A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN. - PubMed - NCBI
A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN.
Watanabe H1,
Atsuta N1,
Hirakawa A2,
Nakamura R1,
Nakatochi M2,
Ishigaki S1,
Iida A3,
Ikegawa S3,
Kubo M4,
Yokoi D1,
Watanabe H1,
Ito M1,
Katsuno M1,
Izumi Y5,
Morita M6,
Kanai K7,
Taniguchi A8,
Aiba I9,
Abe K10,
Mizoguchi K11,
Oda M12,
Kano O13,
Okamoto K14,
Kuwabara S15,
Hasegawa K16,
Imai T17,
Kawata A18,
Aoki M19,
Tsuji S20,
Nakashima K21,
Kaji R5,
Sobue G1.
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 572 983 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
- PMID:
- 26746183
- [PubMed - as supplied by publisher]
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