Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1

Allelic association methods are better suited than linkage analysis for map ping of susceptibility genes that confer modest increases in risk in comple x diseases. In both family- and population-based association studies, it is very useful to have prior knowledge of all sequence variants and the degre e of linkage disequilibrium in a candidate gene region. In this study, we s canned sequence variants in a 2.2-kb promoter sequence and all 13 exons (to talling 3.3 kb) of the matrix metalloproteinase-9 gene, which is associated with coronary heart disease and a candidate for other diseases involving c onnective tissue remodelling, such as cancer metastasis. The sequences had a total of ten variable sites, four in the promoter, five in the coding reg ion (three of which alter the amino acid encoded) and one in the 3' untrans lated sequence. Sequence inspection suggests that some of the variants will have a functional impact on either level of expression or enzymatic activi ty. Tight linkage disequilibrium was detected between variants across the e ntire length of the gene (approximately 9 kb), and frequencies of different haplotypes were determined. The data provide an essential tool for studies of the possible contribution of genetic variation at the matrix metallopro teinase-9 locus to genetically determined susceptibility to a number of imp ortant diseases. The results also provide experimental data on the extent o f linkage disequilibrium in the general population, which is yet to be reso lved.