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.
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.
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).
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: email@example.com
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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