Fibromuscular dysplasia (FMD) is an arteriopathy associated with hypertension, stroke and myocardial infarction, affecting mostly women. We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We find an estimate of SNP-based heritability compatible with FMD having a polygenic basis, and report four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Transcriptome-wide association analysis in arteries identifies one additional locus (SLC24A3). We characterize open chromatin in arterial primary cells and find that FMD associated variants are located in arterial-specific regulatory elements. Target genes are broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. We find significant genetic overlap between FMD and more common cardiovascular diseases and traits including blood pressure, migraine, intracranial aneurysm, and coronary artery disease.

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.

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Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions.

BACKGROUND: Vascular smooth muscle cells (SMCs) plasticity is a central mechanism in cardiovascular health and disease. We aimed at providing cellular phenotyping, epigenomic and proteomic depiction of SMCs derived from induced pluripotent stem cells and evaluating their potential as cellular models in the context of complex diseases. METHODS: Human induced pluripotent stem cell lines were differentiated using RepSox (R-SMCs) or PDGF-BB (platelet-derived growth factor-BB) and TGF-β (transforming growth factor beta; TP-SMCs), during a 24-day long protocol. RNA-Seq and assay for transposase accessible chromatin-Seq were performed at 6 time points of differentiation, and mass spectrometry was used to quantify proteins. RESULTS: Both induced pluripotent stem cell differentiation protocols generated SMCs with positive expression of SMC markers. TP-SMCs exhibited greater proliferation capacity, migration and lower calcium release in response to contractile stimuli, compared with R-SMCs. Genes involved in the contractile function of arteries were highly expressed in R-SMCs compared with TP-SMCs or primary SMCs. R-SMCs and coronary artery transcriptomic profiles were highly similar, characterized by high expression of genes involved in blood pressure regulation and coronary artery disease. We identified FOXF1 and HAND1 as key drivers of RepSox specific program. Extracellular matrix content contained more proteins involved in wound repair in TP-SMCs and higher secretion of basal membrane constituents in R-SMCs. Open chromatin regions of R-SMCs and TP-SMCs were significantly enriched for variants associated with blood pressure and coronary artery disease. CONCLUSIONS: Both induced pluripotent stem cell–derived SMCs models present complementary cellular phenotypes of high relevance to SMC plasticity. These cellular models present high potential to study functional regulation at genetic risk loci of main arterial diseases.

Single nucleotide polymorphisms (SNPs) in genes involved in xenobiotics metabolism (XM) are suspected to play a role in breast cancer risk. However, previous findings based on a SNP by SNP approach need to be replicated taking into account the combined effects of multiple SNPs. We used a gene‐set analysis method to study the association between breast cancer risk and genetic variation in XM genes (seen as a set of SNPs) and in the XM pathway (seen as a set of genes). We also studied the interaction between variants in XM genes and tobacco smoking. The analysis was conducted in a case–control study of 1,125 cases and 1,172 controls. Using a dedicated chip, genotyping data of 585 SNPs in 68 XM genes were available. Genetic variation in the whole XM pathway was significantly associated with premenopausal breast cancer risk (p = 0.008). This association was mainly driven by genetic variation in NAT2, CYP2C18, CYP2C19, AKR1C2 and ALDH1A3. The association between the XM gene pathway and breast cancer was observed among current and previous smokers, but not among never smokers (p = 0.013 for interaction between XM genes and tobacco smoking status). The association with breast cancer risk indicates that XM genes variants may play a role in breast carcinogenesis through their detoxification function of environmental pollutants, such as those contained in tobacco smoke.

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Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Through a meta-analysis of genome-wide association studies including 1917 cases and 9292 controls of European ancestry, we identified 17 risk loci, including 12 new, with odds ratios ranging from 2.04 (95%CI 1.77-2.35) on chr21 to 1.25 (95%CI 1.16-1.35) on chr4. A locus on chr1 containing the tissue factor gene (F3), which is involved in blood coagulation cascade, appears to be specific for SCAD risk. Prioritized genes were mainly expressed in vascular smooth muscle cells and fibroblasts of arteries and are implicated predominantly in extracellular matrix biology (e.g. COL4A1/A2, HTRA1 and TIMP3). We found that several variants associated with SCAD had diametrically opposite associations with CAD suggesting that shared biological processes contribute to both diseases but through different mechanisms. We also demonstrated an inferred causal role for high blood pressure, but not other CAD risk factors, in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and prevention for this disease.