Insulin-like growth factor 1 (IGF1) polymorphism is associated with Alzheimer's disease in Han Chinese

A review of pathogenic findings in Alzheimer's brains and the functional consequences of altered insulin-like growth factor 1 (IGF1) input to the brain suggest the association between Alzheimer's disease (AD) and the disrupted IGF1 signaling. Recently, the identification of polymorphism rs972936 that was associated with both an increased risk of AD and high circulating levels of IGF1 was reported in Southern European population. In order to evaluate the involvement of the IGF1 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 (794 LOAD cases and 796 controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.006, allele P = 0.047). The T allele of rs972936 demonstrated a 1.16-fold risk for developing LOAD when compared with the C allele, which diverges to the report in the Caucasian population. After stratification by apolipoprotein E (APOE) ?4-carrying status, rs972936 polymorphism was only significantly associated with LOAD in non-ApoE ?4 allele carriers (genotype P = 0.002, allele P = 0.039). Multivariate logistic regression analysis also conferred this positive association between the SNP rs972936 and LOAD in the recessive and additive model after adjustment for age, gender, and the ApoE ?4 carrier status. These results suggest that IGF1 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.     

Chromosome 9p21.3 genotype is associated with vascular dementia and Alzheimer's disease

Vascular risk factors have been implicated in the pathogenesis of vascular dementia and Alzheimer's disease. The identification of a novel vascular disease susceptibility locus at 9p21.3 has recently generated great interest. In the present study, we sought to determine whether a common genetic variant (tagged by rs1333049, G/C) in the 9p21.3 locus—that has been previously linked to an increased vascular risk—might influence the susceptibility to vascular dementia (VaD) and late-onset Alzheimer's disease (LOAD). A cohort of 200 VaD patients, 407 LOAD patients and 405 cognitively healthy controls were genotyped for rs1333049 using a fluorogenic 5′ nuclease assay. The frequency of the C allele of rs1333049 was significantly higher in VaD (62.2%, P = 0.005) and LOAD (60.7%, P = 0.004) patients than in controls (53.6%). After adjustment for the APOE ε4 carrier status and other vascular risk factors, the C allele of rs1333049 remained significantly associated with both VaD (OR 1.31, 95% CI 1.07-1.77, P < 0.01) and LOAD (OR 1.28, 95% CI 1.04-1.55, P < 0.01). Altogether, our data indicate for the first time that the C allele of rs1333049 in the vascular disease susceptibility locus is associated with VaD and LOAD, independent of traditional risk factors and the APOE ε4 genotype.     

Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer's disease in a southern Chinese population

In this case-controlled study, we tested susceptible genetic variants for Alzheimer's disease (AD) in CR1, CLU and PICALM from genome-wide association studies (GWAS) in a southern Chinese population. Eight hundred twelve participants consisting of 462 late-onset Alzheimer's disease (LOAD) patients and 350 nondemented control subjects were recruited. We found by multivariate logistic regression analysis, that single nucleotide polymorphisms (SNPs) in CR1 (rs6656401 adjusted allelic p = 0.035; adjusted genotypic p = 0.043) and CLU (rs2279590 adjusted allelic p = 0.035; adjusted genotypic p = 0.006; rs11136000 adjusted allelic p = 0.038; adjusted genotypic p = 0.009) were significantly different between LOAD patients and nondemented controls. For PICALM, LOAD association was found only in the APOE ε4 (−) subgroup (rs3851179 adjusted allelic p = 0.028; adjusted genotypic p = 0.013). Our findings showed evidence of CR1, CLU, and PICALM and LOAD susceptibility in an independent southern Chinese population, which provides additional evidence for LOAD association apart from prior genome-wide association studies in Caucasian populations.     

