A genome-wide scan for genetic loci influencing levels of thrombin-activatable fibrinolysis inhibitor (TAFI)

Abstract number: P0795

Almasy^* L., Cole† S., Soria† J. M., Souto† J. C., Hixson† J., Fontcuberta† J., Blangero† J.

^*Southwest Foundation for Biomedical Research, USA; †Spain †USA;

Thrombin-activatable fibrinolysis inhibitor (TAFI) circulates in an inactive, pro-enzyme form. When activated, primarily by the thrombin-thrombomodulin complex, TAFIa inhibits t-PA-induced fibrinolysis. Levels of TAFI have been associated with myocardial infarction, obesity, and type 2 diabetes, making this phenotype a potential risk factor for disease. To search for genes influencing levels of TAFI, we conducted a genome-wide linkage screen in a sample from the San Antonio Family Heart Study. The San Antonio Family Heart Study is comprised of over 1200 individuals in large Mexican-American families that were selected without regard to any disease phenotype to study genetics of normal variation in risk factors related to cardiovascular disease. A subset of 638 of these individuals, in 24 families, has both measured TAFI antigen levels and genotypes for a whole genome scan. TAFI antigen levels were measured by ELISA. The genome scan consisted of approximately 400 microsatellite markers spaced at approximately 10 cm intervals throughout the genome. Standard multipoint variance component linkage methods, implemented in SOLAR, were used. The heritability of TAFI antigen levels in the San Antonio Family Heart Study sample was 0.53 (P < 0.00001). TAFI levels were lower in females than in males and decreased with age. Correlations were also observed between TAFI levels and total serum cholesterol levels and diastolic blood pressure. In the genome-wide scan, the highest LOD score was 2.68 (P = 0.0002) on chromosome 13q, in the region of the TAFI structural gene, CPB2. No other LOD scores over 1.5 were observed. These results suggest that polymorphisms in the TAFI structural gene or its nearby regulatory elements may be strong determinants of genetic variation in TAFI antigen levels in this normal Mexican American population. This finding is consistent with results from the genetic analysis of idiopathic thrombophilia (GAIT) project, which also identified the chromosome 13q region in a genome-wide linkage scan for TAFI antigen levels in the Spanish population.