Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

Georges, Adrien; Yang, Min; Berrandou, Takiy-Eddine; Mengyao, Y.; Dikilitas, Ozan; Ma, Lijiang; Kyryachenko, Sergiy; Liu, L.; Amar, Laurence; Lorthioir, Aurélien; Debette, Stéphanie; Gornik, Heather L.; Azizi, Michel; Jeunemaı̂tre, Xavier; Januszewicz, A.; Kullo, Iftikhar J.; Persu, Alexandre; Kovacic, Jason; Ganesh, Santhi K.; Bouatia-Naji, Nabila

doi:10.1016/j.acvdsp.2021.04.099

Cited by 6 publications

(9 citation statements)

References 68 publications

(115 reference statements)

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“…The EDNRA locus has been previously implicated in IA risk and the ATP2B1 locus has been implicated in fibromuscular dysplasia and hypertension (risk factors for IA). 32,33 But loci containing SIRT3 and AL359922.1, to our knowledge, have not been identified in prior studies of IA or IA-related disorders. To illustrate the genomic context and contribution of multiple SNPs in the SIRT3 locus, we present LocusZoom plots (Figure 2).…”

Section: Resultsmentioning

confidence: 75%

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

Hale

Jones

2022

Neurosurgery

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BACKGROUND:The genetic mechanisms regulating intracranial aneurysm (IA) formation and rupture are largely unknown. To identify germline-genetic risk factors for IA, we perform a multinational genome-wide association study (GWAS) of individuals from the United Kingdom, Finland, and Japan.OBJECTIVE:To identify a shared, multinational genetic basis of IA.METHODS:Using GWAS summary statistics from UK Biobank, FinnGen, and Biobank Japan, we perform a meta-analysis of IA, containing ruptured and unruptured IA cases. Logistic regression was used to identify IA-associated single-nucleotide polymorphisms. Effect size was calculated using the coefficient r, estimating the contribution of the single-nucleotide polymorphism to the genetic variance of the trait. Genome-wide significance was set at 5.0 × 10−8. Expression quantitative trait loci mapping and functional genomics approaches were used to infer mechanistic consequences of implicated variants.RESULTS:Our cohort contained 155 154 individuals (3132 IA cases and 152 022 controls). We identified 4 genetic loci reaching genome-wide: rs73392700 (SIRT3, effect size = 0.28, P = 4.3 × 10−12), rs58721068 (EDNRA, effect size = −0.20, P = 4.8 × 10−12), rs4977574 (AL359922.1, effect size = 0.18, P = 7.9 × 10−12), and rs11105337 (ATP2B1, effect size = −0.15, P = 3.4 × 10−8). Expression quantitative trait loci mapping suggests that rs73392700 has a large effect size on SIRT3 gene expression in arterial and muscle, but not neurological, tissues. Functional genomics analysis suggests that rs73392700 causes decreased SIRT3 gene expression.CONCLUSION:We perform a multinational GWAS of IA and identify 4 genetic risk loci, including 2 novel IA risk loci (SIRT3 and AL359922.1). Identification of high-risk genetic loci across ancestries will enable population-genetic screening approaches to identify patients with IA.

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Section: Resultsmentioning

confidence: 75%

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

Hale

Jones

2022

Neurosurgery

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“…The genetic basis of complex cardiovascular diseases is mostly impacted by non-coding variants located in specific regulatory regions. To assess iPSC-derived SMCs as cellular models to study these variants, we compared their open chromatin regions (OCRs) to those of primary SMCs derived from human coronary and carotid arteries, in addition to whole healthy coronary arteries 16, 36 . Most OCR identified in arteries were found of at least one cellular model, while a large number of OCR (>83,000) were specific to primary cultured SMCs (Figure 6A).…”

Section: Resultsmentioning

confidence: 99%

“…Then, the transposition reaction was purified with MinElute PCR Purification Kit (QIAGEN, Hilden, Germany). Tagmented fragments were isolated and PCR-amplified for 6-8 cycles as described previously 36 . Amplified DNA was purified using Agencourt AMPure XP beads (Beckman Coulter, Brea, CA), according to manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

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Genomic, transcriptomic and proteomic depiction of iPSC-derived smooth muscle cells as emerging cellular models for arterial diseases

