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Exome sequencing in seven families and gene-based association studies indicate genetic heterogeneity and suggest possible candidates for fibromuscular dysplasia

Kiando, Soto Romualda , b; Barlassina, Cristinac , d; Cusi, Danielec , d , e; Galan, Pilarf; Lathrop, Markg; Plouin, Pierre-Françoisb , h; Jeunemaitre, Xaviera , b , i; Bouatia-Naji, Nabilaa , b

doi: 10.1097/HJH.0000000000000625
ORIGINAL PAPERS: Genetic aspects

Background: Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to stenosis, aneurysm and dissection, mainly of renal arteries and carotids. FMD occurs predominantly in women with nearly four out of 1000 prevalence and cause hypertension, renal ischemia or stroke. The pathogenesis of FMD is unknown and a genetic origin is suspected given its demonstrated familial aggregation.

Method: We performed whole exome sequencing (WES) in 16 cases (seven families). Coding variants in 3971 genes were prioritized on frequency (minor allele frequency < 0.01) and in silico predicted functionality.

Results: No gene harbours variants that are shared among all affected members of at least three families. Variants from 16 genes of vascular and connective tissue diseases are excluded as causative in these families. Genes with at least four variants in the 16 patients and vascular genes were followed-up using genotypes from 249 unrelated cases and 689 controls. Gene-based association analyses using SKAT-O shows nominal significant association with multifocal FMD (N = 164) for myosin light chain kinase (MYLK, P = 0.01) previously involved in thoracic aortic aneurysm, obscurin (OBSCN), a sarcomeric protein (P = 0.003), dynein cytoplasmic heavy chain 1 (DYNC2H1, P = 0.02) and RNF213 previously associated with Moyamoya disease (P = 0.01).

Conclusion: Our study indicates genetic heterogeneity and the unlikely existence of a major gene for FMD and excludes the role of several vascular genes in familial FMD. We also suggest four possible candidate genes for multifocal FMD, though these findings need further genetic and functional confirmation. More powerful WES and association studies [e.g. genome-wide association study (GWAS)] will better decipher the genetic basis of FMD.

aINSERM, UMR970 Paris Cardiovascular Research Center (PARCC)

bUniversité Paris-Descartes, PRES Sorbonne Paris Cité, Paris, France

cDepartment of Health Sciences, Genomic and Bioinformatics Unit

dGraduate School of Nephrology, University of Milano, Division of Nephrology, San Paolo Hospital

eBiomedical Technologies, Italian National Research Council, Milan, Italy

fUniversité Paris 13, Equipe de Recherche en Epidémiologie Nutritionnelle (EREN), Centre d’Epidémiologie et Statistiques Sorbonne Paris Cité, Inserm (U1153), Inra (U1125), Cnam, COMUE Sorbonne Paris Cité, Bobigny

gCentre National de Génotypage, Evry

hAP-HP, Department of Hypertension

iAP-HP, Refferal Center for Rare Vascular Diseases, Hôpital Européen Georges Pompidou, Paris, France

Correspondence to Nabila Bouatia-Naji, PhD, Paris Cardiovascular Research Center, INSERM UMR970 - Team 3, 56 Rue Leblanc, Paris F-75015, France. Tel: +330153987995; fax: +33153987952; e-mail:

Abbreviations: CORAL, Cardiovascular Outcomes in Renal Atherosclerotic Lesion; EVS, exome variant server; FMD, fibromuscular dysplasia; GWAS, Genome-Wide Association Study; HEGP, European Hospital Georges Pompidou; MAF, minor allele frequency; MLCK, myosin light chain kinase; PCA, principal component analysis; RTA, real time analysis; SKAT, SNP-set kernel association test; SKAT-O, optimal SNP-set kernel association test; SMC, smooth muscle cells; SU.VI.MAX, a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals; TGFβ, transforming growth factor beta; WES, whole exome sequencing

Received 16 October, 2014

Revised 10 April, 2015

Accepted 10 April, 2015

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