The Identification and Significance of a Thr→Pro Polymorphism in Kringle IV Type 8 of Apolipoprotein(a)

Prins, J. A.; Leus, F.R.; Hoek, Ytje Y. van der; Kastelein, J.J.P.; Bouma, Bonno N.; Rijn, H. J. M. Van

doi:10.1055/s-0038-1656083

Cited by 19 publications

(18 citation statements)

References 29 publications

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“…G-21A raised LPA promoter activity by 90% in a chloramphenicol acetyltransferase assay in transfected HepG2 cells. 36 Lp(a)-lowering T3888P occurs in apo(a) KIV-8, which is required for lysine-mediated apo(a)-apolipoprotein B-100 interaction during Lp(a) assembly, 37 and reduced maximal attainable binding of Lp(a) to lysine by 75% in vitro. 38 Lp(a)-lowering G+1/inKIV-A markedly impairs Lp(a) assembly.…”

Section: Discussionmentioning

confidence: 99%

Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans

Chretien

Coresh²,

Berthier-Schaad

et al. 2006

Journal of Medical Genetics

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Background: The extent which universally common or population-specific alleles can explain betweenpopulation variations in phenotypes is unknown. The heritable coronary heart disease risk factor lipoprotein(a) (Lp(a)) level provides a useful case study of between-population variation, as the aetiology of twofold higher Lp(a) levels in African populations compared with non-African populations is unknown. Objective: To evaluate the association between LPA sequence variations and Lp(a) in European Americans and African Americans and to determine the extent to which LPA sequence variations can account for between-population variations in Lp(a). Methods: Serum Lp(a) and isoform measurements were examined in 534 European Americans and 249 African Americans from the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease Study. In addition, 12 LPA variants were genotyped, including 8 previously reported LPA variants with a frequency of .2% in European Americans or African Americans, and four new variants. Results: Isoform-adjusted Lp(a) level was 2.23-fold higher among African Americans. Three singlenucleotide polymorphisms (SNPs) were independently associated with Lp(a) level (p,0.02 in both populations). The Lp(a)-increasing SNP (G-21A, which increases promoter activity) was more common in African Americans, whereas the Lp(a)-lowering SNPs (T3888P and G+1/inKIV-8A, which inhibit Lp(a) assembly) were more common in European Americans, but all had a frequency of ,20% in one or both populations. Together, they reduced the isoform-adjusted African American Lp(a) increase from 2.23 to 1.37-fold(a 60% reduction) and the between-population Lp(a) variance from 5.5% to 0.5%. Conclusions: Multiple low-prevalence alleles in LPA can account for the large between-population difference in serum Lp(a) levels between European Americans and African Americans.

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Section: Discussionmentioning

confidence: 99%

Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans

Chretien

Coresh²,

Berthier-Schaad

et al. 2006

Journal of Medical Genetics

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“…2 Kringle IV type 7 polymorphisms originally described by Prins et al [63]. 3 Kringle IV type 8 polymorphism originally described by Prins et al [67]. 4 Kringle IV type 8 polymorphism originally described by Ogorelkova et al [53].…”

Section: Linkage Disequilibrium Within Lpamentioning

confidence: 99%

<i>LPA</i> and <i>PLG</i> Sequence Variation and Kringle IV-2 Copy Number in Two Populations

et al. 2008

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Background/Aims: Lp(a) levels have long been recognized as a potential risk factor for coronary heart disease that is almost completely under genetic control. Much of the genetics impacting Lp(a) levels has been attributed to the highly polymorphic LPA kringle IV-2 copy number variant, and most of the variance in Lp(a) levels in populations of European-descent is inversely correlated with kringle IV copy number. However, less of the variance is explained in African-descent populations for the same structural variation. African-descent populations have, on average, higher levels of Lp(a), suggesting other genetic factors contribute to Lp(a) level variability across populations. Methods: To identify potential cis-acting factors, we re-sequenced the gene LPA for single nucleotide polymorphism (SNP) discovery in 23 European-Americans and 24 African-Americans. We also re- sequenced the neighboring gene plasminogen (PLG) and genotyped the kringle IV copy number variant in the same reference samples. Results: These data are the most comprehensive description of sequence variation in LPA and its relationship with the kringle IV copy number variant. With these data, we demonstrate that only a fraction of LPA sequence diversity has been previously documented. Also, we identify several high frequency SNPs present in the African-American sample but absent in the European-American sample. Finally, we show that SNPs within PLG are not in linkage disequilibrium with SNPs in LPA, and we show that kringle IV copy number variation is not in linkage disequilibrium with either LPA or PLG SNPs. Conclusions: Together, these data suggest that LPA SNPs could independently contribute to Lp(a) levels in the general population.

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“…Some cSNPs resulting in amino acid changes and a splice site mutation have been detected in the K IV types 6-10 (K IV-6 to K IV-10) Prins et al, 1997;Ogorelkova et al, 1999Ogorelkova et al, , 2001. However, neither of these polymorphisms alone or in combination completely explain the genetic variation of Lp(a) levels.…”

Section: Introductionmentioning

confidence: 99%

A common nonsense mutation in the repetitive Kringle IV-2 domain of human apolipoprotein(a) results in a truncated protein and low plasma Lp(a)

et al. 2004

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LPA, the gene coding for apolipoprotein(a) [apo(a)], is the major determinant of lipoprotein(a) [Lp(a)] plasma levels, which are associated with risk for coronary heart disease (CHD) and stroke. It is not completely understood how variation in LPA relates to Lp(a) concentrations. One type of variation related to Lp(a) levels is the number of Kringle (K) IV-2 (g.61C>T; GenBank L14005.1) repeats in LPA, but sequence variation may also contribute. Human apo(a) contains from two to >40 nearly identical K IV-2 repeats of genomic size 5.5 kb, which makes it difficult to detect mutations. To elucidate the genetic variation of the apo(a) K IV-2 domain, we isolated a single "nonexpressing" apo(a) allele with 26 K IV-2 repeats, followed by PCR, cloning and sequencing of 96 clones, resulting in an average coverage of each K IV-2 repeat of approximately four-fold. The previously described K IV types 2A and 2B (K IV-2A and K IV-2B) were detected in 74% of the clones. In addition, a new type designated 2C (K IV-2C) was present. A nonsense mutation in the first exon of K IV-2 (g.61C>T) predicted to result in a truncated protein (p.R21X) was found in nine clones on a K IV-2A background. The presence of this mutation was confirmed by analysis of genomic DNA and was shown to represent the rare allele (frequency 0.02) of a SNP. Immunoblot analysis of apo(a) from plasma confirmed the presence of a truncated apo(a) isoform in the index individual and family members. Our data show that SNPs affecting Lp(a) plasma concentrations also exist in the apo(a) K IV-2 domain.

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The Identification and Significance of a Thr→Pro Polymorphism in Kringle IV Type 8 of Apolipoprotein(a)

Cited by 19 publications

References 29 publications

Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans

Three single-nucleotide polymorphisms in LPA account for most of the increase in lipoprotein(a) level elevation in African Americans compared with European Americans

<i>LPA</i> and <i>PLG</i> Sequence Variation and Kringle IV-2 Copy Number in Two Populations

A common nonsense mutation in the repetitive Kringle IV-2 domain of human apolipoprotein(a) results in a truncated protein and low plasma Lp(a)

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