Association analysis of NAD(P)H:quinone oxidoreductase gene 609 C/T polymorphism with Alzheimer's disease

Alterations of the NAD(P)H:quinone oxidoreductase (NQO1) activity are associated with Alzheimer's disease (AD). A polymorphism consisting of a single nucleotide (C-->T) change at position 609 of NQO1 influences the NQO1 activity. Therefore the NQO1 C609T polymorphism may confer susceptibility for AD developing. To test the hypothesis, we have performed an association study between the NQO1 gene polymorphism C609T and late-onset Alzheimer's disease (LOAD) in Chinese population. Totally 104 LOAD patients and 128 controls were enrolled in our data set. All subjects were genotyped for NQO1 and Apolipoprotein E (APOE). There were no significant differences in NQO1 genotype or allele frequencies between cases and controls. Likewise, with the stratification of APOE psilon4 status, no statistical difference was observed between cases and controls. Our findings suggested that this polymorphism might not represent additional genetic risk factor for LOAD. However, the present study cannot exclude NQO1 as a possible candidate for LOAD. Further study in a larger population and biological functional analysis of NQO1 gene is required to verify the role of NQO1 in LOAD.     

Association of the CR1 polymorphism with late-onset Alzheimer's disease in Chinese Han populations: A meta-analysis

It is well known that genetic variants play a critical role in the pathogenesis of Alzheimer's disease (AD). In 2009, a genome-wide association study (GWAS) demonstrated that a single nucleotide polymorphism (SNP), rs6656401, in complement receptor 1 (CR1) is significantly associated with late-onset Alzheimer's disease (LOAD) in Caucasian population. Subsequently, other researchers have attempted to validate this finding in Chinese Han populations. However, these findings in Chinese Han populations have produced both negative and positive results. To derive a more precise estimation for the relationship, we performed the present meta-analysis by analyzing three published association studies involving CR1 SNP rs6656401 through the use of the RevMan (v.5.1) program. Pooled odds ratios (ORs) were calculated for allele contrasts (A vs. G) and a dominant model [(AA + AG) vs. GG] in three studies that included 1019 cases and 1080 controls, respectively. The statistical results showed a significant difference between patients and controls for the A allele of CR1 SNP rs6656401 (P = 0.005). In addition, carriers of the A allele (AA + AG) of rs6656401 had a 1.69-fold increased risk for LOAD compared with non-carriers (GG) (P = 0.01). In conclusion, despite there are some limitations, this meta-analysis indicates that the A allele of the CR1 SNP rs6656401 is significantly associated with LOAD susceptibility in Chinese Han populations.     

Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population

Recent evidence has suggested that down-regulation of somatostatin (SST) expression in the human brain during early stages of aging leads to an elevation in the steady-state levels of Aβ and therefore may be involved in Alzheimer's disease (AD) progression. We hypothesized that alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). First, we sequenced the entire SST gene in 25 randomly selected controls and 25 SAD patients and then screened for C/T polymorphisms (rs4988514) in the 3′ un-translated region. We genotyped rs4988514 polymorphisms as well as apolipoprotein ?4 (APOE ?4) status in 309 SAD patients and 276 normal controls with restriction fragment length polymorphism (RFLP) analysis. Results showed that the C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group (p = 0.042). In subjects with the APOE ?4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group (genotype p = 0.027, allele p = 0.011). In the whole study group, the age, sex, and APOE ?4 adjusted OR for the risk of AD in C allele carriers was 1.313 (95%CI = 1.068–2.234, p = 0.027) whereas within only APOE ?4 allele carriers, the adjusted OR increased to 2.734 (95%CI = 1.236–5.862, p = 0.012). Our results supported the notion that the C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE ?4 allele.     

