Unraveling the genetic predisposition for aortic aneurysms: is it time for tailored medicine?

A neurysms and dissections are the major pathologies affecting the thoracic aorta. Based on available data, up to 20% of individuals with thoracic aortic aneurysms (TAAs) may have a first-degree relative with aortic aneurysms or dissection, indicating a strong genetic predisposition.1 Within families, TAAs are inherited primarily in an autosomal dominant manner, with decreased penetrance and variable expression.2 Moreover, they are often asymptomatic until a catastrophic event occurs,2 which may be prevented if family members can be identified prior to such events. Based on this premise, recent studies have begun to elucidate the genetic factors that predispose an individual to TAA. The first genetic predisposition for TAA was detected by use of families with multiple members with the disorder. The locus was mapped to the long arm of chromosome 5 (5q13-14), termed the TAAD1 locus.3 Genetic heterogeneity was indicated by the fact that only one-half of the identified families mapped to this locus and was confirmed by mapping another gene causing TAA to the long arm of chromosome 11, 11q23-24 (termed the FAAl locus).4 Hasham et al. also mapped another locus for TAA to 3p24-25, termed the TAAD2 locus, by using a family with multiple affected members.3 Having mapped a TAA locus to 3p24-25, they sequenced the gene for transforming growth factor-β receptor type 2 (TGFBR2) and demonstrated that germline TGFBR2 mutations are responsible for the predisposition to familial TAA in 5% of these cases.5 In this issue of the Journal, Kato et al. performed an association study for 142 polymorphisms of 119 candidate genes and TAA in 1,351 hypertensive Japanese individuals to identify genetic variants that confer susceptibility to TAA. They report that the variant G allele of THBS2 was a risk factor for TAA, whereas the variant C allele of HSPA8, T allele of GPX1, A allele of AGT, and T allele of TNF were protective against this condition. The authors suggest that the determination of genotypes for these polymorphisms may prove informative for assessment of the genetic risk for TAA and may contribute to the personalized prevention of this condition.