Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1.

Abstract

Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10(-5) in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD.

• Authors: Scott A LeMaire, Merry-Lynn N McDonald, Dong-Chuan Guo, Ludivine Russell, Charles C Miller 3rd, Ralph J Johnson, Mir Reza Bekheirnia, Luis M Franco, Mary Nguyen, Reed E Pyeritz, Joseph E Bavaria, Richard Devereux, Cheryl Maslen, Kathryn W Holmes, Kim Eagle, Simon C Body, Christine Seidman, J G Seidman, Eric M Isselbacher, Molly Bray, Joseph S Coselli, Anthony L Estrera, Hazim J Safi, John W Belmont, Suzanne M Leal, Dianna M Milewicz
• Journal: Nature genetics (Nat Genet) Vol. 43 Issue 10 Pg. 996-1000 (Sep 11 2011) ISSN: 1546-1718 [Electronic] United States
• PMID: 21909107 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• FBN1 protein, human
• Fibrillin-1
• Fibrillins
• Microfilament Proteins
• DNA

Topics

• Aortic Aneurysm, Thoracic (genetics, pathology)
• Case-Control Studies
• Chromosomes, Human, Pair 15 (genetics)
• DNA (genetics, isolation & purification)
• Fibrillin-1
• Fibrillins
• Genetic Loci
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genotyping Techniques
• Humans
• Linkage Disequilibrium
• Marfan Syndrome (genetics)
• Microfilament Proteins (genetics, metabolism)
• Mutation
• Polymorphism, Single Nucleotide
• Sequence Analysis, DNA