title: Identification of Genetic Variants Linking Protein C and Lipoprotein Metabolism: The ARIC Study (Atherosclerosis Risk in Communities).
abstract: Previous studies have identified common genetic variants in 4 chromosomal regions that together account for 14% to 15% of the variance in circulating levels of protein C. To further characterize the genetic architecture of protein C, we obtained denser coverage at some loci, extended investigation of protein C to low-frequency and rare variants, and searched for new associations in genes known to influence protein C.
  
  
  
  Genetic associations with protein C antigen level were evaluated in ≤10 778 European and 3190 black participants aged 45 to 64 years. Analyses included >26 million autosomal variants available after imputation to the 1000 Genomes reference panel along with additional low-frequency and rare variants directly genotyped using the Illumina ITMAT-Broad-CARe chip and Illumina HumanExome BeadChip. Genome-wide significant associations (P<5×10-8) were found for common variants in theGCKR,PROC,BAZ1B, andPROCR-EDEM2regions in whites andPROCandPROCR-EDEM2regions in blacks, confirming earlier findings. In a novel finding, the low-density lipoprotein cholesterol-lowering allele of rs12740374, located in the CELSR2-PSRC1-SORT1 region, was associated with lower protein C level in both whites and blacks, reaching genome-wide significance in a meta-analysis combining results from both groups (P=1.4×10-9). To further investigate a possible link between lipid metabolism and protein C level, we conducted Mendelian randomization analyses using 185 lipid-related genetic variants as instrumental variables. The results indicated that triglycerides, and possibly low-density lipoprotein cholesterol, influence protein C levels.
  
  
  
  Discovery of variants influencing circulating protein C levels in the CELSR2-PSRC1-SORT1 region may indicate a novel genetic link between lipoprotein metabolism and hemostasis.
authors.affiliation: From the Division of Epidemiology and Community Health (J.S.P., W.T., L.-C.W., A.R.F.), Department of Laboratory Medicine and Pathology (N.P.), and Division of Biostatistics (W.G.), University of Minnesota, Minneapolis; Department of Medicine (M.C.) and Department of Pathology (M.C.), University of Vermont, Burlington; and Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.). pankow@umn.edu.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: From the Division of Epidemiology and Community Health (J.S.P., W.T., L.-C.W., A.R.F.), Department of Laboratory Medicine and Pathology (N.P.), and Division of Biostatistics (W.G.), University of Minnesota, Minneapolis; Department of Medicine (M.C.) and Department of Pathology (M.C.), University of Vermont, Burlington; and Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.).
authors.forename: Weihong
authors.initials: W
authors.lastname: Tang
authors.affiliation: From the Division of Epidemiology and Community Health (J.S.P., W.T., L.-C.W., A.R.F.), Department of Laboratory Medicine and Pathology (N.P.), and Division of Biostatistics (W.G.), University of Minnesota, Minneapolis; Department of Medicine (M.C.) and Department of Pathology (M.C.), University of Vermont, Burlington; and Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.).
authors.forename: Nathan
authors.initials: N
authors.lastname: Pankratz
authors.affiliation: From the Division of Epidemiology and Community Health (J.S.P., W.T., L.-C.W., A.R.F.), Department of Laboratory Medicine and Pathology (N.P.), and Division of Biostatistics (W.G.), University of Minnesota, Minneapolis; Department of Medicine (M.C.) and Department of Pathology (M.C.), University of Vermont, Burlington; and Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.).
authors.forename: Weihua
authors.initials: W
authors.lastname: Guan
authors.affiliation: From the Division of Epidemiology and Community Health (J.S.P., W.T., L.-C.W., A.R.F.), Department of Laboratory Medicine and Pathology (N.P.), and Division of Biostatistics (W.G.), University of Minnesota, Minneapolis; Department of Medicine (M.C.) and Department of Pathology (M.C.), University of Vermont, Burlington; and Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.).
authors.forename: Lu-Chen
authors.initials: LC
authors.lastname: Weng
authors.affiliation: From the Division of Epidemiology and Community Health (J.S.P., W.T., L.-C.W., A.R.F.), Department of Laboratory Medicine and Pathology (N.P.), and Division of Biostatistics (W.G.), University of Minnesota, Minneapolis; Department of Medicine (M.C.) and Department of Pathology (M.C.), University of Vermont, Burlington; and Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.).
authors.forename: Mary
authors.initials: M
authors.lastname: Cushman
authors.affiliation: From the Division of Epidemiology and Community Health (J.S.P., W.T., L.-C.W., A.R.F.), Department of Laboratory Medicine and Pathology (N.P.), and Division of Biostatistics (W.G.), University of Minnesota, Minneapolis; Department of Medicine (M.C.) and Department of Pathology (M.C.), University of Vermont, Burlington; and Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.).
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: From the Division of Epidemiology and Community Health (J.S.P., W.T., L.-C.W., A.R.F.), Department of Laboratory Medicine and Pathology (N.P.), and Division of Biostatistics (W.G.), University of Minnesota, Minneapolis; Department of Medicine (M.C.) and Department of Pathology (M.C.), University of Vermont, Burlington; and Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston (E.B.).
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Folsom
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D001741:Black or African American / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood*; D002878:Chromosomes, Human, Pair 1; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006487:Hemostasis / Q000235:genetics*; D006801:Humans; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011486:Protein C / Q000235:genetics* / Q000378:metabolism*; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D014481:United States; D044465:White People / Q000235:genetics; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015820:Cadherins; D008078:Cholesterol, LDL; D005819:Genetic Markers; D010750:Phosphoproteins; D011486:Protein C; D014280:Triglycerides; D000099183:Sortilin; C498477:CELSR2 protein, human; C485740:PSRC1 protein, human
keywords: cholesterol, HDL; cholesterol, LDL; genetic association studies; protein C; triglycerides