title: Genetic variants in PLG, LPA, and SIGLEC 14 as well as smoking contribute to plasma plasminogen levels.
abstract: 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 5' 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.
authors.affiliation: Department of Human Genetics.
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Human Genetics.
authors.forename: Ayse B
authors.initials: AB
authors.lastname: Ozel
authors.affiliation: Department of Human Genetics.
authors.forename: Shweta
authors.initials: S
authors.lastname: Ramdas
authors.affiliation: Howard Hughes Medical Institute.
authors.forename: Beth
authors.initials: B
authors.lastname: McGee
authors.affiliation: Department of Internal Medicine, and.
authors.forename: Rami
authors.initials: R
authors.lastname: Khoriaty
authors.affiliation: Howard Hughes Medical Institute.
authors.forename: David
authors.initials: D
authors.lastname: Siemieniak
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI;
authors.forename: Hong-Dong
authors.initials: HD
authors.lastname: Li
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI;
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Guan
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Brody
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD;
authors.forename: James L
authors.initials: JL
authors.lastname: Mills
authors.affiliation: School of Medicine, Trinity College, Dublin, Ireland; and.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.affiliation: Department of Human Genetics, Howard Hughes Medical Institute, Department of Internal Medicine, and Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, MI.
authors.forename: David
authors.initials: D
authors.lastname: Ginsburg
authors.affiliation: Department of Human Genetics.
authors.forename: Jun Z
authors.initials: JZ
authors.lastname: Li
authors.affiliation: Department of Pediatrics and Communicable Disease, University of Michigan, Ann Arbor, MI.
authors.forename: Karl C
authors.initials: KC
authors.lastname: Desch
mesh_terms: D000293:Adolescent; D000328:Adult; D001054:Apolipoproteins A / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D037102:Lectins / Q000235:genetics*; D008297:Male; D010958:Plasminogen / Q000032:analysis* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D012907:Smoking / Q000097:blood*; D055815:Young Adult
chemical_list: D001054:Apolipoproteins A; D037102:Lectins; D011956:Receptors, Cell Surface; C514213:SIGLEC14 protein, human; D010958:Plasminogen