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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lp(a) concentrations are controlled primarily by genetic variation at LPA, the locus encoding the unique protein apo(a). However, the high heritability is in part a consequence of nearly a 1000-fold range of Lp(a) concentrations found in healthy individuals. As determined by use of siblings genetically identical-by-descent at the LPA locus, there is substantial within-genotype variation in Lp(a) concentrations (ranges averaged about 58% of mean values for 87 sibling groups). This within-genotype variation could affect risk of CVD for nearly 15% of individuals in a population. Furthermore, Lp(a) concentrations are significantly and independently correlated with two key indicators of lipoprotein metabolism, plasma cholesterol and triglyceride concentrations. Taken together, these data suggest that it is both possible and desirable to develop strategies for modifying Lp(a) concentrations.
Atherosclerosis 1996 Nov 15
PMID:Lp(a) concentrations are related to plasma lipid concentrations. 900 99

Analyses of 1163 samples from the San Antonio Family Heart Study revealed several elements of genetic control of lipoprotein(a) (Lp(a)) concentrations in Mexican Americans. Apolipoprotein(a) (apo(a)) isoform size variation was inversely related to Lp(a) concentrations and explained about 22% of total phenotypic variation. Segregation analyses suggested the existence of a major gene that influenced an additional 41% of total Lp(a) variation. A G-->A polymorphism in the LPA promoter was in strong disequilibrium with apo(a) isoform size, but did not contribute a significant amount of additional information about Lp(a) variation. However, about 25% of variation in Lp(a) concentrations was influenced by additive polygenic effects, which include the effects of null phenotype alleles. Altogether, these genetic components explained 89% of Lp(a) variation, similar to heritability estimates made in several other studies. Apo(a) size variation and the major gene (explaining a total of about 62% of Lp(a) variation) were linked to each other and, as expected, to the plasminogen locus. Thus, together with the well-established null phenotype allele, these different genetic factors represent at least three distinct elements of control exerted at the LPA locus, which encodes the apo(a) protein.
Atherosclerosis 1997 Feb 10
PMID:Characterization of the genetic elements controlling lipoprotein(a) concentrations in Mexican Americans. Evidence for at least three controlling elements linked to LPA, the locus encoding apolipoprotein(a). 905 Jul 79

We have studied the homology of repeating kringle IV-type 2 (K IV-type 2) elements of the LPA gene. Two K IV-type 2 genomic polymerase chain reaction (PCR) fragment libraries were constructed, one from an individual with high and one from an individual with low Lp(a) lipoprotein level. Only minor K IV-type 2 repeat length heterogeneity was observed. Sequence analysis data from the cloned K IV-type 2 repeats revealed a high degree of LPA sequence conservation in exons as well as in introns both within and between the two libraries. This sequence conservation of the IV-type 2 kringles is in agreement with our previously reported results of simultaneous 'batch' DNA sequence analyses of all the K IV-type 2 repeats from single individuals. Sequence data from the clones, combined with genomic DNA sequencing, revealed that the K IV-type 2 reading frame of exons 1 and 2 are extended into the conserved flanking introns by 519 base pairs (bp) and 312 bp, respectively. The theoretical coding capacity of the exon 1 extended open reading frame (ORF I) is three times larger (173 amino acids, aa) than the translated exon 1, and that of the extended open reading frame of exon 2 (ORF II) is about twice (104 aa) the length of exon 2. A central portion of the intron separating exons 1 and 2 also exhibited a high degree of sequence conservation, with the exception of a polymorphic CA repeat. Within the 61 K IV repeat clones analysed, 19 different CA repeat patterns with 12-18 CA dinucleotide repeats were observed. A comparison between the 37 clones from the individual with high Lp(a) lipoprotein level and the 24 clones from the individual with low Lp(a) lipoprotein level, revealed that seven of the CA repeat variants were present in both clone libraries. The observed high level of sequence conservation in K IV-type 2 exons and introns matches relevant areas of the plasminogen gene, and our findings fit with recent K IV-type 2 duplications and evolutionary selection pressure theories, although gene conversion events could also explain the findings. DNA sequences within K IV-type 2 appeared to have no influence on Lp(a) lipoprotein level.
Atherosclerosis 2000 Feb
PMID:Sequence conservation in kringle IV-type 2 repeats of the LPA gene. 1065 72

The aortic root from 21 LPA transgenic mice and 18 control litter mates on cholesterol enriched chow were studied histologically for the presence of atherosclerotic lesions. Serial sections were cut and the total area of the lesions was measured by use of computerised image analysis. Lipid staining lesions were found in 17 aortas of the transgenic mice and were five times more common than in the controls. Foam cell lesions were the only type of lesion in 12 of the aortas from transgenic animals, while five animals had developed fibrofatty lesions. Immunostaining revealed monocytes/macrophages on the endothelial surface, and in the subendothelial space of foam cell lesions. In fibrofatty lesions, spindle shaped cells formed a cap around the lipid core. This study supports the view that transgenic mice expressing human apolipoprotein (a) on a high fat and cholesterol diet, are more susceptible to aortic lesions than control mice and develop early atherosclerotic lesions comparable to lesions in man. Aminoguanidin in the drinking water had no effect on the aortic lesions, but lesion size was significantly, negatively correlated with plasma glucose concentration.
Atherosclerosis 2000 Dec
PMID:Histopathology of arterial lesions in LPA transgenic mice on cholesterol-enriched chow. 1116 23

