Genomics of Fibromuscular Dysplasia

Abstract

Fibromuscular Dysplasia (FMD) is &ldquo;an idiopathic, segmental, non-atherosclerotic and non-inflammatory disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries&rdquo; (Persu, et al; 2014). FMD can lead to hypertension, arterial dissections, subarachnoid haemorrhage, stroke or mesenteric ischemia. The pathophysiology of the disease remains elusive. While familial cases are rare (<5%) in contemporary FMD registries, there is evidence in favour of the existence of multiple genetic factors involved in this vascular disease. Recent collaborative efforts allowed the identification of a first genetic locus associated with FMD. This intronic variant located in the phosphatase and actin regulator 1 gene (PHACTR1) may influence the transcription activity of the endothelin-1 gene (EDN1) located nearby on chromosome 6. Interestingly, the PHACTR1 locus has also been involved in vascular hypertrophy in normal subjects, carotid dissection, migraine and coronary artery disease. National and international registries of FMD patients, with deep and harmonised phenotypic and genetic characterisation, are expected to be instrumental to improve our understanding of the genetic basis and pathophysiology of this intriguing vascular disease.

Keywords: PHACTR1; cervical artery dissection; fibromuscular dysplasia; genetic association; non atherosclerotic vascular stenosis; spontaneous coronary arteries dissection.

Figure 1

Example of familial FMD from Belgian Multicentric FMD Cohort (BEL-FMD). Patient II.2 came to clinical attention at the age of 64 years for de novo arterial hypertension. The abdominal Computed Tomography Angiogram showed an aspect compatible with multifocal FMD of both renal arteries, significant on the right side. She underwent right percutaneous transluminal renal angioplasty (PTRA), and the hypertensive crises regressed. Patient II.4 was hypertensive from the age of 53 years and was referred at the age of 59 years for worsening of blood pressure control, associated to decreased renal function. Abdominal Magnetic Resonance Angiography (MRA) showed mild irregularities suggestive of FMD in the right renal artery, in the absence of significant stenosis. Patient II.6 came to clinical attention at the age of 58 years for renal asymmetry (kidney length: 9.5 cm on the right side vs. 12 cm on the left). The abdominal MRA identified a focal stenosis of 70% of the right renal artery. Patient II.6 underwent renal arteriography, which disclosed an irregular aspect of the arterial wall on the left side and only a 30% stenosis on the right side. Notably, none of these three patients had lesions of cervico-cephalic or others vascular beds. Estimated Glomerular Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) equation.

Figure 2

Association of rs9349379 locus with PHACTR1 and Endothelin-1 expression, cardio- and cerebrovascular diseases [46,51].