Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disease that is the leading cause of dementia in the elderly individuals. Genetic susceptibility at multiple loci and interactions among these genes influence the risk of developing AD; recent estimates of heritability range from 58%–79% (Gatz et al., 2006). For many years, amyloid precursor protein and the presenilin genes 1 and 2 (PSEN1, PSEN2) have been the only unequivocally established susceptibility genes for early-onset familial AD, and apolipoprotein E (ApoE) the only confirmed susceptibility gene for common late-onset AD (LOAD). In recent years, large genome-wide association studies (GWAS) have identified 9 other genes and/or loci ( Harold et al., 2009, Hollingworth et al., 2011, Lambert et al., 2009, Naj et al., 2011 and Seshadri et al., 2010) that, along with ApoE ε4, contribute to a high proportion of genetic risk for LOAD. Among them, the bridging integrator 1 (BIN1 or amphiphysin 2/AMPH2) gene, located on chromosome 2q14.3, is currently identified as the most important genetic susceptibility locus in LOAD after ApoE, according to the continuously updated Alzgene database (http://www.alzgene.org/) ( Bertram et al., 2007).
As an important AD candidate gene, BIN1 is expressed in many tissues and overexpressed BIN1 has been found in AD brains ( Chapuis et al., 2013). It has been reported that higher BIN1 expression was associated with later age at onset and shorter disease duration in AD patients ( Karch et al., 2012). In addition, our study has recently observed that BIN1 expression was also increased in peripheral blood of AD patients; and plasma BIN1 might become potential biomarker for AD diagnosis ( Sun et al., 2013). Similar to ApoE, numerous studies have presented compelling evidence implicating BIN1 in AD pathogenesis ( Tan et al., 2013a and Tan et al., 2013b). Besides its potential interaction with tau pathology ( Chapuis et al., 2013), BIN1 might also be involved in regulating endocytosis and trafficking, immune, and inflammation, calcium transients, and apoptosis ( Carter, 2011, Elliott et al., 2000, Hong et al., 2012 and Tjondrokoesoemo et al., 2011). All these observations suggest that the BIN1 gene could be considered a functional candidate gene for AD susceptibility.
Initially, BIN1 gene locus was identified as having a possible association with AD using GWAS in the GERAD1 study ( Harold et al., 2009) but it was not until the study by Seshadri et al., 2010 that this locus for AD reached genome-wide statistical significance, a finding that was confirmed in other large GWAS ( Kamboh et al., 2012 and Naj et al., 2011) and the largest family-based GWAS ( Wijsman et al., 2011). After these original observations, several independent candidate gene studies examined the association between BIN1 polymorphisms and LOAD risk in independent cohorts ( Carrasquillo et al., 2011, Lambert et al., 2011, Lee et al., 2011 and Logue et al., 2011), but the results have been conflicting in ethnically distinct populations ( Chung et al., 2013 and Tan et al., 2013a). Based on large, multicenter data sets, meta-analysis results also strongly indicate that BIN1 is an AD susceptibility locus ( Carrasquillo et al., 2011, Hollingworth et al., 2011, Hu et al., 2011, Kamboh et al., 2012 and Lambert et al., 2013). Genetic variants of BIN1 associated with susceptibility to LOAD are known for individuals of European ancestry, but whether the same or different variants within BIN1 gene account for the genetic risk of AD in Han Chinese individuals is still unknown. In this study, to investigate the involvement of the BIN1 gene in LOAD in the Han Chinese individuals, a 2-step design study was carried out. We first sequenced in the promoter, exons, the 5′ and 3′ untranslated regions, and exon–intron boundaries of the BIN1 gene for mutations in a total of 50 LOAD patients and 50 controls. The identified variants were then partially selected to be analyzed in a much larger case–control sample (n = 2292), which was well matched for age, gender, and ethnic background in the Han Chinese individuals.