Serum levels of Lp(a) lipoprotein are under genetic control and a high level is a risk factor for atherosclerotic disease. We have examined the aorta of LPA transgenic mice and their non-transgenic litter mates who had all been given a regular, not lipid fortified diet. When sacrificed, the animals had an average age of 66 weeks. Lipid lesions were observed in the aorta of 13 out of 18 LPA transgenic mice and in five out of 21 non-transgenic animals. The difference is statistically significant. We conclude that LPA transgenic mice develop lipid lesions in aorta more frequently than non-transgenic animals, even on a diet with a low fat content. LPA transgenic mice on a normal diet could be a useful animal model for the study of spontaneous human atherosclerosis, its treatment and prevention.
Atherosclerosis 2002 Jul
PMID:Spontaneous atherosclerosis in the proximal aorta of LPA transgenic mice on a normal diet. 1204 26

Polymorphic genes associated with Alzheimer's disease (see ) delineate a clearly defined pathway related to cerebral and peripheral cholesterol and lipoprotein homoeostasis. They include all of the key components of a glia/neurone cholesterol shuttle including cholesterol binding lipoproteins APOA1, APOA4, APOC1, APOC2, APOC3, APOD, APOE and LPA, cholesterol transporters ABCA1, ABCA2, lipoprotein receptors LDLR, LRP1, LRP8 and VLDLR, and the cholesterol metabolising enzymes CYP46A1 and CH25H, whose oxysterol products activate the liver X receptor NR1H2 and are metabolised to esters by SOAT1. LIPA metabolises cholesterol esters, which are transported by the cholesteryl ester transport protein CETP. The transcription factor SREBF1 controls the expression of most enzymes of cholesterol synthesis. APP is involved in this shuttle as it metabolises cholesterol to 7-betahydroxycholesterol, a substrate of SOAT1 and HSD11B1, binds to APOE and is tethered to LRP1 via APPB1, APBB2 and APBB3 at the cytoplasmic domain and via LRPAP1 at the extracellular domain. APP cleavage products are also able to prevent cholesterol binding to APOE. BACE cleaves both APP and LRP1. Gamma-secretase (PSEN1, PSEN2, NCSTN) cleaves LRP1 and LRP8 as well as APP and their degradation products control transcription factor TFCP2, which regulates thymidylate synthase (TS) and GSK3B expression. GSK3B is known to phosphorylate the microtubule protein tau (MAPT). Dysfunction of this cascade, carved out by genes implicated in Alzheimer's disease, may play a major role in its pathology. Many other genes associated with Alzheimer's disease affect cholesterol or lipoprotein function and/or have also been implicated in atherosclerosis, a feature of Alzheimer's disease, and this duality may well explain the close links between vascular and cerebral pathology in Alzheimer's disease. The definition of many of these genes as risk factors is highly contested. However, when polymorphic susceptibility genes belong to the same signaling pathway, the risk associated with multigenic disease is better related to the integrated effects of multiple polymorphisms of genes within the same pathway than to variants in any single gene [Wu, X., Gu, J., Grossman, H.B., Amos, C.I., Etzel, C., Huang, M., Zhang, Q., Millikan, R.E., Lerner, S., Dinney, C.P., Spitz, M.R., 2006. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am. J. Hum. Genet. 78, 464-479.]. Thus, the fact that Alzheimer's disease susceptibility genes converge on a clearly defined signaling network has important implications for genetic association studies.
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PMID:Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis. 1697 41

Lipoprotein(a) [Lp(a)] is a LDL-like particle containing a single copy of apolipoprotein B-100 (apoB-100), covalently attached to apolipoprotein(a) [apo(a)]. Apo(a) is encoded by LPA gene (6q26-27), and it has been hypothesized that LPA +93C>T and +121G>A polymorphisms in the 5' flanking region could influence the apolipoprotein(a) synthesis, so affecting Lp(a) levels. In order to permit a rapid detection of LPA polymorphisms, we performed an analysis protocol for the SNPs detection through Nanogen Technology with the Universal Reporting System, and we compared our results with those obtained with a more conventional method, such as PCR-RFLP assay. Our experiments evidenced that Nanogen Technology may be used as a high-throughput tool in LPA +93C>T and +121G>A polymorphisms analysis, minimizing the hands-on time and the costs for the SNPs detection. In particular, this Technology allows the analysis of polymorphisms at the LPA locus, able to modulate the levels of Lp(a), a relevant marker of atherosclerosis.
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PMID:LPA +93C>T and +121G>A polymorphisms detection by electronic microchip technology. 1732 1

