Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians

Khalifa, Mahmoud A.; Noureen, Asma; Ertelthalner, Kathrin; Bandegi, Ahmad Reza; Delport, Rhena; Firdaus, Wance; Geethanjali, Finney S.; Luthra, Kalpana; Makemaharn, Orawan; Pang, Roberta; Salem, Abdel Halim; Sasaki, Jun; Schiefenhoevel, Wulf; Lingenhel, Arno; Kronenberg, Florian; Utermann, Gerd; Schmidt, Konrad

doi:10.1016/j.atherosclerosis.2015.07.015

Cited by 23 publications

(27 citation statements)

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“…Interestingly, this SNP is not present at all in Africans, 40 is present in <10% in Asian Indians but is more prevalent (11.6%) in East Asians such as Chinese in Hong Kong. 41,42 LPA SNP rs10455872 is present in 7-15% of the general population in Europeans. 8,43,44 Its prevalence increases with increasing Lp(a) levels and is present in 47% of northern Europeans with Lp(a) levels >95th percentile.…”

Section: Discussionmentioning

confidence: 99%

LPA Gene, Ethnicity, and Cardiovascular Events

et al. 2017

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Background The relationship of LPA single nucleotide polymorphisms (SNPs), apolipoprotein(a) isoforms and lipoprotein(a) [Lp(a)] levels with major adverse cardiovascular (MACE) events in different ethnic groups is not well known. Methods LPA SNPs, apolipoprotein(a) isoforms, Lp(a) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) levels were measured in 1792 Black, 1030 White and 597 Hispanic subjects enrolled in the Dallas Heart Study. Their interdependent relationships and prospective association with MACE after median 9.5-year follow-up were determined. Results LPA SNP rs3798220 was most prevalent in Hispanics (42.38%), rs10455872 in Whites (14.27%) and rs9457951 in Blacks (32.927%). The correlation of each of these SNPs with the major apolipoprotein(a) isoform size was highly variable and in different directions among ethnic groups. In the entire cohort, Cox regression analysis with multivariable adjustment revealed that quartiles 4 of Lp(a) and OxPL-apoB were associated with hazard ratios (HR) (95% CI) for time to MACE of 2.35 (1.50-3.69), p<0.001) and 1.89 (1.26-2.84), p=0.003), respectively, versus quartile 1. Addition of the major apolipoprotein(a) isoform and the 3 LPA SNPs to these models attenuated the risk, but significance was maintained for both Lp(a) and OxPL-apoB. Evaluating specific ethnic groups, in Blacks Lp(a) was a positive predictor and the size of the major apolipoprotein(a) isoform and inverse predictor, in Whites the size of the major apolipoprotein(a) isoform was an inverse predictor and in Hispanics OxPL-apoB was a predictor of time to MACE. Conclusion The prevalence and association of LPA SNPs with size of apolipoprotein(a) isoforms, Lp(a) and OxPL-apoB levels are highly variable and ethnicity-specific. The relationship to MACE is best explained by elevated plasma Lp(a) or OxPL-apoB levels, despite significant ethnic differences in LPA genetic markers.

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Section: Discussionmentioning

confidence: 99%

LPA Gene, Ethnicity, and Cardiovascular Events

et al. 2017

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“…(19) Este es el primer estudio que aporta, en parte, evidencia de la relación estrecha entre niveles, polimorfismos específi-cos y calcificaciones torácicas en un grupo de pacientes de nuestra región.…”

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Lipoprotein a: Extreme elevation and genetic polymorphism association with cardiac and vascular lesions evaluated by computed tomography