Extremely rare incidence of the UBQLN1 polymorphism (UBQ-8i) in Taiwan Chinese with Alzheimer's disease

Recently, a single nucleotide polymorphism (SNP, A → G) in intron 8 of UBQLN 1 at the rs12344615 site (UBQ-8i) on chromosome 9q22 was associated with a higher risk of late-onset Alzheimer's disease (AD). Here, we aimed to investigate whether an association exists between the UBQ-8i polymorphism and AD in Taiwan Chinese. Initially, we included 100 late-onset AD patients and 100 gender- and age-matched non-demented (ND) control participants. The UBQ-8i polymorphism site was successfully determined in 91 AD and 96 ND individuals using the dye terminator nucleotide sequencing technique. Among the 187 participants, we did not detect any subject carrying the G allele. This finding is in agreement with the report listed in the NCBI SNP Reference Assembly, which states that <1% of Asians carry this SNP. The APOE ?4 allele, an established AD genetic risk factor, was overrepresented in the AD cohort. We conclude from these results that the UBQ-8i polymorphism of the UBQLN1 gene is extremely rare in Taiwan Chinese and unlikely to play a significant role in the risk of AD in Taiwan Chinese.     

Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer's disease and age-related cataract

Alzheimer's disease (AD) and age-related cataract, disorders characterized by protein aggregation causing late-onset disease, both involve oxidative stress. We hypothesize that common variants of NFE2L2 and KEAP1, the genes encoding the main regulators of the Nrf2 system, an important defence system against oxidative stress, may influence risk of AD and/or age-related cataract. This case-control study combines an AD material (725 cases and 845 controls), and a cataract material (489 cases and 182 controls). Genetic variation in NFE2L2 and KEAP1 was tagged by eight and three tag single nucleotide polymorphisms (SNPs), respectively. Single SNPs and haplotypes were analyzed for associations with disease risk, age parameters, MMSE and AD cerebrospinal fluid biomarkers. NFE2L2 and KEAP1 were not associated with risk of AD or cataract. However, one haplotype allele of NFE2L2 was associated with 2 years earlier age at AD onset (p_c = 0.013) and 4 years earlier age at surgery for posterior subcapsular cataract (p_c = 0.019). Another haplotype of NFE2L2 was associated with 4 years later age at surgery for cortical cataract (p_c = 0.009). Our findings do not support NFE2L2 or KEAP1 as susceptibility genes for AD or cataract. However, common variants of the NFE2L2 gene may affect disease progression, potentially altering clinically recognized disease onset.     

NEDD9 rs760678 polymorphism and the risk of Alzheimer's disease: A meta-analysis

The NEDD9 rs760678 polymorphism has been extensively investigated for association to Alzheimer's disease (AD), however, results of different studies have been inconsistent. The objective of this study is to assess the relationship of NEDD9 rs760678 polymorphism and AD risk by using meta-analysis. Systematic searches of electronic databases Pubmed and Embase, as well as hand searching of the references of identified articles were performed. Statistical analyses were performed using software Revman 4.2 and STATA 11.0. A total of 4436 cases and 4420 controls in 11 case–control studies were included. The results indicated that the homozygote GG had a 13% decreased risk of AD, when compared with the C allele carriers (CC + CG) (OR = 0.87, 95%CI = 0.77–0.99, P = 0.04 for GG vs. CG + CC). In the subgroup analysis by ethnicity, significant decreased risk was associated with homozygote GG or G allele carriers in Caucasians (OR = 0.84, 95%CI = 0.74–0.96, P = 0.008 for GG vs. CG + CC; OR = 0.79, 95%CI = 0.69–0.91, P = 0.001 for GG vs. CC; OR = 0.90, 95%CI = 0.84–0.96, P = 0.002 for G vs. C), but not in Asians. This meta-analysis suggests that the GG genotype of NEDD9 rs760678 polymorphism would be a protective factor for AD in Caucasians but not in Asians. To further evaluate the effect of gene–gene and gene–environmental interactions between NEDD9 rs760678 polymorphism and the risk of AD, more studies with larger number of subjects are required.     

