مطالعه اکتشافی بر روی STX6، MOBP، MAPT و EIF2AK3 و بیماری آلزایمر دیررس

Both Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are a class of neurodegenerative diseases associated with the pathologic aggregation of tau protein in the human brain. They share some clinical and pathologic characteristics. A recent genome-wide association study reported several single-nucleotide polymorphisms at the STX6, MOBP, MAPT, and EIF2AK3 in association with PSP. To explore whether these single-nucleotide polymorphisms are associated with AD risk, we conducted a case-control study to investigate the PSP-associated loci in 1592 Han Chinese subjects. Rs242557 at the MAPT locus was associated with late-onset AD (LOAD) (odds ratio [OR], 1.175; p = 0.026), which appeared to be stronger for LOAD patients with apolipoprotein E (APOE) ε4 allele (OR, 1.510), and this positive association was not changed after adjusting for age, sex, and the APOE ε4-carrier status (additive model: OR, 1.163; p = 0.036; dominant model: OR, 1.315; p = 0.010). Rs1768208 in MOBP and rs7571971 in EIF2AK3 showed association only in the APOE ε4 positive subjects, and these did not appear to be independent of APOE. As for rs1411478 in STX6, we did not explore any association with LOAD. Our exploratory analysis mainly suggests an association of MAPT with LOAD, especially in APOE ε4 carriers. Genotypes at MOBP and EIF2AK3 confer risk predominantly in APOE ε4-positive subjects, with indications of an interaction between APOE and MOBP or EIF2AK3 on AD risk.

Both Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are a class of neurodegenerative diseases associated with the pathologic aggregation of tau protein in the human brain (Crespo-Biel et al., 2012; Höglinger et al., 2011). These 2 conditions share some clinical and pathologic characteristics. On the 1 hand, PSP cases display tau pathology similar to late-onset AD (LOAD) (Abraham et al., 2009). Both of them involve abnormal accumulation of tau protein within neurons as neurofibrillary tangles (NFT). On the other hand, they are clinically progressive and manifest cognitive decline eventually (Waldemar et al., 2007). These connections suggest that AD and PSP might have some shared risk factors and/or common pathogenic mechanisms. However, little effort to date has been made to research potential genetic risk factors that might contribute to both diseases. Recently, a large genome-wide association study (GWAS) has reported several novel susceptibility genetic loci for PSP, including syntaxin6 (STX6), myelin oligodendrocyte-associated basic protein (MOBP) and eukaryotic translation initiation factor 2-α kinase 3 (EIF2AK3) ( Höglinger et al., 2011). Meanwhile, the tau gene (MAPT) was also confirmed in this PSP GWAS. The expression levels and functional features of these genes exclusively supported their associations with PSP ( Zou et al., 2012). Therefore, we explored the relationship of LOAD with selected single-nucleotide polymorphisms (SNPs) from the PSP GWAS (rs1411478 for STX6, rs1768208 for MOBP, rs7571971 for EIF2AK3, and rs8070723 and rs242557 for MAPT) in a large LOAD case-control study.