et al. 2018

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RESUMENIntroducción: La lipoproteína a [Lp(a)] es una partícula compleja, similar a una lipoproteína de baja densidad, asociada con una molécula de apolipoproteína "a" [apo(a)]. La concentración elevada de Lp(a) plasmática se asocia con riesgo aumentado de enfermedad coronaria y de calcificación valvular aórtica. El riesgo inherente a esta relación está determinado principalmente por factores genéticos. Objetivos: Analizar un grupo de pacientes con elevaciones extremas de Lp(a) [> 100 mg/dl], su asociación con calcificaciones cardiovasculares torácicas (valvulares, coronarias, aorta torácica) detectadas mediante tomografía axial computarizada y evaluar tres polimorfismos genéticos vinculados con los niveles de Lp(a) y lesiones en estas tres regiones. Material y métodos: Se estudiaron 40 pacientes en los que se analizaron los polimorfismos rs10455872 y rs2048327 mediante high resolution melting y el número de repeticiones de la secuencia KIV del exón 2 del gen LPA mediante qPCR. El promedio de edad de los pacientes fue de 52,9 años (37% mujeres) y el valor promedio de Lp(a) fue de 170,4 mg/dl. Resultados: El 75% (30/40) de los pacientes presentó al menos una calcificación en la tomografía (valvular, coronaria y/o aorta torácica); de los pacientes con calcificaciones, el 90% presentaron al menos uno de los factores genéticos asociados con mayor patogenicidad de la Lp(a). Conclusión: En un grupo de pacientes con niveles elevados de Lp(a) encontramos un número importante de calcificaciones cardiovasculares torácicas y determinantes genéticos asociados con diferentes isoformas de Lp(a), que podrían ocasionar los niveles elevados de Lp(a) y el riesgo de desarrollo de lesiones valvulares y/o vasculares. Palabras clave: Lipoproteína -Hiperlipidemia -Polimorfismo genético -Calcificación vascular ABSTRACTBackground: Lipoprotein a [Lp(a)] has a complex structure, similar to low density lipoprotein, associated with one molecule of apolipoprotein a [apo(a)]. Elevated plasma levels of Lp(a) are related to greater risk of coronary artery disease and calcification of the aortic valve. This risk is mainly determined by genetic factors. Objectives: The aim of this study was to analyze a group of patients with extreme Lp(a) levels [>100 mg/dL] and their association with calcifications of the aortic valve, coronary arteries and thoracic aorta detected by computed tomography scan, and to evaluate three genetic polymorphisms associated with Lp(a) levels and lesions in these three regions. Methods: rs10455872 and rs2048327 polymorphisms were analyzed in 40 patients using high resolution melting and the number of KIV-2 repeats in the LPA gene was evaluated using quantitative PCR. Patient mean age was 52.9 years (37% women) and mean Lp(a) was 170.4 mg/dL. Results: Seventy-five percent of patients (30/40) presented at least one calcification in the computed tomography scan (valves, coronary arteries and/or thoracic aorta), and among them, 90% had at least one of the genetic factors associated with Lp(a) pathogenicity. Conclusion: In a gr...

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“…25,26 However, studies that have assessed the association of SNPs with the Lp(a) level and CAD have conflicting results. [27][28][29] Khalifa et al reported that rs3798220 was not a marker for short Kringle IV-2 copy number variation alleles and high Lp(a) levels in East and Southeast Asians, although the haplotype background is shared with Europeans. 29 Lu et al reported that there was no difference in the LPA transcription levels between carriers and noncarriers of rs3798220 in the Amish population.…”

Section: Discussionmentioning

confidence: 99%

“…[27][28][29] Khalifa et al reported that rs3798220 was not a marker for short Kringle IV-2 copy number variation alleles and high Lp(a) levels in East and Southeast Asians, although the haplotype background is shared with Europeans. 29 Lu et al reported that there was no difference in the LPA transcription levels between carriers and noncarriers of rs3798220 in the Amish population. 16 Considering that the previous results from the SNPs in the LPA gene were limited to illuminate the mechanism by which the real causal variant acts, we expanded the region on the chromosome 6q26-27 to include 3 genes-SLC22A3, LPAL2, and LPA.…”

Section: Discussionmentioning

confidence: 99%

Functional Variant in the SLC22A3-LPAL2-LPA Gene Cluster Contributes to the Severity of Coronary Artery Disease

Wang¹,

Chen²,

Zeng³

et al. 2016

ATVB

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Objective— Recent genome-wide association studies have identified that genetic variants in the SLC22A3-LPAL2-LPA gene cluster influence plasma lipoprotein(a) [Lp(a)] concentration. However, the association between this gene cluster and the severity of coronary artery disease (CAD), especially the potential underlying mechanism, remains unclear. The purpose of this study was to investigate the association between variation in the SLC22A3-LPAL2-LPA gene cluster and CAD. Approach and Results— We performed 2-stage case–control studies in a Chinese Han population. The variant genotypes were examined for their association with both Lp(a) level and severity of CAD. Putative mechanisms were also evaluated. One single nucleotide polymorphism, rs3088442, in the SLC22A3-LPAL2-LPA gene cluster was significantly associated with both plasma Lp(a) levels and CAD severity. The gene dosage of the risk allele at rs3088442 indicated a robust association with left main trunk disease ( P =0.046), number of vascular lesions ( P =4.5×10 –3 ), and Gensini scores ( P =0.012) in patients with CAD. Reporter gene analysis indicated that the rs3088442 G allele might suppress miR-147a binding to the 3′ untranslated region of SLC22A3 , resulting in altered SLC22A3 and LPA gene expression ( P =0.015 and 9.2×10 –6 , respectively), possibly explaining the increased plasma Lp(a) levels and risk of CAD. Conclusions— The genotype of rs3088442 within the SLC22A3-LPAL2-LPA gene cluster may contribute to regulation of plasma Lp(a) levels and possibly to the severity of CAD in a Chinese Han population.

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Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians

Cited by 23 publications

References 50 publications

LPA Gene, Ethnicity, and Cardiovascular Events

LPA Gene, Ethnicity, and Cardiovascular Events

Lipoprotein a: Extreme elevation and genetic polymorphism association with cardiac and vascular lesions evaluated by computed tomography

Functional Variant in the SLC22A3-LPAL2-LPA Gene Cluster Contributes to the Severity of Coronary Artery Disease

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