Investigation of a novel pathogenesis of thrombosis-regulation of protein S by sex hormones and its abnormality-

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1. Investigation of regulatory mechanism of the protein S gene by sex hormoneThe effect of various sex hormones on promoter activity of the human protein S gene was examined using plasmid constructs carrying the promoter region of the human protein S gene and luciferase gene in cultured human hepatoma cells. Estrogen suppressed the transcriptional activity of the human protein S gene. Twelve base pairs region in the promoter of the human protein S gene was involved in the inhibitory effect of estrogen on protein S gene transcription.2. Development of protein S measurement and investigation of regulatory mechanism of protein S in miceAn assay system of mouse protein S was developed by modification of human protein S measurement method. Using this system, we investigated the effects of sex hormones on the protein S level in mice. The plasma level of protein S decreased by treatment of estrogen and human gonadotropin as well as by pregnancy.3. Association study of protein S polymorphism with the plasma protein S level in Japanese womenWe examined the plasma free protein S level in a general Japanese population, and investigated the association of single nucleotide polymorphisms (SNPs) of the protein S gene (PROS1) with the plasma protein S level. Three of 379 Japanese women aged 50-75 years showed reduced plasma free protein S. One of these three had a heterozygous missense mutation (R275C) in the PROS1 gene. Furthermore, 11 individuals were heterozygous carriers with a K155E mutation. We conclude that the estimated prevalence of inherited protein S deficiency in Japanese women is at least 3.2% (12/379). Association analyses showed that a promoter SNP in the PROS1 gene was significantly associated with the free protein S level.