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

Katz AE, Yang ML, Levin MG, Tcheandjieu C, Mathis M, Hunker K, Blackburn S, Eliason JL, Coleman DM, Fendrikova-Mahlay N, Gornik HL, Karmakar M, Hill H, Xu C, Zawistowski M, Brummett CM, Zoellner S, Zhou X, O'Donnell CJ, Douglas JA, Assimes TL, Tsao PS, Li JZ, Damrauer SM, Stanley JC, Ganesh SK, VA Million Veteran Program. Fibromuscular Dysplasia and Abdominal Aortic Aneurysms Are Dimorphic Sex-Specific Diseases With Shared Complex Genetic Architecture. Circulation. Genomic and precision medicine. 2022 Dec 1; 15(6):e003496.

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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) 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 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) of 1.5 ([95% CI, 0.75-2.8]; = 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 of 2.3 ([95% CI, 1.12-4.6]; = 0.014) compared with population estimates. The PRS was found to be associated with an AAA (odds ratio, 1.03 [95% CI, 1.01-1.05]; = 2.6×10), and the PRS was found to be associated with FMD (odds ratio, 1.53 [95% CI, 1.2-1.9]; = 9.0×10) 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.