Characterization of polymorphic structure of cathepsin G gene - Role in cardiovascular and cerebrovascular diseases

Cathepsin G (CTSG), a serine protease released from activated neutrophils, may cause platelet activation, leading to intravascular thrombosis, thus co ntributing to cardiovascular and cerebrovascular disease. Applying the cand idate gene approach, we screened the 5'-flanking region and the entire codi ng region of the CTSG gene for genetic variation by using polymerase chain reaction/single-strand conformation polymorphism analysis from 96 patients at high risk for myocardial infarction (MI). We identified 4 polymorphisms in the 5'-flanking region (G-618C, G-315A, C-179T, and C-160T) and 1 polymo rphism in the coding region (Asn125Ser) of the gene and genotyped the parti cipants in the Etude Cas-Temoins sur l'Infarctus du Myocarde (ECTIM Study), a case-control study for MI, and in the Etude du Profil Genetique de l'Inf arctus Cerebral (GENIC Study), a case-control study for brain infarction (B I), for all identified genetic variants. The potential in vitro functionali ty of the 4 variants in the 5'-flanking region was investigated with transi ent transfection analyses in U937 cells with different allelic promoter con structs by using a luciferase assay. Our in vitro analyses did not reveal a ny differences for the investigated allelic constructs with respect to prom oter activity, and none of the polymorphisms in the 5'-flanking region was associated with the available phenotypes in either study. Allele and genoty pe distributions of all identified polymorphisms did not globally differ be tween cases and controls in the ECTIM Study. However, in patients from the ECTIM Study, the Ser125 allele was significantly associated with elevated p lasma fibrinogen levels (P=0.006), but this effect was not seen in controls (case-control heterogeneity, P=0.04). There was a significant interaction between CTSG Asn125Ser and the beta -fibrinogen gene polymorphism G-455A on plasma fibrinogen levels (P=0.04). In the GENIC Study, the odds ratio for BI associated with CTSG Ser125 carrying was 1.82 (95% CI 1.16 to 2.84, P=0. 008) in patients without a history of cardiovascular or cerebrovascular dis eases. Our results indicate that the CTSG Ser125 allele is associated with plasma fibrinogen levels in MI patients from the ECTIM Study and with BI in the GENIC Study. Further studies should be carried out to define the under lying mechanisms.