The CLU Gene rs11136000 Variant is Significantly Associated with Alzheimer’s Disease in Caucasian and Asian Populations

Abstract

Large-scale genomewide association studies have reported that the CLU rs11136000 polymorphism is significantly associated with Alzheimer's disease (AD) in people of Caucasian ancestry. Recently, this association was investigated in Asian populations (Chinese, Japanese, and Korean). However, these studies reported either a weak association or no association between the rs11136000 polymorphism and AD. We believe that this discrepancy may be caused by the relatively small sample size of the previous studies and the genetic heterogeneity of the rs11136000 polymorphism in AD among different populations. For this study, we searched the PubMed and AlzGene databases. We selected 18 independent studies (6 studies of Asian populations and 12 of populations of Caucasian ancestry) that evaluated the association between the rs11136000 polymorphism and AD using a case-control experimental design. We evaluated the genetic heterogeneity of the rs11136000 polymorphism in Caucasian and Asian populations. We then investigated the rs11136000 polymorphism by a meta-analysis in Asian populations using allele, dominant, and recessive models. We identified a significant association between rs11136000 and AD with the allele model (P = 2.00 × 10(-4)) and the dominant model (P = 5.00 × 10(-3)). Meanwhile, a similar genetic risk of the rs11136000 polymorphism in AD was observed in Asian and Caucasian populations. Further meta-analysis in pooled Asian and Caucasian populations indicated a more significant association with the allele (P = 8.30 × 10(-24)), dominant (P = 4.46 × 10(-17)), and recessive (P = 3.92 × 10(-12)) models. Collectively, our findings from this meta-analysis indicate that the effect of the CLU rs11136000 polymorphism on AD risk in Asian cohorts (Chinese, Japanese, and Korean) is consistent with the protective effect observed in Caucasian AD cohorts.

Genomic variants, genes, and pathways of Alzheimer's disease: An overview

“…Subsequent replication efforts have provided confirmation of the signal in ZCWPW1 (Ruiz et al, 2014) as well as evidence of association at TRIP4 . Multiple validation studies (studies examining associations among different ethnicities) in Southeast Asian populations have demonstrated associations at many of these loci: CLU (Komatsu et al, 2011; Liu et al, 2014; Yu et al, 2013), CR1 (Jin et al, 2012), PICALM (Chung et al, 2013; Liu et al, 2013; Miyashita et al, 2013), BIN1 (Liu et al, 2013; Miyashita et al, 2013), and the MS4A gene cluster (Deng et al, 2012; Tan et al, 2013). …”

CR1 rs3818361 Polymorphism Contributes to Alzheimer’s Disease Susceptibility in Chinese Population

“…In addition to the rs6656401 and rs3818361 polymorphisms, we previously analyzed PICALM rs3851179, BIN1 rs744373, and CLU rs11136000 and rs2279590 polymorphisms [1,[6][7][8][9]. We found that there was no significant genetic heterogeneity of these polymorphisms in Asian and European populations.…”

“…We found that there was no significant genetic heterogeneity of these polymorphisms in Asian and European populations. We further analyzed relatively largescale samples and reported significant association between these common variants and AD in Asian populations [1,[6][7][8][9].…”

“…Since 2009-2013, large-scale genome-wide association studies (GWAS) reported several Alzheimer's disease (AD) susceptibility genes including CR1, BIN1, CLU, PICALM, MS4A4/MS4A6E, CD2AP, CD33, EPHA1, and ABCA7 [1][2][3], SORL1 [4], and TREM2 [5]. A recent large meta-analysis of AD GWAS in individuals of European ancestry identified 11 new AD genetic risk factors for AD, which include HLA-DRB5/ DRB1, PTK2B, SLC24A4-0RING3, DSG2, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, and CASS4 [3].…”

“…We previously analyzed the PICALM rs3851179 [6,7], BIN1 rs744373 [8], CLU rs11136000 [1], rs2279590 [9], and rs9331888 [10], CD2AP rs9349407 [11], ABCA7 rs3764650 [12], and CD33 rs3865444 [13] polymorphisms, and identified significant association. In addition to these polymorphisms above, a single nucleotide polymorphism (SNP) rs3818361 in CR1 was reported to be significantly associated with AD in European ancestry with P = 8.5E-08, P = 9.2E-06, and P =3.7E-14 [14][15][16].…”