Integrative Gene Regulatory Network Analysis Discloses Key Driver Genes of Fibromuscular Dysplasia

Fibromuscular dysplasia (FMD) is a poorly understood vascular disease that can lead to hypertension, stroke, myocardial infarction and even death. In 2013 we initiated the DEFINE study (ClinicalTrials.gov Identifier: NCT01967511), which has now recruited > 440 subjects and which aims to unravel the pathobiological mechanisms of this disease. Here, by integrating DNA genotype and RNA sequence data from primary fibroblasts of 83 FMD patients and 71 matched healthy controls from the DEFINE study, and its precursor the CAUSE study, we inferred 18 gene regulatory co-expression networks, four of which were found to act together as an FMD-associated super network in the arterial wall. Molecular studies indicated that this super network, termed SN-A and with the top key driver gene UBR4, governs multiple aspects of vascular cell physiology and functionality, including collagen/matrix production. The effects of UBR4 knockdown were also investigated in commercially available aortic smooth muscle and fibroblast cell lines by RNA sequencing, and these results are included in these datasets.Note, that of the 154 subjects in this analysis, 62 did not provide consent to have their genomic data made publicly available. Therefore the human subject data available here is from the 92 study participants who provided written informed consent to share their deidentified genomic data publicly. ]]>
Inclusion criteria for entry into DEFINE-FMD: ≥ 18 years of age Being freely willing to participate Fluency in English FMD cases are required to have a clinical diagnosis of multifocal FMD that is confirmed by imaging (computed tomographic angiography, magnetic resonance angiography or catheter-based angiography). Similar inclusion criteria also applied for FMD cases in the CAUSE study. Per our original enrollment criteria through until early 2017, only females were included in this analysis. Furthermore, for this analysis we imposed the additional inclusion/exclusion criteria that controls cannot be related to FMD cases. Inclusion criteria for healthy controls No clinical features of FMD, coronary vasomotor disorder (CvAD), or spontaneous coronary artery dissection (SCAD) (including no cervical or abdominal bruits, an absence of family history of sudden death or aneurysm) Absence of any major ongoing systemic disease including any condition requiring hospitalization, immune suppression, intravenous or injected medications or that result in functional impairment in the performance of activities of daily living Healthy controls are pre-screened and matched to FMD cases according to age, sex, race/ethnicity, and body mass index (BMI) Exclusion criteria (for cases and controls) Co-morbidities that reduce life expectancy to one year Any solid organ or hematological transplantation, or those in whom transplantation is considered Active autoimmune disease Illicit drug use Positive for HIV Prior malignancy In controls, an additional exclusion criterion is early-onset family history of any form of vascular disease ]]>
The DEFINE study has been running continuously since October 2013 and has now recruited > 440 participants. The DEFINE study is registered as NCT01967511 and further details are available at the clinicaltrials.gov website.]]>