A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression ofTTN
| Autor: | Koji Abe, Koichi Mizoguchi, Satoshi Kuwabara, Ryoichi Nakamura, Masashi Aoki, Masaya Oda, Masahisa Katsuno, Daichi Yokoi, Takashi Imai, Ryuji Kaji, Yuishin Izumi, Mizuki Ito, Kazuaki Kanai, Shiro Ikegawa, Michiaki Kubo, Akihiro Hirakawa, Aritoshi Iida, Koichi Okamoto, Ikuko Aiba, Shinsuke Ishigaki, Kenji Nakashima, Shoji Tsuji, Naoki Atsuta, Mitsuya Morita, Masahiro Nakatochi, Kazuko Hasegawa, Hazuki Watanabe, Akihiro Kawata, Akira Taniguchi, Gen Sobue, Osamu Kano, Hirohisa Watanabe |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Linkage disequilibrium Single-nucleotide polymorphism Genome-wide association study Biology Polymorphism Single Nucleotide Linkage Disequilibrium 03 medical and health sciences 0302 clinical medicine Polymorphism (computer science) Genetic variation medicine Humans Connectin Genetic Predisposition to Disease Amyotrophic lateral sclerosis Allele Alleles Genetics Amyotrophic Lateral Sclerosis Prognosis medicine.disease Psychiatry and Mental health 030104 developmental biology Expression quantitative trait loci Female Surgery Neurology (clinical) 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | Journal of Neurology, Neurosurgery & Psychiatry. 87:851-858 |
| ISSN: | 1468-330X 0022-3050 |
| DOI: | 10.1136/jnnp-2015-311541 |
| Popis: | 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 . |
| Databáze: | OpenAIRE |
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