Fibromuscular Dysplasia and Abdominal Aortic Aneurysms Are Dimorphic Sex-Specific Diseases With Shared Complex Genetic Architecture

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.

Keywords: aneurysm; aortic aneurysm, abdominal; arteries; dissection; fibromuscular dysplasia; genetics; sex dimorphism.

Figure 1:

FMD and other DAAD on angiographic imaging and family pedigrees. (a) Catheter-directed angiography demonstrating multifocal FMD of the right renal artery. Arrows denote characteristic string of beads appearance. (b) Catheter-directed angiography depicting an isolated aneurysm involving a first order branch of the left renal artery. (c) Coronary angiography demonstrating SCAD. (d) Representative pedigrees of FMD families: dark shading identifies individuals affected with FMD including probands and relatives; vertical lines denote DAAD not formally diagnosed as FMD; dotted shading represents an individual with AAA; and unshaded relatives have no evidence of arterial dysplasia.