Aortic dissection and Marfan's have common genetic basis - by theheart.org

Houston, TX - US researchers have identified, for the first time, a number of genetic variants on chromosome 15 that increase the risk of sporadic thoracic aortic aneurysms and aortic dissections (STAAD) [1]. Of note, the variants are in the same region of the chromosome as a mutation that causes Marfan syndrome, a serious congenital disorder. Dr Scott A LeMaire (Baylor College of Medicine, Houston) and colleagues report their findings in a study published online September 11, 2011 in Nature Genetics.

Aortic dissection is a major cardiovascular complication of Marfan syndrome, and sufferers who have not undergone repair surgery have poor survival, with aortic complications being responsible for 80% of cardiac deaths, senior author Dr Dianna Milewicz (University of Texas Health Science Center, Houston) told heartwire. "The new work shows that what is going on in this subset of the general population is along the same lines as what happens in patients with Marfan syndrome," she noted.

In the US, 1% to 2% of deaths every year are due to sporadic aortic dissections, and an estimated 40% to 60% of patients who suffer this will die before they can reach the emergency room. Milewicz hopes that this new work will help home in on those with thoracic aortic aneurysms—a precursor to dissection—who are most at risk of this disastrous sequelae, so they can have a surgical repair sooner rather than later. And she envisages that some kind of risk-score screening for the general population could one day be developed, "because we could prevent many of these deaths."

Potential for treatment of STAAD with ARBs

In their genomewide-association study, LeMaire and colleagues compared 765 individuals with STAAD with 874 controls and identified common single nucleotide polymorphisms (SNPs) on chromosome 15 that were associated with STAAD, with significant odds ratios of 1.6 to 1.8.

They also discovered that some of these SNPs fall into a large region that also contains the gene FBN1, which encodes fibrillin-1. "Our major hit was on chromosome 15, right on top of FBN1, which, when it mutates, leads to Marfan syndrome," Milewicz observes.

 

"The work suggests a common pathogenesis of aortic disease in Marfan syndrome and sporadic thoracic aortic aneurysms and dissections," she and her colleagues say.

Milewicz notes, however, that although the newly discovered SNPs are found in quite a high percentage of the general population, "they increase the risk [of STAAD] only slightly," so they will need to be added in with other factors to generate a risk score.

There is also the promise of a therapeutic intervention in the future, she notes, because angiotensin receptor blockers (ARBs) are in multiple clinical trials in Marfan syndrome following successful experiments in a Marfan mouse model whereby the ARB losartan prevented aneurysms.

"It may be that those results could be rapidly translated into patients who have these aneurysms but don't have Marfan's to prevent the dissection," she comments.