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Genetic modifiers of ambulation in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study.

Bello L, Kesari A, Gordish-Dressman H, Cnaan A, Morgenroth LP, Punetha J, Duong T, Henricson EK, Pegoraro E, McDonald CM, Hoffman EP, Cooperative International Neuromuscular Research Group Investigato - Ann. Neurol. (2015)

Bottom Line: Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test.Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (hazard ratio = 1.61, p = 0.016).After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024).

View Article: PubMed Central - PubMed

Affiliation: Children's National Medical Center, Washington, DC; Department of Neuroscience (Neurological, Psychiatric, Sensory, Reconstructive, Rehabilitative Science), University of Padua, Padua, Italy.

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Kaplan–Meier plots of age at loss of ambulation grouped by SPP1 rs28357094 genotype. (A) All patients genotyped for SPP1 rs28357094, including all races and ethnicities (n = 279), grouped 2 ways by rs28357094 genotype (black line = TT; gray line = TG/GG). (B) All patients genotyped for SPP1 rs28357094, including all races and ethnicities (n = 279), grouped 4 ways by rs28357094 genotype (black lines = TT; gray lines = TG/GG) and GC treatment (continuous lines = at least 1 year while ambulatory; dashed lines = <1 year or untreated). (C) Caucasian cohort controlled for population stratification and genotyped for SPP1 rs28357094 (n = 116), grouped 2 ways by rs28357094 genotype (black line = TT; gray line = TG/GG). (D) Caucasian cohort controlled for population stratification and genotyped for SPP1 rs28357094 (n = 116), grouped 4 ways by rs28357094 genotype (black lines = TT; gray lines = TG/GG) and GC treatment (continuous lines = at least 1 year while ambulatory; dashed lines = <1 year or untreated).
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fig02: Kaplan–Meier plots of age at loss of ambulation grouped by SPP1 rs28357094 genotype. (A) All patients genotyped for SPP1 rs28357094, including all races and ethnicities (n = 279), grouped 2 ways by rs28357094 genotype (black line = TT; gray line = TG/GG). (B) All patients genotyped for SPP1 rs28357094, including all races and ethnicities (n = 279), grouped 4 ways by rs28357094 genotype (black lines = TT; gray lines = TG/GG) and GC treatment (continuous lines = at least 1 year while ambulatory; dashed lines = <1 year or untreated). (C) Caucasian cohort controlled for population stratification and genotyped for SPP1 rs28357094 (n = 116), grouped 2 ways by rs28357094 genotype (black line = TT; gray line = TG/GG). (D) Caucasian cohort controlled for population stratification and genotyped for SPP1 rs28357094 (n = 116), grouped 4 ways by rs28357094 genotype (black lines = TT; gray lines = TG/GG) and GC treatment (continuous lines = at least 1 year while ambulatory; dashed lines = <1 year or untreated).

Mentions: Analyses relative to SPP1 and LTBP4 genotypes were limited to 283 patients with available genomic DNA samples (see Fig 1). Of these, 279 (because of limited availability of genomic DNA for a few participants) were successfully genotyped for SPP1 rs28357094. Median ages at LoA for genotype groups and results of log-rank and Cox regression analyses are summarized in Table3. Median ages at LoA were 11.8 years in 84 participants carrying the minor allele (TG/GG), and 13.0 years in 195 participants carrying the TT genotype (log-rank p = 0.048, Fig 2A). This closely reproduces the methodology of the previously reported association of rs28357094 genotype with LoA in 106 Italian patients,4 representing an independent validation of association with this phenotype. In the Cox regression model with GC treatment as time-varying covariate, the hazard ratio (HR) ± SE for TG/GG genotype was 1.22 ± 0.20 (p = nonsignificant [n.s.]). The HR for GC treatment was 0.41 ± 0.07 (p < 0.001).


Genetic modifiers of ambulation in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study.

Bello L, Kesari A, Gordish-Dressman H, Cnaan A, Morgenroth LP, Punetha J, Duong T, Henricson EK, Pegoraro E, McDonald CM, Hoffman EP, Cooperative International Neuromuscular Research Group Investigato - Ann. Neurol. (2015)

Kaplan–Meier plots of age at loss of ambulation grouped by SPP1 rs28357094 genotype. (A) All patients genotyped for SPP1 rs28357094, including all races and ethnicities (n = 279), grouped 2 ways by rs28357094 genotype (black line = TT; gray line = TG/GG). (B) All patients genotyped for SPP1 rs28357094, including all races and ethnicities (n = 279), grouped 4 ways by rs28357094 genotype (black lines = TT; gray lines = TG/GG) and GC treatment (continuous lines = at least 1 year while ambulatory; dashed lines = <1 year or untreated). (C) Caucasian cohort controlled for population stratification and genotyped for SPP1 rs28357094 (n = 116), grouped 2 ways by rs28357094 genotype (black line = TT; gray line = TG/GG). (D) Caucasian cohort controlled for population stratification and genotyped for SPP1 rs28357094 (n = 116), grouped 4 ways by rs28357094 genotype (black lines = TT; gray lines = TG/GG) and GC treatment (continuous lines = at least 1 year while ambulatory; dashed lines = <1 year or untreated).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403971&req=5

fig02: Kaplan–Meier plots of age at loss of ambulation grouped by SPP1 rs28357094 genotype. (A) All patients genotyped for SPP1 rs28357094, including all races and ethnicities (n = 279), grouped 2 ways by rs28357094 genotype (black line = TT; gray line = TG/GG). (B) All patients genotyped for SPP1 rs28357094, including all races and ethnicities (n = 279), grouped 4 ways by rs28357094 genotype (black lines = TT; gray lines = TG/GG) and GC treatment (continuous lines = at least 1 year while ambulatory; dashed lines = <1 year or untreated). (C) Caucasian cohort controlled for population stratification and genotyped for SPP1 rs28357094 (n = 116), grouped 2 ways by rs28357094 genotype (black line = TT; gray line = TG/GG). (D) Caucasian cohort controlled for population stratification and genotyped for SPP1 rs28357094 (n = 116), grouped 4 ways by rs28357094 genotype (black lines = TT; gray lines = TG/GG) and GC treatment (continuous lines = at least 1 year while ambulatory; dashed lines = <1 year or untreated).
Mentions: Analyses relative to SPP1 and LTBP4 genotypes were limited to 283 patients with available genomic DNA samples (see Fig 1). Of these, 279 (because of limited availability of genomic DNA for a few participants) were successfully genotyped for SPP1 rs28357094. Median ages at LoA for genotype groups and results of log-rank and Cox regression analyses are summarized in Table3. Median ages at LoA were 11.8 years in 84 participants carrying the minor allele (TG/GG), and 13.0 years in 195 participants carrying the TT genotype (log-rank p = 0.048, Fig 2A). This closely reproduces the methodology of the previously reported association of rs28357094 genotype with LoA in 106 Italian patients,4 representing an independent validation of association with this phenotype. In the Cox regression model with GC treatment as time-varying covariate, the hazard ratio (HR) ± SE for TG/GG genotype was 1.22 ± 0.20 (p = nonsignificant [n.s.]). The HR for GC treatment was 0.41 ± 0.07 (p < 0.001).

Bottom Line: Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test.Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (hazard ratio = 1.61, p = 0.016).After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024).

View Article: PubMed Central - PubMed

Affiliation: Children's National Medical Center, Washington, DC; Department of Neuroscience (Neurological, Psychiatric, Sensory, Reconstructive, Rehabilitative Science), University of Padua, Padua, Italy.

Show MeSH
Related in: MedlinePlus