Fibromuscular Dysplasia and Abdominal Aortic Aneurysms Are Dimorphic Sex-Specific Diseases With Shared Complex Genetic Architecture
Authors: Katz Alexander E. , Yang Min-Lee , Levin Michael G. , Tcheandjieu Catherine , Mathis Michael , Hunker Kristina , Blackburn Susan , Eliason Jonathan L. , Coleman Dawn M. , Fendrikova-Mahlay Natalia , Gornik Heather L. , Karmakar Monita , Hill Hannah , Xu Chang , Zawistowski Matthew , Brummett Chad M. , Zoellner Sebastian , Zhou Xiang , O’Donnell Christopher J. , Douglas Julie A. , Assimes Themistocles L. , Tsao Phillip S. , Li Jun Z. , Damrauer Scott M. , Stanley James C. , Ganesh Santhi K. , Gaziano J. Michael , Muralidhar Sumitra , Ramoni Rachel , Beckham Jean , Chang Kyong-Mi , O’Donnell Christopher J. , Tsao Philip S. , Breeling James , Huang Grant , Casas Juan P. , Muralidhar Sumitra , Moser Jennifer , Whitbourne Stacey B. , Brewer Jessica V. , Aslan Mihaela , Connor Todd , Argyres Dean P. , Tsao Philip S. , Gaziano J. Michael , Stephens Brady , Brophy Mary T. , Humphries Donald E. , Selva Luis E. , Do Nhan , Shayan Shahpoor (Alex) , Cho Kelly , Churby Lori , O’Donnell Christopher J. , O’Donnell Christopher J. , Pyarajan Saiju , Tsao Philip S. , Cho Kelly , DuVall Scott L. , Pyarajan Saiju , Hauser Elizabeth , Sun Yan , Zhao Hongyu , Wilson Peter , McArdle Rachel , Dellitalia Louis , Mattocks Kristin , Harley John , Whittle Jeffrey , Jacono Frank , Beckham Jean , Wells John , Gutierrez Salvador , Gibson Gretchen , Hammer Kimberly , Kaminsky Laurence , Villareal Gerardo , Kinlay Scott , Xu Junzhe , Hamner Mark , Mathew Roy , Bhushan Sujata , Iruvanti Pran , Godschalk Michael , Ballas Zuhair , Ivins Douglas , Mastorides Stephen , Moorman Jonathan , Gappy Saib , Klein Jon , Ratcliffe Nora , Florez Hermes , Okusaga Olaoluwa , Murdoch Maureen , Sriram Peruvemba , Yeh Shing Shing , Tandon Neeraj , Jhala Darshana , Aguayo Samuel , Cohen David , Sharma Satish , Liangpunsakul Suthat , Oursler Kris Ann , Whooley Mary , Ahuja Sunil , Constans Joseph , Meyer Paul , Greco Jennifer , Rauchman Michael , Servatius Richard , Gaddy Melinda , Wallbom Agnes , Morgan Timothy , Stapley Todd , Sherman Scott , Ross George , Tsao Philip , Strollo Patrick , Boyko Edward , Meyer Laurence , Gupta Samir , Huq Mostaqul , Fayad Joseph , Hung Adriana , Lichy Jack , Hurley Robin , Robey Brooks , Striker Robert 
Published: November 2022

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.