Inherited factors play a role in the pathogenesis of myocardial infarction (MI), and there is growing interest in identifying common genetic susceptibility markers that interact with common environmental exposures to contribute to the occurrence of MI in the population. The preliminary data address the contribution of common genetic and environmental factors to the risk of MI among women under 45 years of age. Those data show that common polymorphisms in genes coding for two clotting factors, coagulation Factor V and coagulation Factor II, are risk factors for MI only among cigarette smokers in this sample. These relationships, and others observed, provide strong evidence of gene-environment interactions between thrombotic and atherosclerotic factors in early-onset MI. The plan is to extend this work to investigate the relationship of common putative susceptibility genotypes to the occurrence of early-onset MI in both men and women. One intent is to determine whether the risk of early-onset MI is related to interactions between environmental factors (e.g., cigarette smoking, exercise, alcohol consumption) and common polymorphisms in genes coding for thrombotic factors (coagulation Factor V, coagulation Factor II, plasminogen activator inhibitor-1, and beta-fibrinogen) and atherosclerotic factors (the adhesion molecule E-selectin and metalloproteinase stromelysin-1; the lipid metabolism enzymes paraoxinase, lipoprotein lipase, cholesterol ester transfer protein; and the apolipoproteins apolipoprotein E and apolipoprotein B). Additionally, there are plans to determine whether the risk of early-onset MI is related to interactions between plasma lipoprotein(a) levels (which are largely genetically determined) and environmental risk factors and/or polymorphisms in the candidate genes. Interactions among candidate polymorphisms will also be assessed. Cases will be all 18-49 year old male (n=386) and 18-59 female (n=386) residents of King, Pierce and Snohomish counties, Washington State, newly diagnosed with a first, non-fatal MI during a 3.25 year period. Demographically similar controls (n=772) will be ascertained and recruited through random digit telephone dialing. Cases and controls will be interviewed in person to assess medical and behavioral characteristics related to MI risk. A venous blood sample will be obtained and processed into aliquots of plasma and white cells. DNA extracted from the white cells will be tested using the polymerase chain reaction (PCR), PCR/restriction fragment length polymorphisms (RFLP), and oligonucleotide ligation assays to determine the genotypes of interest. Plasma will be tested for lipid, lipoprotein, and homocysteine concentrations. Analyses will address both the overall association between the genotypes and MI risk, along with posited gene-environment and gene-gene interactions. In addition to providing powerful tests of the Specific Aims, this large study will provide a unique resource for testing future hypotheses regarding the role of common genetic susceptibility factors in the pathogenesis of early-onset MI among both men and women.
Showing the most recent 10 out of 12 publications
