The Analysis of Two BDNF Polymorphisms G196A/C270T in Chinese Sporadic Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is an ethnically heterogeneous motor neuron disease that results from the selective death of motor neurons in the brain and spinal cord. Brain-derived neurotrophic factor (BDNF) is widely distributed across the central and peripheral nervous systems and plays neurotrophic and other physiological roles in various brain regions. Alterations of neurotrophin availability have been proposed as a pathogenic mechanism underlying ALS neurodegeneration. Several genetic studies have shown a significant association between schizophrenia, Alzheimer's disease, and Parkinson's disease and certain BDNF polymorphisms, specifically G196A (rs6265) and C270T (rs56164415). However, the relationship between the G196A and C270T polymorphisms and ALS has never been investigated. We hypothesized that sporadic ALS (sALS) and disease susceptibility could arise due to BDNF polymorphisms and investigated the relationship between ALS and the BDNF polymorphisms G196A and C270T in a large Chinese cohort. We demonstrate that the frequency of the CT genotype and of the C270T T allele was significantly higher in the ALS group than in controls, although G196A was not associated with sALS. These data provide the first demonstration that the BDNF C270T polymorphism may be a candidate susceptibility locus for sALS, at least in Han Chinese.

Genetic Variants of the Brain-Derived Neurotrophic Factor and Metabolic Indices in Veterans With Posttraumatic Stress Disorder

“…Unlike BDNF Val66Met, the BDNF C270T polymorphism has only recently gained attention in studies of neuropsychiatric disorders ( 101 ). The T allele of the BDNF C270T polymorphism was reported to be a risk factor for PTSD ( 46 ), schizophrenia ( 29 ), bulimia nervosa ( 102 ), and amyotrophic lateral sclerosis ( 24 ), but not for Alzheimer's disease ( 78 ). The T allele prevalence in our study was 17% and it was the same as the T allele frequency in a Chinese sample with PTSD ( 46 ).…”

“…In humans, BDNF is encoded by the BDNF gene which extends over 70 kb, located on chromosome 11, region p13–14 ( 22 ). There are hundreds of polymorphisms in the BDNF gene, however, the most frequently studied functional polymorphisms include the Val66Met single-nucleotide polymorphism (rs6265) in the coding exon ( 23 ), and the C270T single-nucleotide polymorphism (rs56164415), in the 5′-untranslated region (UTR) of the BDNF gene ( 24 ). The A (Met) allele, compared to the G (Val) allele, of the BDNF Val66Met is associated with disrupted cellular processing, trafficking and intracellular packaging of the pro-BDNF and reduced activity-dependent secretion of the mature BDNF ( 23 , 25 ).…”

“…The A (Met) allele, compared to the G (Val) allele, of the BDNF Val66Met is associated with disrupted cellular processing, trafficking and intracellular packaging of the pro-BDNF and reduced activity-dependent secretion of the mature BDNF ( 23 , 25 ). The other polymorphism, BDNF C270T, in the BDNF 5'-non-coding region ( 26 ), may affect BDNF expression ( 27 ) and might lead to regionally specific quantitative BDNF disbalance in the brain ( 24 ). Consequently, both BDNF polymorphisms, BDNF Val66Met ( 19 , 28 ) and BDNF C270T ( 24 , 29 ) have been associated with different neuropsychiatric disorders.…”

“…The other polymorphism, BDNF C270T, in the BDNF 5'-non-coding region ( 26 ), may affect BDNF expression ( 27 ) and might lead to regionally specific quantitative BDNF disbalance in the brain ( 24 ). Consequently, both BDNF polymorphisms, BDNF Val66Met ( 19 , 28 ) and BDNF C270T ( 24 , 29 ) have been associated with different neuropsychiatric disorders.…”

The rs696880 Polymorphism in the Nogo-A Receptor Gene (RTN4R) Is Associated With Susceptibility to Sporadic Amyotrophic Lateral Sclerosis in the Chinese Population

“…SALS may result from the interaction between susceptible genes and the environment; therefore, identifying SALS susceptibility genes is as important as identifying pathogenic genes. Several previous studies have identified different susceptibility genes in various ethnic cohorts, including DPP6 , ITPR2 , UNC13A , FGGY , ELP3 , KIFAP3 , 9p21.2 , ZNF512B , TIMA1 , SCNN1A , BDNF , C21orf2 , MOBP , SCFD1 and GPX3-TNIP1 (van Es et al, 2007 , 2008 , 2009a , b ; Cronin et al, 2008 ; Landers et al, 2009 ; Simpson et al, 2009 ; Iida et al, 2011 ; Cai et al, 2014 ; Chen et al, 2014 ; van Rheenen et al, 2016 ; Xu et al, 2017 ).…”