Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

LeMaire, Scott A.; McDonald, Merry-Lynn; Guo, Dong; Russell, Ludivine; Miller, Charles C.; Johnson, Ralph J.; Bekheirnia, Mir Reza; Franco, Luis M.; Nguyen, Mary; Pyeritz, Reed E.; Bavaria, Joseph E.; Devereux, Richard B.; Maslen, Cheryl L.; Holmes, Kathryn W.; Eagle, Kim A.; Body, Simon C.; Seidman, Christine E.; Seidman, Jonathan G.; Isselbacher, Eric M.; Bray, Molly S.; Coselli, Joseph S.; Estrera, Anthony L.; Safi, Hazim J.; Belmont, John W.; Leal, Suzanne M.; Milewicz, Dianna M.

doi:10.1038/ng.934

Cited by 193 publications

(152 citation statements)

References 25 publications

(15 reference statements)

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“…Increased TGF-β1 signaling has been associated with defective fibrillin-1 in the pathology of MFS (2). Genome-wide association study identified FBN1 SNPs rs2118181 and rs10519177 to be associated with sporadic DPAA (4). The data were in part replicated by two independent studies (5,6), therefore strengthening intRODUCtiOn FBN1 mutations are associated with the development of dilative pathology of ascending aorta (DPAA) (1).…”

Section: Study Subjectssupporting

confidence: 66%

Association between Fibrillin1 Polymorphisms (rs2118181, rs10519177) and Transforming Growth Factor β1 Concentration in Human Plasma

Sepetiene

Patamsytė

Žukovas

et al. 2015

Mol Med

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Section: Study Subjectssupporting

confidence: 66%

Association between Fibrillin1 Polymorphisms (rs2118181, rs10519177) and Transforming Growth Factor β1 Concentration in Human Plasma

Sepetiene

Patamsytė

Žukovas

et al. 2015

Mol Med

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“…Thus, it seems that common variation at the FBN1 locus may explain part of the susceptibility to aneurysm formation in STAAD. 134 Genome-wide copy number variant analysis in a large number of STAAD cases further suggested the involvement of VSMC adhesion and contraction in the development of TAA.…”

Section: Col4a1 Col4a3/4/5 Plod3)mentioning

confidence: 99%

Genetics of Thoracic Aortic Aneurysm

Gillis

Laer

Loeys

2013

Circulation Research

158

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Aortic aneurysm, including both abdominal aortic aneurysm and thoracic aortic aneurysm, is the cause of death of 1% to 2% of the Western population. This review focuses only on thoracic aortic aneurysms and dissections. During the past decade, the genetic contribution to the pathogenesis of thoracic aortic aneurysms and dissections has revealed perturbed extracellular matrix signaling cascade interactions and deficient intracellular components of the smooth muscle contractile apparatus as the key mechanisms. Based on the study of different Marfan mouse models and the discovery of several novel thoracic aortic aneurysm genes, the involvement of the transforming growth factor-β signaling pathway has opened unexpected new avenues. Overall, these discoveries have 3 important consequences. First, the pathogenesis of thoracic aortic aneurysms and dissections is better understood, although some controversy still exists. Second, the management strategies for the medical and surgical treatment of thoracic aortic aneurysms and dissections are becoming increasingly gene-tailored. Third, the pathogenetic insights have delivered new treatment options that are currently being investigated in large clinical trials.

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“…Except for a genome-wide association study (GWAS), no previous studies have systematically investigated the genetic basis of sporadic spontaneous AD or the relationship between genotype and phenotype heterogeneity, especially for collagens and matrix metalloproteases (MMPs)/tissue inhibitors of MMPs (TIMPs) (LeMaire et al, 2011). However, GWASs were performed using only known genetic markers involved in both cases and healthy controls, the ability to identify novel pathogenesis is limited compared with direct sequencing (Marian and Belmont, 2011;Salomon et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

Zhou

Tan

et al. 2016

Sci. China Life Sci.

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Aortic dissection (AD) is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases (MMPs)/tissue inhibitors of MMPs (TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens (45 genes), MMPs/TIMPs (27 genes) in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% (64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05% (218/702) sporadic AD patients. In them, 84.86% patients (185/218) carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probably pathogenic loss-of-function (LOF) variants (20 nonsense, 16 frameshift, 14 splice sites, one stop-loss, one initiation codon) in 11.06% (50/452) AD patients, which were absent in 163 controls (P=2.5×10 −5 ). Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2 −/− rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis. aortic dissection, collagen, matrix metalloproteinase, next-generation sequencing, genetic diagnosis Citation:Li, Z., Zhou, C., Tan, L., Chen, P., Cao, Y., Li, C., Li, X., Yan, J., Zeng, H., Wang, D.W., and Wang, D.W. (2017). Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissec. Sci China Life Sci 60, 57-65.

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Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

Cited by 193 publications

References 25 publications

Association between Fibrillin1 Polymorphisms (rs2118181, rs10519177) and Transforming Growth Factor β1 Concentration in Human Plasma

Association between Fibrillin1 Polymorphisms (rs2118181, rs10519177) and Transforming Growth Factor β1 Concentration in Human Plasma

Genetics of Thoracic Aortic Aneurysm

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

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