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. (Blood. 2010;116(23):5032-5036) IntroductionProtein C, a vitamin K-dependent plasma glycoprotein synthesized in the liver, is one of the most important endogenous anticoagulants. 1 Upon activation by the thrombin-thrombomodulin complex, it inactivates factor Va and FVIIIa and thus reduces the coagulation reaction and consequently formation of thrombi. Hereditary protein C deficiencies, characterized by reduction of protein C antigen/ activity due to rare genetic mutations, contribute to familial venous thrombosis. [2][3][4][5] In the general population, a low level of circulating protein C as well as common variants in the protein C gene are associated with increased risk of venous thromboembolism. [6][7][8][9] Activated protein C also exerts other physiologic effects including anti-inflammatory and antiapoptotic properties and endothelial barrier stabilization. 10 Treatment with activated protein C is effective for patients with severe sepsis and acute organ dysfunction. 10 Plasma levels of protein C are influenced by genetic factors, with a heritability of 0.36 and 0.50 in Spanish and MexicanAmerican families, respectively. 11,12 To date, only a few candidate genes studies of protein C focusing on a few variants have been reported. 9,13-15 A comprehensive investigation of genomic variants influencing protein C is not available in the literature. We performed a genome-wide association (GWA) scan for plasma protein C concentration with approximately 2.5 million singlenucleotide polymorphisms (SNPs), based on the data from a large population of individuals of European ance...

Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes

“…This association has been widely replicated in additional studies and populations (40)(41)(42). Further genome-wide analyses have documented associations of this region with risk of type 2 diabetes (T2D), total cholesterol, fasting insulin, C peptide, homeostasis model assessment of insulin resistance (HOMA-IR), and concentrations of a number of other metabolites, including C-reactive protein (CRP), mannose, the liver enzyme γ-glutamyl transferase, and urate (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). Functionally, p.Pro446Leu-GKRP has been shown to decrease F6P-mediated inhibition of GCK and reduce nuclear sequestration of GCK (13,43).…”

“…Given its central role in hepatic glucose metabolism, it is probably not surprising that GCKR has emerged as an important locus for susceptibility to diabetes and related traits (12,(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). GWAS initially identified a 400-kb region on chromosome 2 significantly associated with serum triglycerides (28).…”

The endothelial protein C receptor (PROCR) Ser219Gly variant and risk of common thrombotic disorders: a HuGE review and meta-analysis of evidence from observational studies

“…In a GWAS of plasma levels of PC including more than 8000 participants, the strongest association was observed at the PROCR locus, and the rs867186 polymorphism explained an estimated 10.4% of the variance in PC. 51 In 2 studies included in the systematic review that measured prothrombin (fragment 1 and 2) levels relative to genotype, a significant increase was seen for those with the G allele. 17,18 The G allele was also associated with elevated levels of FVII and FVIIa in a study of approximately 2000 healthy middle-aged men.…”

Common genetic factors for hematological traits in Humans

“…Although we do not discuss the results in this review, GWAS for coagulation and fibrinolysis have also been reported. [81][82][83][84][85] Associations at 12q24 Given the close biological relationship between PLT and CAD, 3 Soranzo et al 28 evaluated the risks of CAD in the loci associated with PLT and found an overlap between these two traits at 12q24. The variants identified at 12q24 were encompassed by a long-range haplotype that extended 41.5 Mbps on which significant pressure of natural selection was observed.…”