Association between clusterin gene polymorphism rs11136000 and late-onset Alzheimer's disease susceptibility: A review and meta-analysis of case-control studies

Abstract

The present study aimed to evaluate the association between rs11136000 in clusterin (CLU) and late-onset Alzheimer's disease (LOAD) by meta-analysis. Several databases including PubMed, EMbase, CBMdisc and CMCC were searched for relevant case-control studies based on defined selection criteria. Odds ratios (OR) and 95% confidence interval (CI) of the rs11136000 genotype and allele distribution were analyzed with RevMan and Stata software. The control population and heterogeneity between populations were examined in the selected studies using the Hardy-Weinberg equilibrium. Overall OR among the frequencies of the genotype and allele in both patients with AD and controls was estimated using fixed or random effect models. The summary of the OR and 95% CI were then analyzed to obtain the effects across the studies. Publication bias was examined using a funnel plot, Egger's test and Begg's test, and a Fail-safe Number (Nfs). A total of 20 reports were used. The summary OR for studies in the Caucasian population with a frequency of TT+TC/CC genotype and T/C allele at rs11136000 locus in CLU were 0.79 (95% CI, 0.73–0.86; P<0.00001) and 0.87 (95% CI, 0.85–0.90; P<0.00001). The summary OR for the studies conducted in the Asian population were 0.90 (95% CI, 0.81–0.99; P=0.04) and 0.87 (95% CI, 0.81–0.93; P<0.0001). The summary OR in other mixed ethnic groups with regards to the frequency of T/C allele was 0.82 (95% CI, 0.68–0.99; P=0.04). These results demonstrated the presence of a statistically significant difference in LOAD susceptibility between individuals with the T allele CLU rs11136000 polymorphism and those without. The studies conducted in populations of African descent or Hispanics showed no statistically significant difference. Negligible publication bias was present, with Nfs being 750.604. In summary, polymorphism rs11136000 in the CLU gene may contribute to susceptibility to LOAD, and the presence of the T allele may reduce the risk of LOAD in Caucasian and Asian populations. However, no definitive association was found between the presence of the CLU rs11136000 polymorphism and LOAD in populations of African or Hispanic descent.

Analyzing 74,248 Samples Confirms the Association Between CLU rs11136000 Polymorphism and Alzheimer’s Disease in Caucasian But Not Chinese population

“…4b ) and recessive model ( OR = 0.615, 95% CI = 0.355–1.068, P = 0.0841) (Fig. 4c ), which was different from the findings in the previous studies 29 , 30 .

Figure 4 Forest plot for the meta-analysis of rs11136000 polymorphism in Chinese population.

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“…Although the two independent meta-analyses found a significant association between the minor allele (T) of rs11136000 and a decreased risk of AD in Caucasian and Asian ethnicities by integrating the data from related GWAS studies published before June 20, 2013 (18 studies) and August 31, 2014 (25 studies), respectively 29 , 30 , many of the following studies also reported the inconsistent results 31 – 47 . Moreover, according to our further investigation, the two meta-analyses missed out a total six related GWAS studies published before August 31, 2014 48 – 52 , and a GWAS study about American and German populations is misclassified to the Asian ethnicity subgroup in Du et al .’s meta-analysis 22 .…”

“… 27 , respectively. Then, two independent meta-analysis studies re-assess the results of these GWAS studies published before June 20, 2013 (18 studies) and August 31, 2014 (25 studies), respectively, and both of them found this SNP is significantly associated with AD in populations of Asian and Caucasian 29 , 30 . But among the subsequent 18 GWAS studies published after August 31, 2014, many of them report inconsistent results in the corresponding populations 31 – 47 .…”

“… 29 miss two GWAS articles about Caucasian populations 16 , 24 , and Du et al . 30 miss a GWAS article about Asian population 27 . In fact, through our further investigation, a total five related GWAS articles published before August 31, 2014 are not collected in the two meta-analysis studies 48 – 52 .…”

“…We suspected that the small-scale and incompletion or heterogeneity of the samples maybe lead to different results of these studies. In this study, we selected 50 related GWAS studies with large-scale samples from 40 articles (28,464 cases and 45,784 controls, about 40.3% increase over the total number of the previous two meta-analysis studies 29 , 30 ) by searching the PubMed, ClinicalKey, AlzGene, Google Scholar, CNKI, Wanfang and VIP databases, and reevaluated the association between AD and rs11136000 polymorphism in Caucasian, Asian and Chinese population using the method of meta-analysis as previously described 53 – 63 . The use of more complete and larger scale samples would make the results more reliable.…”