Linkage disequilibrium and haplotype analysis among eight novel single-nucleotide polymorphisms in the human tissue-type plasminogen activator (t-PA)gene

Tissue-type plasminogen activator (t-PA), a serine protease, activates the conversion of plasminogen to the fibrinolytic protein, plasmin. The t-PA ge ne, mapped to chromosome 8p12-p11.2, contains 14 exons. An Alu insertion/de letion (I/D) polymorphism in this gene has been associated with an increase d risk for myocardial infarction. In the work reported here we sequenced 11 kilobases (kb) of genomic DNA from 50 normal Japanese volunteers (100 alle les), to include all 14 exons of the t-PA gene, flanking intronic sequences , and 6kb of the 5 ' sequence. These experiments identified eight novel sin gle-nucleotide polymorphisms (SNPs), in addition to the known Alu I/D polym orphism, from which genotypic data we constructed 12 haplotypes in the test ed population. Two-way comparisons of SNPs and the Alu polymorphism reveale d strong linkage disequilibrium between the Alu site and SNPs at positions 20,209 (chi (2) = 92.263) and 27,555 (chi (2) = 47.53), and between SNPs at positions 27,849 and 28,902 (chi (2) = 66.331). A phylogenic tree was cons tructed to infer a process of genome construction that would reflect the se quence variations we observed. Our results help to explain the lack of agre ement among results of various disease-association studies in which a contr ibution of the human t-PA gene has been suspected but not always confirmed.