title: Genome-wide association study identifies novel loci for plasma levels of protein C: the ARIC study.
abstract: Protein C is an important endogenous anticoagulant in hemostasis. Deficiencies of protein C due to genetic mutations or a low level of circulating protein C increase the risk of venous thromboembolism. We performed a genome-wide association scan for plasma protein C antigen concentration with approximately 2.5 million single-nucleotide polymorphisms in 8048 individuals of European ancestry and a replication analysis in a separate sample of 1376 individuals in the Atherosclerosis Risk in Communities Study. Four independent loci from 3 regions were identified with genome-wide significance: 2p23 (GCKR, best SNP rs1260326, P = 2.04 × 10(-17)), 2q13-q14 (PROC, rs1158867, P = 3.77 × 10(-36)), 20q11 (near and within PROCR, rs8119351, P = 2.68 × 10(-203)), and 20q11.22 (EDEM2, rs6120849, P = 7.19 × 10(-37) and 5.23 × 10(-17) before and after conditional analysis, respectively). All 4 loci replicated in the independent sample. Furthermore, pooling the discovery and replication sets yielded an additional locus at chromosome 7q11.23 (BAZ1B, rs17145713, P = 2.83 × 10(-8)). The regions marked by GCKR, EDEM2, and BAZ1B are novel loci that have not been previously reported for association with protein C concentration. In summary, this first genome-wide scan for circulating protein C concentration identified both new and known loci in the general population. These findings may improve the understanding of physiologic mechanisms in protein C regulation.
authors.affiliation: Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA. tang0097@umn.edu
authors.forename: Weihong
authors.initials: W
authors.lastname: Tang
authors.forename: Saonli
authors.initials: S
authors.lastname: Basu
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Kong
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.forename: Nena
authors.initials: N
authors.lastname: Aleksic
authors.forename: Adrian
authors.initials: A
authors.lastname: Tan
authors.forename: Mary
authors.initials: M
authors.lastname: Cushman
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Folsom
mesh_terms: D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011486:Protein C / Q000235:genetics*
chemical_list: D011486:Protein C
references.citation: Circ Cardiovasc Genet. 2009 Feb;2(1):73-80
references.pmid: 20031568
references.citation: J Thromb Haemost. 2007 Jul;5 Suppl 1:73-80
references.pmid: 17635713
references.citation: J Thromb Haemost. 2005 Jul;3(7):1428-31
references.pmid: 15978099
references.citation: Ann Epidemiol. 1992 Sep;2(5):723-33
references.pmid: 1342324
references.citation: JAMA. 2007 Feb 7;297(5):489-98
references.pmid: 17284699
references.citation: N Engl J Med. 1983 Aug 11;309(6):340-4
references.pmid: 6688122
references.citation: Thromb Haemost. 2001 Jan;85(1):88-92
references.pmid: 11204594
references.citation: Hum Biol. 2005 Feb;77(1):1-15
references.pmid: 16114812
references.citation: Arterioscler Thromb Vasc Biol. 2002 Jun 1;22(6):1018-22
references.pmid: 12067914
references.citation: Diabetes. 2008 Nov;57(11):3112-21
references.pmid: 18678614
references.citation: Arterioscler Thromb Vasc Biol. 1995 Feb;15(2):214-8
references.pmid: 7749828
references.citation: Blood. 1995 May 15;85(10):2756-61
references.pmid: 7742536
references.citation: Circulation. 2000 Apr 4;101(13):1546-51
references.pmid: 10747348
references.citation: Thromb Haemost. 2008 Sep;100(3):405-12
references.pmid: 18766255
references.citation: Curr Med Chem. 2004 Sep;11(17):2275-90
references.pmid: 15379712
references.citation: Am J Epidemiol. 1989 Apr;129(4):687-702
references.pmid: 2646917
references.citation: J Clin Invest. 1981 Nov;68(5):1370-3
references.pmid: 6895379
references.citation: Glycobiology. 2005 Apr;15(4):421-36
references.pmid: 15537790
references.citation: Am J Hum Genet. 2009 Nov;85(5):628-42
references.pmid: 19913121
references.citation: Arterioscler Thromb Vasc Biol. 1999 Jun;19(6):1573-6
references.pmid: 10364092
references.citation: J Biol Chem. 2005 Jan 28;280(4):2424-8
references.pmid: 15579471
references.citation: Am J Hum Genet. 2008 May;82(5):1185-92
references.pmid: 18439548
references.citation: Circulation. 2010 Mar 30;121(12):1382-92
references.pmid: 20231535
references.citation: Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1968-74
references.pmid: 19696402
references.citation: J Thromb Haemost. 2008 Oct;6(10):1625-32
references.pmid: 18680534
references.citation: Hum Mol Genet. 2008 Oct 15;17(R2):R122-8
references.pmid: 18852200
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W635-41
references.pmid: 16845089
references.citation: Thromb Haemost. 1996 Nov;76(5):651-62
references.pmid: 8950768
references.citation: Bioinformatics. 2007 May 15;23(10):1294-6
references.pmid: 17384015
references.citation: Thromb Haemost. 2009 Jan;101(1):62-7
references.pmid: 19132190
references.citation: Nat Genet. 2006 Aug;38(8):904-9
references.pmid: 16862161
references.citation: Int J Biochem Cell Biol. 2008;40(12):2692-7
references.pmid: 18249579
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14511-6
references.pmid: 10588736