Plasma lipoprotein(a) levels and expression of the apolipoprotein(a) gene are dependent on the nucleotide polymorphisms in its 5'-flanking region.

Suzuki, Kazuko; Kuriyama, Masaru; Saitô, Tetsuo; Ichinose, Akitada

doi:10.1172/jci119295

Cited by 69 publications

(56 citation statements)

References 39 publications

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“…LPA encodes apolipoprotein(a), a protein component of Lp(a), and variation in this gene is known to affect the concentration of Lp(a) in the blood. The þ 93 promoter polymorphism influences expression of LPA 43 and has been associated with serum Lp(a) levels in Japanese and Africans. 44,45 In the Hutterites, the þ 93T allele was very significantly associated with high Lp(a) levels by the GTAM and CC tests.…”

Section: Discussionmentioning

confidence: 99%

Are common disease susceptibility alleles the same in outbred and founder populations?

et al. 2004

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Founder populations have been the subjects of complex disease studies because of their decreased genetic heterogeneity, increased linkage disequilibrium and more homogeneous environmental exposures. However, it is possible that disease alleles identified in founder populations may not contribute significantly to susceptibility in outbred populations. In this study we examine the Hutterites, a founder population of European descent, for 103 polymorphisms in 66 genes that are candidates for cardiovascular or inflammatory diseases. We compare the frequencies of alleles at these loci in the Hutterites to their frequencies in outbred European-American populations and test for associations with cardiovascular disease-associated phenotypes in the Hutterites. We show that alleles at these loci are found at similar frequencies in the Hutterites and in outbred populations. In addition, we report associations between 39 alleles or haplotypes and cardiovascular disease phenotypes (Po0.05), with five loci remaining significant after adjusting for multiple comparisons. These data indicate that this founder population is informative and offers considerable advantages for genetic studies of common complex diseases.

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Section: Discussionmentioning

confidence: 99%

Are common disease susceptibility alleles the same in outbred and founder populations?

et al. 2004

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“…However, alleles with eight repeats are the most frequent in all populations (156,175,181). This polymorphism has been repeatedly shown to be associated with Lp(a) levels (175,(181)(182)(183) and explains, in a statistical sense, 3-14% of the variability in Lp(a) levels in Europeans (181). Higher Lp(a) levels have been reported for alleles harboring a lower number of pentanucleotide repeats in Europeans, but this association was not found in Africans (181).…”

Section: The 5′pentanucleotide Repeat Polymorphismmentioning

confidence: 99%

Structure, function, and genetics of lipoprotein (a)

Schmidt

Noureen

Kronenberg

et al. 2016

Journal of Lipid Research

444

346

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between apoB-100 of the LDL moiety and one of the kringle domains in apo(a) (4,5,(14)(15)(16). The assembly of Lp(a) is believed to occur at the hepatocyte cell membrane surface (17), but other scenarios have also been proposed [reviewed in (18, 19)].Lp(a) was originally described as a dichotomous (Lp+, Lp) genetic trait (20), but it soon became evident that it is quantitative rather than qualitative in nature (21-23). Lp(a) plasma concentrations are highly heritable (24-28). The major locus controlling the Lp(a) concentrations is the LPA gene (MIM 152200; ENSG00000198670) on the reverse strand of chromosome 6q27 (29-31), which encodes the apo(a) component of Lp(a) (25,26,(32)(33)(34). Close LPA orthologs are found in all apes and in Old World monkeys. INTRA-AND INTER-POPULATION DIFFERENCES INLp ( INTRODUCTION TO THE LIPOPROTEIN (a) TRAITHuman lipoprotein (a) [Lp(a)] is a macromolecular complex in plasma that was first described in 1963 by the Norwegian physician Kåre Berg (1). Ever since its discovery, this enigmatic particle has intrigued basic researchers and clinicians due to its unknown physiological function and its association with atherosclerotic diseases, in particular coronary heart disease (CHD) [reviewed in (2)]. Lp(a) is composed of one molecule of a LDL-particle containing apoB-100 and one molecule of a large highly polymorphic glycoprotein named apo(a) (3-6). A characteristic feature of apo(a) is the presence of loop-like structures called kringles (7,8). Kringle domains are triple loop structures stabilized by three internal disulfide bonds and are also present in other coagulation factors, such as plasminogen (PLG), prothrombin, urokinase, and tissue-type PLG activators (9-12). In contrast to PLG, the linker domain between kringles is glycosylated in apo(a). The apo(a) is synthesized by the liver (13). The two components of Lp(a) are covalently linked together by a disulfide bond

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“…As reported recently, genetic variation in these non-coding sequences may affect enzyme expression, transcript stability or splicing. 17,18 In the present study, we analysed a variable number of tandem repeats (VNTR) of 31 bp which spans the exon 13-intron 13 boundary of the CBS gene in 190 patients with arterial occlusive disease and in 381 populationbased controls. This VNTR was first described by Kraus et al 19 Each repeat unit contains a consensus splice donor site and this VNTR may therefore affect homocysteine metabolism.…”

Section: Introductionmentioning

confidence: 99%

A 31 bp VNTR in the cystathionine β-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels

Lievers¹,

Kluijtmans²,

Heil³

et al. 2001

Eur J Hum Genet

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Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinaemia, an independent and graded risk factor for cardiovascular disease (CVD). Although heterozygosity for cystathionine b-synthase (CBS) deficiency has been excluded as a major genetic cause of mild hyperhomocysteinaemia in vascular disease, mutations in (non-)coding DNA sequences may lead to a mildly decreased CBS expression and, consequently, to elevated plasma homocysteine levels. We assessed the association between a 31 bp VNTR, that spans the exon 13-intron 13 boundary of the CBS gene, and fasting, post-methionine load and increase upon methionine load plasma homocysteine levels in 190 patients with arterial occlusive disease, and in 381 controls. The 31 bp VNTR consists of 16, 17, 18, 19 or 21 repeat units and shows a significant increase in plasma homocysteine concentrations with an increasing number of repeat elements, in particular after methionine loading. In 26 vascular disease patients the relationship between this 31 bp VNTR and CBS enzyme activity in cultured fibroblasts was studied. The CBS enzyme activity decreased with increasing number of repeat units of the 31 bp VNTR. RT ± PCR experiments showed evidence of alternative splicing at the exon 13-intron 13 splice junction site. The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.

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Plasma lipoprotein(a) levels and expression of the apolipoprotein(a) gene are dependent on the nucleotide polymorphisms in its 5'-flanking region.

Abstract: The apolipoprotein(a) (

Cited by 69 publications

References 39 publications

Are common disease susceptibility alleles the same in outbred and founder populations?

Are common disease susceptibility alleles the same in outbred and founder populations?

Structure, function, and genetics of lipoprotein (a)

A 31 bp VNTR in the cystathionine β-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels

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