The TF-603A/G gene promoter polymorphism and circulating monocyte tissue factor gene expression in healthy volunteers

Summary

Three single nucleotide polymorphisms (-603A/G, -1322C/T, -1812C/T) and one deletion/insertion polymorphism (-1208D/I) are present in the tissue factor (TF) gene promoter sequence. These polymorphisms are in complete linkage disequilibrium, determining two haplotypes with almost equal frequency. The -603A/-1208D/-1322C/-1812C haplotype, presently defined as TF-603A, has been linked to venous thromboembolic disease, with a potentially protecting effect. The effects of the TF-603A/G gene polymorphism on monocyte gene expression and on a whole-blood clotting time (WBCT) are not known. We determined the WBCT in basal conditions (H0) and after 4 hours of LPS stimulation ex vivo (H4LPS) on blood samples from 100 young healthy caucasian male subjects on 2 visits, 7 days apart. Monocyte TF mRNA was quantified at H0 and H4LPS by real-time quantitative reverse-transcription PCR. The monocyte TF mRNA values determined at the first and second visits were concordant. In H4LPS samples, TF mRNA levels were increased 70-fold. The TF-603A haplotype was associated with 40%-lower TF mRNA levels at H0 (P=0.0002) and this association followed the same trend but was no longer significant at H4LPS. At H4LPS, TF mRNA levels were associated with WBCT shortening (P=0.0003). WBCT at H0 was not concordant over time, precluding any genotype-phenotype analysis. WBCT at H4LPS was concordant over time but was not related to the TF-603A/G polymorphism. The TF-603A/G gene promoter polymorphism thus significantly influences constitutive TF gene expression in human monocytes but has no major effect on TF gene expression or on WBCT in LPS stimulated conditions.

Keywords

Monocyte - gene expression - tissue factor - coagulation - thrombosis

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