on April 21, 2005
Published online before print April 21, 2005, doi: 10.1161/01.ATV.0000166602.04711.2e
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Submitted on February 8, 2005
Accepted on April 7, 2005
A Locus on Chromosome 2 Influences Levels of Tissue Factor Pathway Inhibitor. Results From the GAIT study
L. Almasy *;
From the Southwest Foundation for Biomedical Research (L.A., D.M.W, J.B.), San Antonio, Tex; the Hospital de la Santa Creu i Sant Pau (J.M.S., J.C.S., A.B., J.F.), Barcelona, Spain; the Institut de Recerca Oncologica (X.M., N.S.), Barcelona, Spain; and the Centre National de Genotypage (M.L.), Evry, France.
* To whom correspondence should be addressed. E-mail: almasy{at}darwin.sfbr.org.
Objective--Levels of tissue factor pathway inhibitor (TFPI) have been associated with arteriosclerosis and thrombotic disease. Although a genetic component to variation in TFPI levels is well-documented, no systematic genome-wide screens have been conducted to localize genes influencing levels of TFPI.
Methods and Results--We studied TFPI levels in 397 individuals in 21 Spanish families participating in the Genetic Analysis of Idiopathic Thrombosis (GAIT) study. Twelve families were selected through a proband with idiopathic thrombosis and 9 were ascertained without regard to phenotype. A genome scan was performed using microsatellite markers spaced at approximately 10 cM intervals. Standard multipoint variance component linkage methods were used. The heritability of TFPI levels was 0.52 (P<0.0001), with no evidence for shared household effects. In the genome screen, only 1 LOD score >2 was observed. On chromosome 2q, the maximum multipoint LOD score was 3.52 near marker D2S1384. This is near the structural gene for TFPI, which is located at 2q32. In follow-up association analyses, marginal evidence of association (P=0.04) was observed with the TFPI promoter variant C-399T.
Conclusion--These results suggest that polymorphisms in and around the TFPI structural gene may be the major genetic determinants of variation in TFPI levels.
Key words: TFPI • linkage • association • heritability