Liu

Jouve

Henry

et al. 2022

Preprint

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BackgroundVascular smooth muscle cells (VSMCs) plasticity is a central mechanism in cardiovascular health and disease. We aimed at providing deep cellular phenotyping, epigenomic and proteomic depiction of SMCs derived from induced pluripotent stem cells (iPSCs) and evaluating their potential as cellular models in the context of complex genetic arterial diseases.MethodsWe differentiated 3 human iPSC lines using either RepSox (R-SMCs) or PDGF-BB and TGF-β (TP-SMCs), during the second half of a 24-days-long protocol. In addition to cellular assays, we performed RNA-Seq and assay for transposase accessible chromatin (ATAC)-Seq at 6 time-points of differentiation. The extracellular matrix content (matrisome) generated by iPSCs derived SMCs was analyzed using mass spectrometry.ResultsBoth iPSCs differentiation protocols generated SMCs with positive expression of SMC markers. TP-SMCs exhibited greater capacity of proliferation, migration and lower calcium release in response to contractile stimuli compared to R-SMCs. RNA-Seq data showed that genes involved in the contractile function of arteries were highly expressed in R-SMCs compared to TP-SMCs or primary SMCs. Matrisome analyses supported an overexpression of proteins involved in wound repair in TP-SMCs and a higher secretion of basal membrane constituents by R-SMCs. Open chromatin regions of R-SMCs and TP-SMCs were significantly enriched for variants associated with coronary artery disease and blood pressure, while only TP-SMCs were enriched for variants associated with peripheral artery disease.ConclusionsOur study portrayed two iPSCs derived SMCs models presenting complementary cellular phenotypes of high relevance to SMC plasticity. In combination with genome-editing tools, our data supports high relevance of the use of these cellular models to the study of complex regulatory mechanisms at genetic risk loci involved in several arterial diseases.Graphical Abstract

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“…It is characterized by the proliferation of connective tissue and muscle fibers within the arterial vessel walls, which can result in stenosis of small and medium‐sized arteries, impairing perfusion of the affected organ and resulting in ischemia. The most frequent form of FMD is multifocal disease, which is characterized by multiple stenoses occurring in the same artery, and it accounts for 70–80% of cases (Georges et al, 2021). Renal artery stenosis is a cause of hypertension but is a preventable risk factor for stroke and myocardial infarction, and FMD accounts for about 10% of cases.…”

Section: The First Gwas Meta‐analysis Has Identified Loci and Genes A...mentioning

confidence: 99%

Gene Variants Identified for Fibromuscular Dysplasia

2022

American J of Med Genetics Pt A

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ibromuscular dysplasia (FMD) is a nonatherosclerotic, noninflammatory vascular disease that primarily affects the renal and internal carotid arteries, although its effects have been described in almost every arterial bed throughout the entire body. It is characterized by the proliferation of connective tissue and muscle fibers within the arterial vessel walls, which can result in stenosis of small and medium-sized arteries, impairing perfusion of the affected organ and resulting in ischemia. The most frequent form of FMD is multifocal disease, which is characterized by multiple stenoses occurring in the same artery, and it accounts for 70-80% of cases (Georges et al, 2021). Renal artery stenosis is a cause of hypertension but is a preventable risk factor for stroke and myocardial infarction, and FMD accounts for about 10% of cases. Although FMD primarily affects young to middle-aged women it can manifest at any age.Atherosclerosis in general has been extensively studied, and genetic susceptibilities have been defined. While progress has been made, knowledge of the pathogenesis or genetics of FMD is limited. PHACTR1, a pleiotropic locus involved in the genetic risk of several cardiovascular and neurovascular diseases, is the only one reported to be associated with FMD to date. Findings from a new study, however, show that 4 genetic variants that regulate gene expression in the arteries are connected to FMD (Georges et al, 2021). The study also confirmed the importance of a genetic target that had already been identified as associated with the disease.

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Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

Cited by 6 publications

References 68 publications

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

Genomic, transcriptomic and proteomic depiction of iPSC-derived smooth muscle cells as emerging cellular models for arterial diseases

Gene Variants Identified for Fibromuscular Dysplasia

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