Genetic variants associated with protein C levels
Version of Record online: 11 APR 2013
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 4, pages 715–723, April 2013
How to Cite
Genetic variants associated with protein C levels. J Thromb Haemost 2013; 11: 715–23., , , , , , ,
- Issue online: 11 APR 2013
- Version of Record online: 11 APR 2013
- Accepted manuscript online: 7 FEB 2013 03:29AM EST
- Manuscript Accepted: 30 JAN 2013
- Manuscript Received: 11 OCT 2012
- NHS. Grant Number: 2009B084
- NHLBI. Grant Number: HL46703
- Leducq Foundation, Paris, France, for the development of Transatlantic Networks of Excellence in Cardiovascular Research. Grant Number: 04 CVD 02
- The Netherlands Heart Foundation. Grant Number: 89.063
- genetic factors;
- next-generation sequencing;
- normal variation;
- protein C
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.
We performed a genome scan of normal PC levels to identify genes that regulate normal PC levels.
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).
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.
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.