Dataset Information

A plasma proteogenomic signature for fibromuscular dysplasia.

ABSTRACT:

Aims

Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these protein data to conduct systems analyses to provide biologic insights on FMD, and explore if this could be developed into a blood-based FMD test.

Methods and results

Females with 'multifocal' FMD and matched healthy controls underwent clinical phenotyping, dermal biopsy, and blood draw. Using dual-capture proximity extension assay and nuclear magnetic resonance-spectroscopy, we evaluated plasma levels of 981 proteins and 31 lipid sub-classes, respectively. In a discovery cohort (Ncases?=?90, Ncontrols?=?100), we identified 105 proteins and 16 lipid sub-classes (predominantly triglycerides and fatty acids) with differential plasma abundance in FMD cases vs. controls. In an independent cohort (Ncases?=?23, Ncontrols?=?28), we successfully validated 37 plasma proteins and 10 lipid sub-classes with differential abundance. Among these, 5/37 proteins exhibited genetic control and Bayesian analyses identified 3 of these as potential upstream drivers of FMD. In a 3rd cohort (Ncases?=?506, Ncontrols?=?876) the genetic locus of one of these upstream disease drivers, CD2-associated protein (CD2AP), was independently validated as being associated with risk of having FMD (odds ratios ?=?1.36; P?=?0.0003). Immune-fluorescence staining identified that CD2AP is expressed by the endothelium of medium-large arteries. Finally, machine learning trained on the discovery cohort was used to develop a test for FMD. When independently applied to the validation cohort, the test showed a c-statistic of 0.73 and sensitivity of 78.3%.

Conclusion

FMD exhibits a plasma proteogenomic and lipid signature that includes potential causative disease drivers, and which holds promise for developing a blood-based test for this disease.

SUBMITTER: Olin JW

PROVIDER: S-EPMC6918065 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

A plasma proteogenomic signature for fibromuscular dysplasia.

Olin Jeffrey W JW Di Narzo Antonio F AF d'Escamard Valentina V Kadian-Dodov Daniella D Cheng Haoxiang H Georges Adrien A King Annette A Thomas Allison A Barwari Temo T Michelis Katherine C KC Bouchareb Rihab R Bander Emir E Anyanwu Anelechi A Stelzer Paul P Filsoufi Farzan F Florman Sander S Civelek Mete M Debette Stephanie S Jeunemaitre Xavier X Björkegren Johan L M JLM Mayr Manuel M Bouatia-Naji Nabila N Hao Ke K Kovacic Jason C JC

Cardiovascular research 20200101 1

<h4>Aims</h4>Fibromuscular dysplasia (FMD) is a poorly understood disease that predominantly affects women during middle-life, with features that include stenosis, aneurysm, and dissection of medium-large arteries. Recently, plasma proteomics has emerged as an important means to understand cardiovascular diseases. Our objectives were: (i) to characterize plasma proteins and determine if any exhibit differential abundance in FMD subjects vs. matched healthy controls and (ii) to leverage these pro ...[more]

PMID: 31424497

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Project description:Fibromuscular dysplasia (FMD), formerly called fibromuscular fibroplasia, is a group of nonatherosclerotic, noninflammatory arterial diseases that most commonly involve the renal and carotid arteries. The prevalence of symptomatic renal artery FMD is about 4/1000 and the prevalence of cervicocranial FMD is probably half that. Histological classification discriminates three main subtypes, intimal, medial and perimedial, which may be associated in a single patient. Angiographic classification includes the multifocal type, with multiple stenoses and the 'string-of-beads' appearance that is related to medial FMD, and tubular and focal types, which are not clearly related to specific histological lesions. Renovascular hypertension is the most common manifestation of renal artery FMD. Multifocal stenoses with the 'string-of-beads' appearance are observed at angiography in more than 80% of cases, mostly in women aged between 30 and 50 years; they generally involve the middle and distal two-thirds of the main renal artery and in some case also renal artery branches. Cervicocranial FMD can be complicated by dissection with headache, Horner's syndrome or stroke, or can be associated with intracerebral aneurysms with a risk of subarachnoid or intracerebral hemorrhage. The etiology of FMD is unknown, although various hormonal and mechanical factors have been suggested. Subclinical lesions are found at arterial sites distant from the stenotic arteries, and this suggests that FMD is a systemic arterial disease. It appears to be familial in 10% of cases. Noninvasive diagnostic tests include, in increasing order of accuracy, ultrasonography, magnetic resonance angiography and computed tomography angiography. The gold standard for diagnosing FMD is catheter angiography, but this invasive procedure is only used for patients in whom it is clinically pertinent to proceed with revascularization during the same procedure. Differential diagnosis include atherosclerotic stenoses and stenoses associated with vascular Ehlers-Danlos and Williams' syndromes, and type 1 neurofibromatosis. Management of cases with renovascular hypertension includes antihypertensive therapy, percutaneous angioplasty of severe stenoses, and reconstructive surgery in cases with complex FMD that extends to segmental arteries. The therapeutic options for securing ruptured intracerebral aneurysms are microvascular neurosurgical clipping and endovascular coiling. Stenosis progression in renal artery FMD is slow and rarely leads to ischemic renal failure.

Dataset Information

A plasma proteogenomic signature for fibromuscular dysplasia.

Aims

Methods and results

Conclusion

Publications

A plasma proteogenomic signature for fibromuscular dysplasia.

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