title: Genetic variants associated with protein C levels.
abstract: BACKGROUND
  Normal protein C (PC) plasma levels range widely in the general population. Factors influencing normal PC levels are thought to influence the risk of venous thrombosis. Little is known about the underlying genetic variants.
  
  
  OBJECTIVE
  We performed a genome scan of normal PC levels to identify genes that regulate normal PC levels.
  
  
  METHODS
  We performed a variance components linkage analysis for normal PC levels in 275 individuals from a single, large family. We then sequenced candidate genes under the identified linkage peak in eight family members: four with high and four with low, but normal, PC levels. For variants showing a difference in carriers between those with high and low PC levels, we re-evaluated linkage in the 275 family members conditional on the measured genotype effect. Genotype-specific mean PC levels were determined using likelihood analysis. Findings were replicated in the Leiden Thrombophilia Study (LETS).
  
  
  RESULTS
  We identified a quantitative trait locus at chromosome 5q14.1 affecting normal PC plasma level variability. Next-generation sequencing of 113 candidate genes under the linkage peak revealed four SNPs in BHMT2, ACOT12, SSBP2 and XRCC4, which significantly increased PC levels in our thrombophilic family, but not in LETS.
  
  
  CONCLUSIONS
  We identified four genes at chromosome 5q14.1 that might influence normal PC levels. BHMT2 seems the most likely candidate to regulate PC levels via homocysteine, a competitive inhibitor to thrombin. Failure to replicate our findings in LETS might be due to differences between the studies in genetic background and linkage disequilibrium patterns.
authors: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands.
authors: C Y
authors: CY
authors: Vossen
authors: B P
authors: BP
authors: Koeleman
authors: S J
authors: SJ
authors: Hasstedt
authors: I J
authors: IJ
authors: Nijman
authors: I J
authors: IJ
authors: Renkens
authors: P W
authors: PW
authors: Callas
authors: F R
authors: FR
authors: Rosendaal
authors: E G
authors: EG
authors: Bovill
mesh_terms: D016022:Case-Control Studies; D008040:Genetic Linkage; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011486:Protein C / Q000235:genetics / Q000378:metabolism*
chemical_list: D011486:Protein C
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