Title:Polymorphism Rs2421943 of the Insulin-Degrading Enzyme Gene and the
Risk of Late-Onset Alzheimer’s Disease
Volume: 19
Issue: 3
Author(s): Omar Šerý*, Tomáš Zeman, Alice Hálová, Vladimír Janout, Jana Janoutová, Jan Lochman and Vladimir J. Balcar
Affiliation:
- Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of Science, Masaryk University,
Brno 62500, Czech Republic
- Laboratory of Neurobiology and Pathological Physiology, Institute of Animal Physiology
and Genetics, Czech Academy of Sciences, Brno, Czech Republic
Keywords:
Alzheimer’s disease, mild cognitive impairment, insulin-degrading enzyme, type-2 diabetes mellitus, amyloid-β peptide, single nucleotide polymorphisms.
Abstract:
Background: Insulin-degrading enzyme (IDE) is a widely distributed Zn2+-binding metalloprotease
that cleaves multiple short and medium-sized peptides prone to form β-structures. These
include insulin and amyloid-β peptides. Accumulation and fibrillation of amyloid-β peptides leading
to the formation of amyloid plaques is a characteristic sign of Alzheimer’s disease (AD) pathology.
Objective: The study investigated the rs2421943 single nucleotide polymorphism (SNP) of the IDE
gene as a risk factor for MCI (mild cognitive impairment) and AD.
Methods: Two independent groups of 1670 patients and controls were included. The AD group consisted
of 595 patients and 400 controls; the MCI group involved 135 patients and 540 matched controls.
PCR and restriction fragment length analysis were used to analyze the rs2421943 polymorphism.
Using the miRBase and RNA22 prediction tools in silico indicated that the rs2421943 polymorphism
is a potential target for a specific miRNA (hsa-miR-7110-5p).
Results: AG and GG genotypes of rs2421943 significantly increased the risk of AD, and the AG genotype
increased the risk of MCI. It seems the G allele both increases the risk of AD and accelerates the
transition through the MCI phase. In silico study revealed that rs2421943 is inside the sequence binding
miRNA hsa-miR-7110-5p. The polymorphism could affect the rate of IDE pre-RNA (heterogeneous
nuclear RNA, hnRNA) processing, resulting in slower translation, lower levels of IDE, deficient
removal of amyloid-β fragments, and greater risk of and/or accelerated progression of AD.
Conclusion: GG and AG genotypes of the single nucleotide polymorphism rs2421943 of insulindegrading
enzyme gene increase the risk of AD and MCI.
