TY - JOUR
T1 - Genotype impacts survival in Marfan syndrome
AU - Franken, Romy
AU - Groenink, Maarten
AU - de Waard, Vivian
AU - Feenstra, Helena M. A.
AU - Scholte, Arthur J.
AU - van den Berg, Maarten P.
AU - Pals, Gerard
AU - Zwinderman, Aeilko H.
AU - Timmermans, Janneke
AU - Mulder, Barbara J. M.
PY - 2016/11/14
Y1 - 2016/11/14
N2 - Aims The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFS patients. Methods and results We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORvitia registry since the start in 2001. Mean age was 36.5 +/- 13.5 years (51.2% male, 28.9% prior aortic surgery, 8.2% prior aortic dissection). Patients were prospectively followed for a mean duration of 8.2 +/- 3.1 years. Men had more frequently aortic surgery at baseline (38.0 vs. 19.4%, P <0.001) and during follow-up (24.0 vs. 15.1%, P = 0.008) compared with women. After 10-year follow-up cumulative survival was 93.8% and dissection-free survival was 84.2%. We found a pathogenic FBN1 mutation in 357 patients, of whom 146 patients (40.9%) were positive for a mutation causing haploinsufficiency (reduced fibrillin-1 protein) and 211 (59.1%) for a mutation leading to aDNeffect (abnormal fibrillin1 protein). Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient (HI) mutation had a 2.5-fold increased risk for cardiovascular death (hazard ratio, HR: 2.5, 95% CI: 1.0-6.1, P = 0.049), a 2.4-fold increased risk for the combined endpoint comprising death and dissection (HR: 2.4, 95% CI: 1.4-4.2, P <0.001) and a 1.6-fold increased risk for any aortic complication compared with patients with a DN mutation (HR: 1.6, 95% CI 1.1-2.3, P = 0.014). Conclusion Marfan syndrome patients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation
AB - Aims The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFS patients. Methods and results We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORvitia registry since the start in 2001. Mean age was 36.5 +/- 13.5 years (51.2% male, 28.9% prior aortic surgery, 8.2% prior aortic dissection). Patients were prospectively followed for a mean duration of 8.2 +/- 3.1 years. Men had more frequently aortic surgery at baseline (38.0 vs. 19.4%, P <0.001) and during follow-up (24.0 vs. 15.1%, P = 0.008) compared with women. After 10-year follow-up cumulative survival was 93.8% and dissection-free survival was 84.2%. We found a pathogenic FBN1 mutation in 357 patients, of whom 146 patients (40.9%) were positive for a mutation causing haploinsufficiency (reduced fibrillin-1 protein) and 211 (59.1%) for a mutation leading to aDNeffect (abnormal fibrillin1 protein). Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient (HI) mutation had a 2.5-fold increased risk for cardiovascular death (hazard ratio, HR: 2.5, 95% CI: 1.0-6.1, P = 0.049), a 2.4-fold increased risk for the combined endpoint comprising death and dissection (HR: 2.4, 95% CI: 1.4-4.2, P <0.001) and a 1.6-fold increased risk for any aortic complication compared with patients with a DN mutation (HR: 1.6, 95% CI 1.1-2.3, P = 0.014). Conclusion Marfan syndrome patients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation
KW - Aortic aneurysm
KW - Aortic dissection
KW - FBN1 mutation
KW - Marfan syndrome
KW - Survival
U2 - https://doi.org/10.1093/eurheartj/ehv739
DO - https://doi.org/10.1093/eurheartj/ehv739
M3 - Article
C2 - 26787436
SN - 0195-668X
VL - 37
SP - 3285
EP - 3290
JO - European Heart journal
JF - European Heart journal
IS - 43
ER -