Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels

Abstract

• Genome-wide association analyses revealed common DNA variants in PLG, LPA, and near SIGLEC14 that contribute to plasma plasminogen level variation.• Tobacco smoking and female sex were associated with higher levels of plasminogen.Plasminogen is the precursor of the serine protease plasmin, a central enzyme of the fibrinolytic system. Plasma levels of plasminogen vary by almost 2-fold among healthy individuals, yet little is known about its heritability or genetic determinants in the general population. In order to identify genetic factors affecting the natural variation of plasminogen levels, we performed a genome-wide association study and linkage analysis in a sample of 3456 young healthy individuals who participated in the Genes and Blood Clotting Study (GABC) or the Trinity Student Study (TSS). Heritability of plasminogen levels was 48.1% to 60.0%. Tobacco smoking and female sex were associated with higher levels of plasminogen. In the meta-analysis, 11 single-nucleotide polymorphisms (SNPs) in 2 regions reached genome-wide significance (P < 5.0E-8). Of these, 9 SNPs were near the PLG or LPA genes on Chr6q26, whereas 2 were on Chr19q13 and 59 upstream of SIGLEC14. These 11 SNPs represented 4 independent signals and collectively explained 6.8% of plasminogen level variation in the study populations. The strongest association was observed for a nonsynonymous SNP in the PLG gene (R523W). Individuals bearing an additional copy of this allele had an average decrease of 13.4% in plasma plasminogen level. (Blood. 2014;124(20):3155-3164)

Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels

“…Details of genotyping and the data-cleaning process have been previously published. 11,16 Nine hundred forty of the 1152 GABC participants and all 2304 TSS participants had verified European ancestry. 11,16 The final cleaned genotype data set contained 795 544 single nucleotide polymorphisms (SNPs) for 1152 GABC participants and 755 451 SNPs for 2304 TSS participants.…”

“…11,16 Nine hundred forty of the 1152 GABC participants and all 2304 TSS participants had verified European ancestry. 11,16 The final cleaned genotype data set contained 795 544 single nucleotide polymorphisms (SNPs) for 1152 GABC participants and 755 451 SNPs for 2304 TSS participants. After combining imputed genotypes from both cohorts, 17 the final data set contained ;5.82 million SNPs common to both cohorts.…”

“…18 We used 557 sibships (1139 GABC and 138 TSS sibs) and also used 2 pedigree-based methods to estimate the narrow-sense heritability of ADAMTS13 levels: (1) intraclass correlation of sibpairs 16 using the irr package 19 in R 20 and (2) pedigree-wide regression analysis using MERLIN-REGRESS (v1.1.2). 21 …”

The Dihydrofolate Reductase 19 bp Polymorphism Is Not Associated with Biomarkers of Folate Status in Healthy Young Adults, Irrespective of Folic Acid Intake

“…The subjects for this study have been described previously (14)(15)(16)(17)(18) and consisted of healthy students with Irish grandparents who had attended the University of Dublin, Trinity College, during a 12 mo recruitment period between February 2003 and February 2004. Overall, 3569 students applied; of these, 2524 individuals who had Irish grandparents and had no major medical problems were invited to participate.…”

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

“…Furthermore, plasma plasminogen concentrations vary by about twofold among healthy individuals. The heritability of plasminogen is estimated to range from 0.48 to 0.68 ( Ma et al 2014). The plasminogen gene ( PLG ) and LPA gene are located on chromosome 6q26 within ∼40 kb of each other (Crawford et al 2008).…”