Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia

Abstract

Aims Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. Methods and Results We analyzed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (MAFgnomAD=0.000075) shared by two FMD sisters in the prostaglandin I2 receptor (hIP) gene (PTGIR), a key player in vascular remodeling. Follow-up was conducted by targeted or Sanger sequencing (1,071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD=8 × 10−4), but not a significant enrichment (PTRAPD=0.12) in SCAD. The biological effects of variants on receptor signaling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. Conclusions Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signaling in non-atherosclerotic stenosis and dissection. Translational perspectives This study adds evidence to the possibility of FMD and SCAD share a common genetic basis. We show that rare loss of function variants in the gene encoding the prostacyclin receptor (PTGIR) are enriched in FMD patients and present in SCAD patients. This pathway is a target of widely used drugs such as aspirin or iloprost. If this mechanism is confirmed by further larger genetic and clinical studies, these findings may help the clinicians identify the best therapeutic strategy to treat FMD and SCAD patients in the future.

Epigenome-wide association study and epigenetic age acceleration associated with cigarette smoking among Costa Rican adults

“…Similarly, the HNRNPM and PTGIR proteins have been shown to promote cancerous cell growth and be associated with poorer oncogenic outcomes 65 , 66 . The latter is also involved with vascular remodeling, and its loss of function may increase risk for vessel stenosis and dissection 67 . If MAPK4 (TSS1500), HNRNPM , and PTGIR hypomethylation among smokers—what we observed—leads to greater protein expression, this could partially explain their increased risk for lung and heart diseases and several cancers.…”

Genetic association studies of fibromuscular dysplasia identify new risk loci and shared genetic basis with more common vascular diseases

“…On the other hand, SLC24A3, which we identified through the TWAS analyses in tibial arteries to associate with FMD, encodes a transmembrane sodium/potassium/calcium exchanger also involved in calcium homeostasis 33 . The relevance of impaired vasodilation and/or enhanced vasoconstriction in FMD pathogenesis is supported by our recent study where we reported an enrichment among FMD patients for rare loss-offunction mutations in the gene encoding the receptor for prostacyclin, a major vasodilator hormone 34 . In line with these findings, impaired dilation of arteries in response to sublingual glyceryl trinitrate, a proxy for VSMC dysfunction, was reported in FMD patients, including in arterial segments clinically unaffected by the disease 35 .…”

Spontaneous dissection of proximal left main coronary artery in a healthy adolescent presenting with syncope: A case report

“…In the majority of patients, SCAD is not an isolated event but is reflective of an underlying vascular, genetic, or as-yet undetected condition[ 24 ]. Accordingly, all patients who have experienced SCAD should undergo a complete vascular physical examination of the abdominal aorta, cervical carotid arteries, and arteries of the upper and lower extremities[ 25 ]. To search for FMD, we ordered a computed tomography (CT) angiogram of the aorta and renal arteries and duplex ultrasonography of extracranial carotid arteries, which showed normal-appearing arteries and were negative for FMD (Figure 3 ).…”