95%

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confidence: 99%

Two Hepatic Enhancers, HCR.1 and HCR.2, Coordinate the Liver Expression of the Entire Human Apolipoprotein E/C-I/C-IV/C-II Gene Cluster

Allan

Taylor

1997

Journal of Biological Chemistry

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“…One such locus, APOE, is the structural gene for an apolipoprotein involved in lipid transport and metabolism. 16 An association of the APOE E4 allele with late-onset familial and sporadic AD has been observed in many populations throughout the world and is now well established. 17,18 The known AD susceptibility genes have been estimated to account for only a portion of the heritability of AD, 19 underscoring the importance of continuing the search for additional AD risk loci.…”

Section: Introductionmentioning

confidence: 99%

D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

2001

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Typical, later-onset forms of Alzheimer's disease (AD) appear to be influenced by multiple susceptibility loci, combinations of which contribute to the development of this disorder. We previously reported the results of a systematic survey of the human genome for the identification of highly informative DNA polymorphisms (SSTRPs) that target new AD risk genes. In addition to the APOE locus, our survey detected five new candidate susceptibility loci for AD, including D10S1423. An association of the D10S1423 234-bp allele with AD has been reported in three independent samples of AD cases and controls (Boston, Pittsburgh, Bonn). Data from our case-control studies suggest a strong synergistic interaction between the D10S1423 234-bp and APOE E4 risk alleles (234-bp carrier: OR = 2.5, 95% CI = 1.4-4.5; E4 carrier: OR = 8.3, 95% CI = 4.3-15.8; both alleles: OR = 23.1, 95% CI = 5.3-99.5). This report describes the prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 234-bp allele, the APOE E4 allele, or both, after 11.5 years of systematic follow-up. A total of 18 incident cases of AD were detected during the first 3379 subject-years of this longitudinal study. The effects of carrying either or both of the D10S1423 234-bp and APOE E4 alleles on the age-specific risk of developing AD were determined using Kaplan-Meier survival analysis. The age-specific risk of developing AD was the greatest for individuals who carried both alleles (Mantel-Cox statistic = 20.12, df = 3, P = 0.0002; Breslow statistic = 13.36, df = 3, P = 0.004). Cox proportional hazards models were developed to estimate the risk ratios for each genotype, controlling for the potential effects of age at recruitment, sex, and years of education. In the resulting best fitting model, only individuals who carried both risk alleles exhibited a risk ratio that differed significantly from 1 (risk ratio = 16.2, P = 0.008, 95% CI = 2.1-128.3). After controlling for these genotypes, female gender was also significantly associated with increased risk of developing AD (risk ratio = 5.1, P = 0.02, 95% CI = 1.2-21.1). Neither age at recruitment nor years of education made significant contributions to the model. Molecular Psychiatry (2001) 6, 413-419.

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“…The amino-terminal domain of apolipoprotein E, around arginine 158, contains the region that binds to the cysteine rich repeats on the LDL and LDL receptor related protein/a 2 -macrpglobulin-receptor (2) which bears homologous repeats. The human apolipoprotein E gene spans 3.7 Χ 10 3 bases including four exons (3,4) and is located on chromosome 19 (4) in a gene family that is also close to the locus of the complement factor C3 gene (5). Apolipoprotein E polymorphic with three common isoforms, ε2 (112cys, ISScys), ε3 (112cys, 158arg, the most common) and ε4 (112arg, 158arg), which are determined by separate alleles at the apolipoprotein Ε locus.…”

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confidence: 99%

Apolipoprotein E and Complement C3 Polymorphism and Their Role in the Response to Gemfibrozil and Low Fat Low Cholesterol Therapy

Németh

Szakmary

Kramer

et al. 1995

CCLM

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Summary:Three different allelic variants of apolipoprotein E determine, in concert with other gene products, the levels of plasma lipoproteins. Recently, cleavage products of the complement C3 molecule have also been implicated in determining plasma triacylglycerol concentrations.This study presents data of an ongoing study to dissect the role of the apolipoprotein E gene locus in the response to low fat/low cholesterol diet combined with gemfibrozil treatment. In addition, for the first time, the significance of C3 allelic variants to such hypolipidaemic therapy response was analysed. To this end data from 81 obese hyperlipoproteinaemic patients (Fredrickson type II/A and B and type IV and V) confirmed the usefulness of the combined gemfibrozil/diet treatment and unveiled apolipoprotein E allele group specific therapy responses. The mean changes of lipid properties due to combined treatment was 15% for total cholesterol, 48% for triacylglycerols and 28% for atherogenic index. Division into hyperlipidaemia types according to Fredrickson and subgrouping into E2, E3 and E4 groups (apolipoprotein E2/2 and 2/3, apolipoprotein E3/3 and apolipoprotein E4/2 and 4/3 phenotype groups respectively) exposed pronounced differences from these mean changes, suggesting substantial influence of apolipoprotein E variants on this therapy. We observed triacylglycerol reductions of from 17% in type IIA-apolipoprotein E3 group patients up to 78% in the type IV and V-apolipoprotein E2 group. Thus it might be concluded the apolipoprotein E genotyping aides therapy success prediction. Although, low sample numbers in some subgroups obscures significance in this pilot study, significant therapy success emerges for the E3 and E4 group in type IV and V hyperlipidaemia and type IIB-apolipoprotein E3 homozygous patients can be predicted to respond better than apolipoprotein E2 carriers.Finally, we present evidence that positive changes of lipid properties are also determined by the "fast" complement C3 allel (C3-F). Patients with complement factor C3-FS pattern respond better to treatment than patients with C3-SS configuration, In summary these data endorse the genotyping of apolipoprotein E alleles to predict maximal success of "fibrate" treatment. In addition they argue strongly for further assessment of the involvement of complement C3 allelic variations in lipid homeostasis.

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A physical map of the apolipoprotein gene cluster on human chromosome 19

Abstract: We have generated a restriction map around the cloned genes for human apolipoproteins CI, CII, and E by pulsed-field gel analysis. We show that the genes are clustered within an area of about 50 kb on chromosome 19. The genes are all oriented in the same direction, head to tail.

Cited by 62 publications

References 27 publications

Two Hepatic Enhancers, HCR.1 and HCR.2, Coordinate the Liver Expression of the Entire Human Apolipoprotein E/C-I/C-IV/C-II Gene Cluster

Two Hepatic Enhancers, HCR.1 and HCR.2, Coordinate the Liver Expression of the Entire Human Apolipoprotein E/C-I/C-IV/C-II Gene Cluster

D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

Apolipoprotein E and Complement C3 Polymorphism and Their Role in the Response to Gemfibrozil and Low Fat Low Cholesterol Therapy

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