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Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis.

ABSTRACT: Two genetic variants (rs3798220 and rs10455872) in the apolipoprotein (a) gene (LPA) have been implicated in cardiovascular disease (CVD), presumably through their association with lipoprotein (a) [Lp(a)] levels. While Lp(a) is recognized as a lipoprotein with atherogenic and thrombogenic characteristics, it is unclear whether or not the two Lp(a)-associated genetic variants are also associated with markers of thrombosis (i.e., plasminogen levels and fibrinolysis). In the present study, we genotyped the two genetic variants in 2919 subjects of the Old Order Amish (OOA) and recruited 146 subjects according to the carrier and noncarrier status for rs3798220 and rs10455872, and also matched for gender and age. We measured plasma Lp(a) and plasminogen levels in these subjects, and found that the concentrations of plasma Lp(a) were 2.62- and 1.73-fold higher in minor allele carriers of rs3798220 and rs10455872, respectively, compared with noncarriers (P = 2.04 × 10-17 and P = 1.64 × 10-6, respectively). By contrast, there was no difference in plasminogen concentrations between carriers and noncarriers of rs3798220 and rs10455872. Furthermore, we observed no association between carrier status of rs3798220 or rs10455872 with clot lysis time. Finally, plasminogen mRNA expression in liver samples derived from 76 Caucasian subjects was not significantly different between carriers and noncarriers of these two genetic variants. Our results provide further insight into the mechanism of action behind two genetic variants previously implicated in CVD risk and show that these polymorphisms are not major modulating factors for plasma plasminogen levels and fibrinolysis.

SUBMITTER: Wang H

PROVIDER: S-EPMC5100851 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis.

Wang Hong H Hong Chan E CE Lewis Joshua P JP Zhu Yanbei Y Wang Xing X Chu Xin X Backman Joshua J Hu Ziying Z Yang Peixin P Still Christopher D CD Gerhard Glenn S GS Fu Mao M

G3 (Bethesda, Md.) 20161108 11

Two genetic variants (rs3798220 and rs10455872) in the apolipoprotein (a) gene (<i>LPA</i>) have been implicated in cardiovascular disease (CVD), presumably through their association with lipoprotein (a) [Lp(a)] levels. While Lp(a) is recognized as a lipoprotein with atherogenic and thrombogenic characteristics, it is unclear whether or not the two Lp(a)-associated genetic variants are also associated with markers of thrombosis (<i>i.e.</i>, plasminogen levels and fibrinolysis). In the present s ...[more]

PMID: 27605514

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Project description:To examine the relations between genetic loci, plasma lipoprotein(a) [Lp(a)] levels, and cardiovascular disease (CVD) risk among diabetic patients and compare with the observations in the general population.In two prospective cohorts of patients with type 2 diabetes (n= 2308) from the Nurses' Health Study and the Health Professional Follow-Up Study, we performed (i) genome-wide association (GWA) scans for plasma Lp(a); (ii) prospective analysis of plasma Lp(a) for CVD risk and mortality; and (iii) genetic association analysis for CVD risk and mortality. Meta-analysis of the two GWA scans yielded 71 single-nucleotide polymorphisms (SNPs) on chromosome 6q associated with plasma Lp(a) levels at a genome-wide significance level (P< 5 × 10(-8)). The SNP rs10455872 in LPA was most strongly associated with Lp(a) (P= 4.60 × 10(-39)). Forward-selection analysis indicated that rs10455872 and other five SNPs in a region encompassing LPA, PLG, SLC22A3, and LPAL2 genes were independently associated with Lp(a) levels and jointly explained ?20% of variation in diabetic patients. In prospective analysis, we did not find any significant association between plasma levels and CVD incidence; the relative risk for coronary heart disease (CHD), CVD, and CVD death was 1.05 [95% confidence interval (CI): 0.95-1.15], 1.05 (0.96-1.15), and 1.21 (0.99-1.47) per 1-SD higher log-transformed Lp(a) levels, respectively. Consistently, none of the Lp(a) SNPs were associated with CVD risk or mortality (all P> 0.09). For the best SNP rs10455872 for plasma Lp(a) levels, the OR for CHD, CVD, and CVD death was 0.94 (95% CI: 0.69-1.28), 0.97 (0.72-1.29), and 1.23 (0.79-1.92), respectively. The genetic effect on CHD risk showed a significant heterogeneity between the diabetic and the general populations (P= 0.006).Our data indicate that the effect of Lp(a) on CVD risk among diabetic patients might be different from that in the general population. Diabetes status may attenuate the relation between Lp(a) and cardiovascular risk.

Dataset Information

Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis.

Publications

Effect of Two Lipoprotein (a)-Associated Genetic Variants on Plasminogen Levels and Fibrinolysis.

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