TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome

GenTAC Registry Investigators

doi:10.1371/journal.pgen.1007692

TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome

GenTAC Registry Investigators

Pediatrics

Research output: Contribution to journal › Article › peer-review

82 Scopus citations

Abstract

Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10⁻⁷), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91–178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57–99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.

Original language	English (US)
Article number	e1007692
Journal	PLoS genetics
Volume	14
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1007692
State	Published - Oct 1 2018

Funding

The GenTAC Registry was supported by US Federal Government contracts HHSN268200648199C and HHSN268201000048C from the National Heart Lung and Blood Institute (NHLBI) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (Bethesda, MD). Whole exome sequencing services were provided by the University of Washington, Department of Genome Sciences under U.S. Federal Government contract number, US Federal Government contract number HHSN268201100037C (to D. Nickerson). This work is supported in part by the Ravelle Family Fund of the Turner Syndrome Society of the United States (MS). HC receives support from The Friends of Doernbecher Foundation and The American Heart Association Western States Affiliate grant number 16PRE30190012. SAM is supported by NHLBI grant K23HL127266. CLM receives support from the OHSU School of Medicine, and the Knight Cardiovascular Institute at Oregon Health & Science University. The Danish replication cohort development was supported by grants from the Lundbeck Foundation, the Augustinus Foundation, The Toyota Foundation, the Aase og Einar Danielsen Foundation, the Novo Nordisk Foundation (NNF13OC0003234, NNF15OC0016474).

Funders	Funder number
National Institute of Health National Heart, Lung, and Blood Institute	HHSN268201100037C, HHSN268200648199C, K23HL127266
National Institute for Arthritis and Musculoskeletal and Skin Diseases
Hjerteforeningen
Toyota Foundation
Novo Nordisk Foundation Center for Basic Metabolic Research	NNF13OC0003234, NNF15OC0016474
Lundbeckfonden
Augustinus Fonden
Fonden til Lægevidenskabens Fremme

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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10.1371/journal.pgen.1007692

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title = "TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome",

abstract = "Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in \textasciitilde{}1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10−7), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50\% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95\% CI = 1.91–178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95\% CI = 2.57–99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.",

author = "\{GenTAC Registry Investigators\} and Holly Corbitt and Morris, \{Shaine A.\} and Gravholt, \{Claus H.\} and Mortensen, \{Kristian H.\} and Rebecca Tippner-Hedges and Michael Silberbach and Maslen, \{Cheryl L.\}",

note = "Publisher Copyright: {\textcopyright} 2018 Corbitt et al. http://creativecommons.org/licenses/by/4.0/.",

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doi = "10.1371/journal.pgen.1007692",

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T1 - TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome

AU - GenTAC Registry Investigators

AU - Corbitt, Holly

AU - Morris, Shaine A.

AU - Gravholt, Claus H.

AU - Mortensen, Kristian H.

AU - Tippner-Hedges, Rebecca

AU - Silberbach, Michael

AU - Maslen, Cheryl L.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10−7), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91–178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57–99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.

AB - Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that TIMP3 was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10−7), which was replicated in a separate cohort. The analysis of Xp genes revealed that TIMP1, which is a functionally redundant paralogue of TIMP3, was hemizygous in >50% of our discovery cohort and that having only one copy of TIMP1 increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91–178.80, p = 0.029). The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57–99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome TIMP1 hemizygosity and variants of its autosomal paralogue TIMP3, significantly increases the risk of aortopathy in Turner syndrome.

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AN - SCOPUS:85055075571

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ER -

TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome

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