Two decades of research on etiology and genetic factors in the abdominal aortic aneurysm (AAA)--with a glimpse into the 21st century.

Long gone are the days when the question of "etiology" of the abdominal aortic aneurysm (AAA) required a simplistic response. AAA is caused by an interplay of environmental and genetic factors, each of which may modify the expression of the other. A low penetrance, an insidious onset, and a wide distribution have forced scientists to rely on complex approaches to elucidate the pathophysiology of AAA. Hypotheses over the last twenty years have evaluated several components of connective tissue structure, function, and regulation. Although there has been considerable overlap in the many genetic approaches undertaken to explain aneurysm development, research recently has focused on reverse-engineering techniques. While earlier investigations using a "forward" or "candidate gene approach" have provided many insights in the understanding of AAA disease, advances in statistical modeling, new techniques in molecular biology, and gross computing power have now made more feasible the development of a reverse approach. New hope lies with the development of biochemical and computing tools which have paralleled information's vast dissemination in this rapidly widening field. Aortic inflammation and the upregulation of proteases and dysfunctional tissue-turnover are receiving more attention. No doubt, the interplay of all of these technologies will occupy investigators with an interest in AAA etiology for many years to come.