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 ~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 summary

BAV is the most frequent congenital heart defect, occurring in about 1–2% of the population with 70% of cases occurring in males. BAV increases risk for thoracic aortic aneurysm (TAA) and early death. Approximately 30% of individuals with Turner syndrome have BAV/TAA, making this an important population for the study of this disease. Given that individuals with Turner syndrome are missing a complete or partial second sex chromosome, it is presumed that X chromosome genes are involved in causing the defect. This is consistent with the bias towards occurrence in euploid males. However, not everyone with Turner syndrome has a BAV, so we hypothesized that autosomal genes may also play a role. Using whole exome sequencing we have shown that deleterious variation in TIMP3 is associated with BAV and indices of TAA. We further found that there is a synergistic interaction between loss of the X chromosome gene, TIMP1, and deleterious variation in TIMP3 that significantly increases that risk. TIMP1 and TIMP3 play roles in aortic valve morphogenesis and in stabilizing the aortic wall, loss of which leads to TAA. Hence our findings have implications for understanding the cause of BAV/TAA in all populations and as a potential therapeutic target.