Kiando Soto Romuald, Barlassina Cristina, Cusi Daniele, Galan Pilar, Lathrop Mark, Plouin Pierre-François, Jeunemaitre Xavier, Bouatia-Naji Nabila
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.
J Hypertens. 2015 Sep;33(9):1802-10; discussion 1810. doi: 10.1097/HJH.0000000000000625.
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.
纤维肌性发育不良（FMD）是一种非动脉粥样硬化性血管疾病，主要导致肾动脉和颈动脉狭窄、动脉瘤及夹层形成。FMD主要发生于女性，患病率约为千分之四，可引起高血压、肾缺血或中风。FMD的发病机制尚不清楚，鉴于其明显的家族聚集性，怀疑有遗传起源。
我们对16例患者（7个家系）进行了全外显子组测序（WES）。根据频率（次要等位基因频率<0.01）和计算机预测功能对3971个基因中的编码变异进行优先级排序。
没有一个基因携带至少三个家系中所有受累成员共有的变异。在这些家系中，已排除16个血管和结缔组织疾病基因的变异作为病因。对16例患者中至少有四个变异的基因以及血管基因，使用来自249例无关病例和689例对照的基因型进行随访。使用SKAT-O进行的基于基因的关联分析显示，肌球蛋白轻链激酶（MYLK，P = 0.01）与多灶性FMD（N = 164）存在名义上的显著关联，MYLK先前与胸主动脉瘤有关； obscurin（OBSCN），一种肌节蛋白（P = 0.003）；动力蛋白胞质重链1（DYNC2H1，P = 0.02）；以及RNF213，先前与烟雾病有关（P = 0.01）。
我们的研究表明FMD存在遗传异质性，不太可能存在主要致病基因，并排除了几个血管基因在家族性FMD中的作用。我们还提出了四个多灶性FMD的可能候选基因，不过这些发现需要进一步的遗传和功能验证。更强大的WES和关联研究[如全基因组关联研究（GWAS）]将更好地解读FMD的遗传基础。
