Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Thromb Haemost. 2013 Apr;11(4):715-23. doi: 10.1111/jth.12157.

Genetic variants associated with protein C levels.

Author information

  • 1Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands.

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.

OBJECTIVES:

We performed a genome scan of normal PC levels to identify genes that regulate normal PC levels.

PATIENTS/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.

© 2013 International Society on Thrombosis and Haemostasis.

PMID:
23387557
[PubMed - indexed for MEDLINE]
PMCID:
PMC3631611
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Blackwell Publishing Icon for PubMed Central
    Loading ...
    Write to the Help Desk