Genetic modifiers of ambulation in the cooperative international Neuromuscular Research Group Duchenne natural history study

• Autores: Bello, Luca; Kesari, Akanchha; Gordish Dressman, Heather; Cnaan, Avital; Morgenroth, Lauren P.; Punetha, Jaya; Duong, Tina; Henricson, Erik K.; Pegoraro, Elena; McDonald, Craig M.; Hoffman, Eric P.; Dubrovsky, Alberto; Andreone, Luz; Cooperative International Neuromuscular Research Group Investigators
• Año de publicación: 2015
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: DUCHENNE MUSCULAR DYSTROPHY; POLYMORPHISM; AMBULATION
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

OBJECTIVE: We studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy (DMD) cohort. METHODS: We genotyped SPP1 rs28357094 and LTBP4 haplotype in 283 of 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time-varying Cox regression) and for population stratification (multidimensional scaling of genome-wide markers). RESULTS: Hispanic and South Asian participants (n=18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian subjects (p=0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2-year-earlier median LoA (p=0.048). This difference was greater (1.9 years, p=0.038) in GC-treated participants, whereas no difference was observed in untreated subjects. Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (hazard ratio = 1.61, p=0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but it was not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p =0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 for those who were treated with GC. INTERPRETATION: SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG-DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD
Fil: Bello, Luca. Children's National Medical Center; Estados Unidos. Università di Padova; Italia
Fil: Kesari, Akanchha. Children's National Medical Center; Estados Unidos
Fil: Gordish Dressman, Heather. Children's National Medical Center; Estados Unidos
Fil: Cnaan, Avital. Children's National Medical Center; Estados Unidos. The George Washington University; Estados Unidos
Fil: Morgenroth, Lauren P.. Children's National Medical Center; Estados Unidos
Fil: Punetha, Jaya. Children's National Medical Center; Estados Unidos. The George Washington University; Estados Unidos
Fil: Duong, Tina. Children's National Medical Center; Estados Unidos
Fil: Henricson, Erik K.. University of California at Davis; Estados Unidos
Fil: Pegoraro, Elena. Università di Padova; Italia
Fil: McDonald, Craig M.. University of California at Davis; Estados Unidos
Fil: Hoffman, Eric P.. Children's National Medical Center; Estados Unidos. The George Washington University; Estados Unidos
Fil: Dubrovsky, Alberto. Cooperative International Neuromuscular Research Group Investigators; Argentina
Fil: Andreone, Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Cooperative International Neuromuscular Research Group Investigators; Argentina. Fundación Favaloro; Argentina
Fil: Cooperative International Neuromuscular Research Group Investigators. No especifica;