Rosina De Cario1, Elena Sticchi2, Laura Lucarini3, Monica Attanasio4, Stefano Nistri5, Rossella Marcucci6, Guglielmina Pepe2, Betti Giusti7. 1. Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Florence, Italy; Marfan Syndrome and Related Disorders Regional (Tuscany) Referral Center, Careggi Hospital, Florence, Italy. 2. Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Florence, Italy; Marfan Syndrome and Related Disorders Regional (Tuscany) Referral Center, Careggi Hospital, Florence, Italy; Center of Excellence for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, DENOTHE Center, University of Florence, Florence, Italy. 3. Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Florence, Italy. 4. Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Florence, Italy; Center for Bleeding Disorders, Careggi University Hospital, Florence, Italy. 5. Cardiology Service, CMSR Veneto Medica, Altavilla Vicentina, Vicenza, Italy. 6. Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Florence, Italy; Center of Excellence for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, DENOTHE Center, University of Florence, Florence, Italy; Atherothrombotic Diseases Center, Careggi Hospital, Florence, Italy. 7. Department of Experimental and Clinical Medicine, Section of Critical Medical Care and Medical Specialities, University of Florence, Florence, Italy; Marfan Syndrome and Related Disorders Regional (Tuscany) Referral Center, Careggi Hospital, Florence, Italy; Center of Excellence for the Study at Molecular and Clinical Level of Chronic, Degenerative and Neoplastic Diseases to Develop Novel Therapies, DENOTHE Center, University of Florence, Florence, Italy; Atherothrombotic Diseases Center, Careggi Hospital, Florence, Italy. Electronic address: betti.giusti@unifi.it.
Abstract
OBJECTIVE: Genetic variants in transforming growth factor beta (TGF-β) receptors type 1 (TGFBR1) and type 2 (TGFBR2) genes have been associated with different hereditary connective tissue disorders sharing thoracic aortic aneurysm and dissection (TAA/D). Mutations in both TGFBR1/2 genes have been described in patients with TAA/D and Marfan syndrome (MFS), and they are associated consistently with Loeys-Dietz syndrome. The existing literature shows discordant data resulting from mutational screening of TGFBR1/2 genes in patients with MFS. The aim of the study was to investigate the role of TGFBR1/2 genetic variants in determining and/or modulating MFS clinical phenotype. METHODS: We investigated 75 unrelated patients with MFS referred to the Center for Marfan Syndrome and Related Disorders (Careggi University Hospital, Florence) who were subjected to FBN1 and TGFBR1/2 Sanger mutational screening. RESULTS: Forty-seven patients with MFS (63%) carried a pathogenetic FBN1 mutation. No pathogenetic mutations were detected in TGFBR1/2 genes. Ten common polymorphisms were identified in TGFBR2 and 6 in TGFBR1. Their association with cardiovascular manifestations was evaluated. Carriers of the A allele of rs11466512, delA allele of c.383delA or delT allele of c.1256-15del1T polymorphisms had a trend toward or significantly reduced z-scores (median [interquartile range (IQR)], 2.2 [1.13-4.77]; 2.1 [1.72-3.48]; 2.5 [1.85-3.86]) with respect to homozygous patients with wild-type MFS (median [IQR], 4.20 [2.39-7.25]; 3.9 [2.19-7.00]; 3.9 [2.14-6.93]). Carriers of the A allele of the rs2276767 polymorphism showed a trend toward increased z-score (median [IQR], 4.9 [2.14-7.16]) with respect to patients with wild-type MFS (median [IQR], 3.3 [1.75-5.45]). The protective effect of TGFBR1/2 genetic score including all the 4 variants was also evaluated. Patients with MFS with two or more protective alleles included in the score had statistically significant reduced aortic z-scores (median [IQR], 2.20 [1.48-3.37]) with respect to patients with 1 or no protective alleles (median [IQR], 4.20 [2.48-7.12]; P = .007). Patients with severe aortic manifestations (aortic z-score ≥ 2 or aortic surgery) showed a significantly lower prevalence of subjects with two or more protective alleles included in the genetic score (29.7%) than patients with no or milder cardiovascular involvement (63.6%; P = .029). The genetic score protective effect on global aortic manifestations severity (aortic z-score ≥ 2 or aortic surgery) was also observed at the logistic regression analysis adjusted for the presence of FBN1 gene mutations (odds ratio, 0.21; 95% CI, 0.05-0.84; P = .028). CONCLUSIONS: In conclusion, our data reappraise the role of TGFBR1 and TGFBR2 as major genes in patients with MFS, and suggest that TGFBR1/2 genetic variants (in particular when evaluated as a burden by score) might play a role in modulating the severity of cardiovascular manifestation in MFS.