High plasma lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for atherosclerotic diseases. To date, no effective intervention strategies on reducing Lp(a) concentrations have been reported. The aim of the study was to evaluate the possible modulation of two polymorphisms of LPA gene (LPA 93C>T and LPA 121G>A) and nutritional habits on Lp(a) concentrations. We studied 647 healthy Italian subjects (260 M; 387 F) with a median age of 48 years (range: 19-78) enrolled in an epidemiological study conducted in Florence, Italy. A linear regression analysis showed a significant negative influence of fish intake (beta=-0.174+/-0.084; p=0.04) on Lp(a) concentrations, after adjustment for smoking habit, C-reactive protein serum concentrations, dietary habits and LDL-cholesterol concentrations. With regard to LPA polymorphisms, LPA 93C>T polymorphism resulted to significantly affect Lp(a) circulating concentrations in a dose-dependent manner, with lower concentrations shown by subjects carrying the T rare allele, whereas no significant influence of LPA 121G>A polymorphism on Lp(a) concentrations was observed. Moreover, by analyzing the possible interplay between LPA 93C>T and dietary fish intake, a significant interaction between these two determinants in lowering Lp(a) concentrations was reported. In addition, lower Lp(a) concentrations were observed in subjects carrying the T allele of the LPA 93C>T polymorphism and consuming a high intake of fish with respect to those being in the highest tertile of fish consumption but homozygotes for the common allele of the polymorphism. In conclusion, this study reported a significant interaction of daily fish intake and LPA 93C>T polymorphism in decreasing Lp(a) concentrations.
Atherosclerosis 2007 Dec
PMID:Fish intake and LPA 93C>T polymorphism: gene-environment interaction in modulating lipoprotein (a) concentrations. 1760 63

Despite successes in identifying genetic contributors to common metabolic phenotypes, only part of the heritable component of these traits has thus far been explained. Copy number variation (CNV) is likely to be responsible for some of the unexplained variation. As observed with single nucleotide changes, it is probable that both rare and common CNVs will contribute to susceptibility to metabolic disease. For instance, CNVs in the LDLR gene underlie a substantial portion of disease in patients with heterozygous familial hypercholesterolemia. As well, a common CNV in LPA encoding apolipoprotein(a) is the primary determinant of plasma lipoprotein(a) concentrations, a risk factor for atherosclerosis. Recent efforts to map CNVs in control populations have defined their size, frequency and distribution. Many of the identified CNVs overlap genes with important functions in metabolic pathways. The overlap of CNVs that were found in control datasets with functional candidate genes or genes with previous evidence of association with metabolic syndrome presents an important subset for future CNV association studies. Finally, we describe an approach to search for CNVs in a rare high-penetrance metabolic disorder, namely lipodystrophy. As methods to identify CNVs increase in precision and accuracy, the prospect of identifying their role in both rare Mendelian and common complex metabolic phenotypes will become a reality.
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PMID:Copy number variation in metabolic phenotypes. 1928 52

The aim of this review is to summarize present evidence of a causal association of lipoprotein(a) with risk of ischemic heart disease (IHD). Evidence for causality includes reproducible associations of a proposed risk factor with risk of disease in epidemiological studies, evidence from in vitro and animal studies in support of pathophysiological effects of the risk factor, and preferably evidence from randomized clinical trials documenting reduced morbidity in response to interventions targeting the risk factor. Elevated and in particular extreme lipoprotein(a) levels have in prospective studies repeatedly been associated with increased risk of IHD, although results from early studies are inconsistent. Data from in vitro and animal studies implicate lipoprotein(a), consisting of a low density lipoprotein particle covalently bound to the plasminogen-like glycoprotein apolipoprotein(a), in both atherosclerosis and thrombosis, including accumulation of lipoprotein(a) in atherosclerotic plaques and attenuation of t-PA mediated plasminogen activation. No randomized clinical trial of the effect of lowering lipoprotein(a) levels on IHD prevention has ever been conducted. Lacking evidence from randomized clinical trials, genetic studies, such as Mendelian randomization studies, can also support claims of causality. Levels of lipoprotein(a) are primarily determined by variation in the LPA gene coding for the apolipoprotein(a) moiety of lipoprotein(a), and genetic epidemiologic studies have documented association of LPA copy number variants, influencing levels of lipoprotein(a), with risk of IHD. In conclusion, results from epidemiologic, in vitro, animal, and genetic epidemiologic studies support a causal association of lipoprotein(a) with risk of IHD, while results from randomized clinical trials are presently lacking.
Atherosclerosis 2010 Jul
PMID:Lipoprotein(a) and ischemic heart disease--a causal association? A review. 2010 78


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