Fibromuscular Dysplasia and Abdominal Aortic Aneurysms Are Dimorphic Sex-Specific Diseases With Shared Complex Genetic Architecture
Alexander Katz, Min‐Lee Yang, Michael G. Levin, Catherine Tcheandjieu, Michael R. Mathis, Kristina L. Hunker, Susan Blackburn, Jonathan L. Eliason, Dawn M. Coleman, Natalia Fendrikova-Mahlay, Heather L. Gornik, Monita Karmakar, Hannah Hill, Chang Xu, Matthew Zawistowski, Chad M. Brummett, Sebastian Zoellner, Xiang Zhou, Christopher J. O’Donnell, Julie A. Douglas, Themistocles L. Assimes, Phillip S. Tsao, Jun Z. Li, Scott M. Damrauer, James C. Stanley, Santhi K. Ganesh, J. Michael Gaziano, Sumitra Muralidhar, Rachel Ramoni, Jean C. Beckham, Kyong‐Mi Chang, Christopher J. O’Donnell, Philip S. Tsao, James L. Breeling, Grant D. Huang, Juan P. Casas, Sumitra Muralidhar, Jennifer Moser, Stacey B. Whitbourne, Jessica V. Brewer, Mihaela Aslan, Todd Connor, Dean P. Argyres, Philip S. Tsao, J. Michael Gaziano, Brady Stephens, Mary T. Brophy, Donald E. Humphries, Luis E. Selva, Nhan Do, Shahpoor Shayan, Kelly Cho, Lori Churby, Christopher J. O’Donnell, Christopher J. O’Donnell, Saiju Pyarajan, Philip S. Tsao, Kelly Cho, Scott L. DuVall, Saiju Pyarajan, Elizabeth R. Hauser, Yan V. Sun, Hongyu Zhao, Peter W.F. Wilson, Rachel McArdle, Louis J. Dell’Italia, Kristin Mattocks, John B. Harley, Jeff Whittle, Frank J. Jacono, Jean Beckham, John A. Wells, Salvador Gutierrez, Gretchen Gibson, Kimberly Hammer, Laurence S. Kaminsky, Gerardo Villareal, Scott Kinlay, Junzhe Xu, Mark B. Hamner, Roy O. Mathew, Sujata Bhushan, Pran Iruvanti, Michael Godschalk, Zuhair K. Ballas, Douglas Ivins, Stephen Mastorides, Jonathan P. Moorman, Saib Gappy, Jon Klein, Nora Ratcliffe, Hermes Flórez, Olaoluwa Okusaga, Maureen Murdoch, Peruvemba Sriram, Shing Shing Yeh, Neeraj Tandon, Darshana Jhala, Samuel M. Aguayo, David Cohen
Abstract
Background: The risk of arterial diseases may be elevated among family members of individuals having multifocal fibromuscular dysplasia (FMD). We sought to investigate the risk of arterial diseases in families of individuals with FMD. Methods: Family histories for 73 probands with FMD were obtained, which included an analysis of 463 total first-degree relatives focusing on FMD and related arterial disorders. A polygenic risk score for FMD (PRS FMD ) was constructed from prior genome-wide association findings of 584 FMD cases and 7139 controls and evaluated for association with an abdominal aortic aneurysm (AAA) in a cohort of 9693 AAA cases and 294 049 controls. A previously published PRS AAA was also assessed among the FMD cases and controls. Results: Of all first degree relatives of probands, 9.3% were diagnosed with FMD, aneurysms, and dissections. Aneurysmal disease occurred in 60.5% of affected relatives and 5.6% of all relatives. Among 227 female first-degree relatives of probands, 4.8% (11) had FMD, representing a relative risk (RR) FMD of 1.5 ([95% CI, 0.75–2.8]; P =0.19) compared with the estimated population prevalence of 3.3%, though not of statistical significance. Of all fathers of FMD probands, 11% had AAAs resulting in a RR AAA of 2.3 ([95% CI, 1.12–4.6]; P =0.014) compared with population estimates. The PRS FMD was found to be associated with an AAA (odds ratio, 1.03 [95% CI, 1.01–1.05]; P =2.6×10 −3 ), and the PRS AAA was found to be associated with FMD (odds ratio, 1.53 [95% CI, 1.2–1.9]; P =9.0×10 −5 ) as well. Conclusions: FMD and AAAs seem to be sex-dimorphic manifestations of a heritable arterial disease with a partially shared complex genetic architecture. Excess risk of having an AAA according to a family history of FMD may justify screening in family members of individuals having FMD.