A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN.
J Neurol Neurosurg Psychiatry
; 87(8): 851-8, 2016 08.
Article
in En
| MEDLINE
| ID: mdl-26746183
ABSTRACT
OBJECTIVE:
To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns.METHODS:
We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572â 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs.RESULTS:
We identified the following four clusters of longitudinal functional decline in the cases a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34×10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p=8.6×10(-10)-1.1×10(-7)). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002).CONCLUSIONS:
We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Predisposition to Disease
/
Connectin
/
Amyotrophic Lateral Sclerosis
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
J Neurol Neurosurg Psychiatry
Year:
2016
Type:
Article
Affiliation country:
Japan