OBJECTIVE: Genetic variants in transforming growth factor beta (TGF-β) receptors type 1 (TGFBR1) and type 2 (TGFBR2) genes have been associated with different hereditary connective tissue disorders sharing thoracic aortic aneurysm and dissection (TAA/D). Mutations in both TGFBR1/2 genes have been described in patients with TAA/D and Marfan syndrome (MFS), and they are associated consistently with Loeys-Dietz syndrome. The existing literature shows discordant data resulting from mutational screening of TGFBR1/2 genes in patients with MFS. The aim of the study was to investigate the role of TGFBR1/2 genetic variants in determining and/or modulating MFS clinical phenotype. METHODS: We investigated 75 unrelated patients with MFS referred to the Center for Marfan Syndrome and Related Disorders (Careggi University Hospital, Florence) who were subjected to FBN1 and TGFBR1/2 Sanger mutational screening. RESULTS: Forty-seven patients with MFS (63%) carried a pathogenetic FBN1 mutation. No pathogenetic mutations were detected in TGFBR1/2 genes. Ten common polymorphisms were identified in TGFBR2 and 6 in TGFBR1. Their association with cardiovascular manifestations was evaluated. Carriers of the A allele of rs11466512, delA allele of c.383delA or delT allele of c.1256-15del1T polymorphisms had a trend toward or significantly reduced z-scores (median [interquartile range (IQR)], 2.2 [1.13-4.77]; 2.1 [1.72-3.48]; 2.5 [1.85-3.86]) with respect to homozygous patients with wild-type MFS (median [IQR], 4.20 [2.39-7.25]; 3.9 [2.19-7.00]; 3.9 [2.14-6.93]). Carriers of the A allele of the rs2276767 polymorphism showed a trend toward increased z-score (median [IQR], 4.9 [2.14-7.16]) with respect to patients with wild-type MFS (median [IQR], 3.3 [1.75-5.45]). The protective effect of TGFBR1/2 genetic score including all the 4 variants was also evaluated. Patients with MFS with two or more protective alleles included in the score had statistically significant reduced aortic z-scores (median [IQR], 2.20 [1.48-3.37]) with respect to patients with 1 or no protective alleles (median [IQR], 4.20 [2.48-7.12]; P = .007). Patients with severe aortic manifestations (aortic z-score ≥ 2 or aortic surgery) showed a significantly lower prevalence of subjects with two or more protective alleles included in the genetic score (29.7%) than patients with no or milder cardiovascular involvement (63.6%; P = .029). The genetic score protective effect on global aortic manifestations severity (aortic z-score ≥ 2 or aortic surgery) was also observed at the logistic regression analysis adjusted for the presence of FBN1 gene mutations (odds ratio, 0.21; 95% CI, 0.05-0.84; P = .028). CONCLUSIONS: In conclusion, our data reappraise the role of TGFBR1 and TGFBR2 as major genes in patients with MFS, and suggest that TGFBR1/2 genetic variants (in particular when evaluated as a burden by score) might play a role in modulating the severity of cardiovascular manifestation in MFS.
Authors: Philipp Erhart; Daniel Körfer; Susanne Dihlmann; Jia-Lu Qiao; Ingrid Hausser; Peter Ringleb; Jörg Männer; Nicola Dikow; Christian P Schaaf; Caspar Grond-Ginsbach; Dittmar Böckler Journal: J Clin Med Date: 2022-06-07 Impact factor: 4.964