Laboratory StudyIs there an association of regulatory region polymorphism in the alpha-1-antichymotrypsin gene with sporadic Alzheimer’s disease in the northern Han-Chinese population?
Introduction
Alzheimer’s disease (AD) is characterized by the formation of senile plaques (SP) and neurofibrillary tangles in the brain. Alpha-1-antichymotrypsin (ACT) and amyloid beta peptide (Aβ) are the major components of SP.1 Increasing biochemical and pathological evidence shows that ACT could increase the neurotoxicity of Aβ and promote amyloid filament formation.[2], [3], [4], [5] Therefore, the ACT gene (ACT, MIM 107280) may be involved in AD onset.
Initial observations indicated that a common variant in the ACT signal sequence (rs4934) was associated with increased risk of AD,[6], [7] and might affect age-at-onset (AAO) and disease duration of AD.8 However, results from additional studies were inconsistent.[9], [10], [11], [12] Increasing evidence has suggested that variants in the regulatory regions may be relevant to the pathogenetic characteristics of particular diseases by altering transcriptional activity. In 1998, the construct containing the −156 to +25 fragment (relative to the transcriptional start site) of the ACT gene was found to be the promoter of ACT.13 The −51G/T polymorphism (rs1884082, named ACT4) in the ACT promoter was directly associated with altered gene expression and the TT genotype was associated with an increased risk of early onset AD.[13], [14], [15], [16] Other reports suggested that the TT genotype was associated with late onset AD, whereas the single nucleotide polymorphism (SNP) was not associated with AD.[17], [18]
To our knowledge, there have been no reports on ACT regulatory region polymorphism in Chinese patients with AD. To determine whether variants in the regulatory region of the ACT gene are associated with SAD in the northern Han-Chinese population, we systematically screened these regions [promoter, the −13 kb enhancer (413 base pair [bp] fragment) and the −11.5 kb enhancer (160 bp fragment)].[19], [20] In addition, we examined the impact of the ACT regulatory region variants on mean AAO in 244 patients with AD.
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Recruitment of patients
The study group consisted of 244 patients with SAD (105 males and 139 females; of mean age 74.9 ± 8.3 years; mean AAO = 70.0 ± 9.5 years). We gained access to patients via the Beijing Xuan Wu Hospital, the Beijing Senile Hospital and several other hospitals in Beijing City. Probable AD was clinically diagnosed according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA). All
Results
We screened the promoter and enhancers of ACT and found three polymorphisms in the −11.5 kb enhancer (−11510T/C, rs10145747, ACT1; −11496G/A, rs4375593, ACT2; and −11491T/C, rs4508366, ACT3) and one polymorphism in the promoter (−51G/T, rs1884082, ACT4). We also found one variant in the −11.5 kb enhancer (−11664G/A) and one variant in the promoter (−271T/C, rs4362321) during screening or sequencing. Since the frequencies of the latter two genotypes (−11664G/A and −271T/C, rs4362321) were lower
Discussion
Polymorphisms in one promoter of the ACT gene have been related to the formation of SP.[13], [14], [15], [16] Some reports showed that the TT genotype in ACT4 might increase the risk of AD onset.[14], [15], [16] Others have indicated that the GG genotype is a risk factor for the disease.17 Those studies were trying to associate SNP with susceptibility to AD. But the additive and/or opposing associations with other SNP have been ignored. Recently, a report on combining several SNP of ACT did not
Acknowledgements
This work was supported by National Key Technology R&D Program in the Eleventh Five-year Plan Period (2006BAI02B01), the National Basic Research 973 Program (2006CB500700), National Natural Science Key Foundation (30830045), Beijing Natural Science Key Foundation (7071004), and Funding Project for Academic Human Resources Development in Institutions of Higher Learning under the Jurisdiction of Beijing Municipality. This work was also supported by and partially conducted in the Key
References (26)
- et al.
Effects of Alzheimer’s peptide and 1-antichymotrypsin on astrocyte gene expression
Neurobiol Aging
(2007) - et al.
Alzheimer’s peptide A beta 1–42 binds to two beta-sheets of alpha1-antichymotrypsin and transforms it from inhibitor to substrate
J Biol Chem
(1998) - et al.
Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer’s disease
Neurobiol Aging
(2006) - et al.
Absence of association of alpha 1-antichymotrypsin polymorphisms with Alzheimer’s disease: a report on autopsy-confirmed cases
Exp Neurol
(1998) - et al.
Oncostatin M and the interleukin-6 and soluble interleukin-6 receptor complex regulate alpha1-antichymotrypsin expression in human cortical astrocytes
J Biol Chem
(1998) - et al.
A new promoter polymorphism in the alpha-1-antichymotrypsin gene is a disease modifier of Alzheimer’s disease
Neurobiol Aging
(2005) - et al.
Allele-specific overexpression in astrocytes of an Alzheimer’s disease associated alpha-1-antichymotrypsin promoter polymorphism
Brain Res Mol Brain Res
(2004) - et al.
Alpha-1-antichymotrypsin polymorphism in the gene promoter region affects survival and synapsis loss in Alzheimer’s disease
Arch Gerontol Geriatr Suppl
(2004) - et al.
A SNP in the ACT gene associated with astrocytosis and rapid cognitive decline in AD
Neurobiol Aging
(2008) - et al.
Strocyte-specific expression of the alpha1-antichymotrypsin and glial fibrillary acidic protein genes requires activator protein-1
J Biol Chem
(2006)