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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1489.)
© 2005 American Heart Association, Inc.

Thrombosis

A Locus on Chromosome 2 Influences Levels of Tissue Factor Pathway Inhibitor

Results From the GAIT study

L. Almasy; J.M. Soria; J.C. Souto; D.M. Warren; A. Buil; M. Borrell; X. Muñoz; N. Sala; M. Lathrop; J. Fontcuberta; J. Blangero

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.

Correspondence to Laura Almasy, Department of Genetics, Southwest Foundation, P.O. Box 760549, San Antonio TX 78245-0549. 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.

This is the first genome-wide screen for genes influencing levels of TFPI. Linkage (LOD=3.52, genome-wide P=0.01) was observed on chromosome 2q, near the TFPI structural gene. These results suggest that polymorphisms in and around the TFPI gene are the major genetic determinants of variation in TFPI levels.

Key Words: TFPI • linkage • association • heritability