Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population.

OBJECTIVE: Five genomewide association studies (GWAS) in white populations have recently identified and confirmed 9 novel Alzheimer's disease (AD) susceptibility loci (CLU, CR1, PICALM, BIN1, ABCA7, MS4A gene cluster, CD2AP, CD33, and EPHA1). These studies have been conducted almost exclusively in white populations and it is unclear whether these observations generalize to populations with different ethnicities. METHODS: We recruited 1224 unrelated northern Han Chinese subjects comprising 612 patients with a clinical diagnosis of late-onset AD (LOAD) according to the criteria of the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association and 612 healthy age- and sex-matched control subjects. Because of our previous study investigating CLU, CR1, and PICALM in the Han population, we limited the current analysis to BIN1, ABCA7, MS4A gene cluster, CD2AP, CD33, and EPHA1. RESULTS: In a multivariate analysis, associations of MS4A6A (rs610932; odds ratio = 0.632, Bonferroni corrected P = .019) and CD33 (rs3865444; odds ratio = 1.492, Bonferroni corrected P = .017) with LOAD were replicated successfully. When these data were stratified by apolipoprotein E (APOE) ε4 status, both rs610932 and rs610932 were evident only among subjects without the APOE ε4 allele. For BIN1, assuming a dominant model of inheritance, a positive association for rs7561528 in APOE ε4 carriers was observed. This association, however, did not remain significant after Bonferroni correction. As for ABCA7, CD2AP, and EPHA1 single nucleotide polymorphisms from recent GWAS, despite the similar directional effects, no significant differences in genotype and estimated allele frequency distribution between patients and control subjects were observed. CONCLUSIONS: This study provides the first independent evidence that MS4A and CD33 loci are associated with the risk of LOAD in northern Han Chinese population. Genotypes at the two loci confer risk predominantly in APOE ε4-negative subjects.

Genetic association of SLC2A14 polymorphism with Alzheimer's disease in a Han Chinese population.

Glucose uptake and metabolism are impaired in Alzheimer's disease (AD) brain, which appear to be a cause, rather than a consequence of neurodegeneration. Recently, the gene of the 14th isoform of subfamily A of solute carrier family 2 (SLC2A14), encoding glucose transporter 14 (GLUT14), was identified for the association in vivo with AD pathology of Tau, and rs10845990 within SLC2A14 showed association with AD in Caucasians. In order to evaluate the involvement of the SLC2A14 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (597 LOAD cases and 605 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.015, allele P = 0.039). The G-carrying genotype (GT + GG) individuals showed a 1.41-fold increased risk compared with the TT genotype carriers (odds ratio (OR) = 1.41, 95 % confidence interval (CI) = 1.11-1.79, P = 0.005, Power = 83.6 %). After stratification by ApoE ε4-carrying status, rs10845990 polymorphism was only significantly associated with LOAD in non-ApoE ε4 allele carriers (P < 0.001). Multivariate logistic regression analysis also conferred this positive association between the SNP rs10845990 and LOAD in the dominant and additive model after adjustment for age, gender, and the ApoE ε4 carrier status. These results suggested that SLC2A14 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.

Blood clusterin levels, rs9331888 polymorphism, and the risk of Alzheimer's disease.

Variants in the clusterin gene have been associated with Alzheimer's disease (AD) through replicated genome-wide studies, but the underlying mechanisms remain unknown. In this study the association of the AD clusterin common risk polymorphism rs9331888 with blood clusterin levels was tested in 104 AD subjects and 104 healthy controls. Blood clusterin levels were significantly elevated in AD patients (p < 0.05). The rs9331888 AD-risk variant was associated with low clusterin mRNA and protein levels in an allele-dose dependent manner in both groups (p < 0.001). This study indicates that the rs9331888 AD-risk variant is associated with low blood clusterin levels.

Common variants in toll-like receptor 4 confer susceptibility to Alzheimer's disease in a Han Chinese population.

Toll-like receptor 4 (TLR4) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located within the previous identified linkage region of AD on chromosome 9q, and functionally is involved in the microglia-mediated inflammatory response, amyloid-ß (Aß) plaque formation and Aß clearance. To test whether variants in the TLR4 gene are associated with late-onset AD (LOAD), we organized a multicenter study of 785 subjects (399 cases and 386 matched controls) in a Han Chinese population. Ten single nucleotide polymorphisms (SNPs) that span the TLR4 gene, from approximately 5 kb of the predicted 5'-untranslated region (UTR) to approximately 6 kb of the predicted 3'- UTR, were selected and their associations with LOAD risk factors were assessed. With respect to allelic diversity, the minor alleles of seven SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, rs7037117, and rs7045953) in TLR4 showed consistent protective effects against the risk of developing LOAD. With regard to genotypic diversity, individuals carrying at least one minor allele of each SNP above had a consistently lower risk of LOAD than those with no copies of the minor alleles (ORs ranging from 0.445 to 0.637). rs7045953, located in the 3'-UTR of TLR4, was most strongly associated with LOAD, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 1.7x10-6, Pc s1.0x10-4). Our data suggests that the TLR4 gene contributes to the susceptibility for LOAD in Han Chinese.

No association of toll-like receptor 2 polymorphisms with Alzheimer's disease in Han Chinese.

Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and is functionally involved in the microglia-mediated inflammatory response and amyloid ß (Aß) clearance. In the current study, 7 single nucleotide polymorphisms (SNPs) that span the TLR2 were selected and their associations with late-onset AD (LOAD) risk were assessed in a case-control sample comprising 785 individuals in a Han Chinese population. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the AD cases were detected compared with the controls. TLR2 gene might not play a major role in the genetic predisposition to late-onset Alzheimer's disease in this population.

[Percutaneous radiofrequency ablation combined with transcatheter arterial chemoembolization and percutaneous ethanol injection for recurrent small hepatocellular carcinoma].

OBJECTIVE: To explore the value of percutaneous radiofrequency ablation (PRFA) combined with transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) in the management of recurrent small hepatocellular carcinoma. METHODS: Between March 2001 and March 2005, 52 patients with recurrent hepatocellular carcinoma (tumor size< or =5 cm) underwent PRFA, and 14 of the patients (tumor size 3-5 cm) also received TACE and PEI, and their clinical data were analyzed retrospectively. RESULTS: MRI or CT after PRFA revealed complete coagulative necrosis of the tumor in 38 cases (tumor size <3 cm). In the 14 patients (tumor size 3-5 cm) with also TACE and PEI, complete necrosis occurred in 11 cases (78.6%). In the patients involved in this study, the 1-, 2-, 3- and 4-year survival rates were 96.2%, 69.4%, 45.5% and 30.0%, respectively. CONCLUSIONS: PRFA is an effective modality for local treatment of recurrent small hepatocellular carcinoma, capable of total elimination of tumors <3 cm. For tumors of 3-5 cm, combination with TACE and PEI may help increase the tumor necrosis rate following the ablation and raise the patients' survival rate.