Association between late-onset Alzheimer's disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene

The amyloid beta protein (Aβ) deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 2 (TLR2) is thought to contribute to Aβ clearance. Studies have reported the presence and functional implications of guanine-thymine (GT) repeat microsatellite polymorphisms in intron II of the human TLR2 gene. The present study evaluated the association of the microsatellite polymorphism and sporadic late-onset AD (LOAD) in the Han Chinese population. The numbers of (GT) repeats were counted in 137 AD patients and in 137 non-AD control subjects, using polymerase chain reaction and genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele, (GT)17 to (GT)22 as the M allele, and (GT)23 or more as the L allele. Patients with AD had more S alleles (P < 0.001; odds ratio (OR) = 2.32; 95% confidence interval (CI) = 1.57–3.42) and fewer L alleles (P = 0.02; OR = 0.66; 95% CI = 0.46–0.93) than did healthy controls. Genotypes SS and SM were more common, whereas ML and SL were less common in patients with AD. In subgroup analyses, the genotypes including S alleles were associated with an increased risk of LOAD (OR = 2.05, 95% CI = 1.26–3.34), and this association was influenced by the presence of APOE ?4 alleles. This study demonstrates an association of microsatellite polymorphisms in intron II of the human TLR2 gene with risk for LOAD in Han Chinese.     

Evidence for apolipoprotein E ϵ4 association in early-onset Alzheimer's patients with late-onset relatives

Recently several reports have extended the apolipoprotein E (APOE) ?4 association found in late-onset Alzheimer's disease (LOAD) patients to early-onset (EO) AD patients. We have studied this question in a large population of 119 EOAD patients (onset ?60 years) in which family history was carefully assessed and in 109 controls. We show that the APOE ?4 allele frequency is increased only in the subset of patients who belong to families where LOAD secondary cases are present. Our sampling scheme permits us to demonstrate that, for an individual, bearing at least one ?4 allele increases both the risk of AD before age 60 and the probability of belonging to a family with late-onset affected subjects. Our results suggest that a subset of EOAD cases shares a common determinism with LOAD cases. © 1995 Wiley-Liss, Inc.     

Risk of late-onset Alzheimer's disease associated with BDNF C270T polymorphism

We examined the frequency of the T allele of the C270T polymorphism of the brain-derived nerve growth factor (BDNF) gene in a test and replication test design. Our objective was to determine if there is an association between the BDNF gene and Alzheimer's Disease (AD) in a US population. There were 106 autopsy-proven AD cases and 101 controls of similar ages in each test for a total of 212 AD cases and 202 controls. We found that there was a significant increase in the T allele in both the initial set (p=.04) and in the replication set (p=.018). For both groups combined p=.0008. Odds ratio=3.28, 95% CI=1.69-6.34. There were 54 cases of early-onset AD (EOAD) and 159 cases of late-onset AD (LOAD). The results were only significant for LOAD, p=.0002, odds ratio=3.81, 95% CI=1.93-7.52. The r2 or fraction of the variance attributed to the BDNF gene for the LOAD cases was .046. The results were independent of the APOE epsilon4 allele. When the younger controls were removed, providing a close age match to the AD subjects, the frequency of the T allele was even lower and the differences were still significant for both total AD and LOAD cases. In a logistic regression analysis including APOE, age, sex and BDNF, BDNF was significant at p<.0001. We concluded that BDNF gene variants are significant risk factors for late onset AD.     

LRRK2 variant associated with Alzheimer's disease

Overlapping neurodegenerative pathologies (including Alzheimer's disease, AD) have been described in Parkinson's disease (PD) patients with leucine-rich repeat kinase-2 (LRRK2) mutations. We analyzed a LRRK2 PD (R1628P) risk variant in a group of 885 subjects comprising of AD and controls. The frequency of the R1628P allele was higher in AD compared to controls (3.5% vs. 1.6%, OR 2.3, 95 CI 1.2-4.4, p = 0.018). In vitro, the mean percentage of apoptosis and cell death observed for the R1628P transfected human cell lines was higher compared to wild type 21.8 ± 1.9, vs. 17.1 ± 1.3, p < 0.05, 30.2 ± 2.2 vs. 25.7 ± 1.3, p < 0.05). The LRRK2 R1628P variant increases the risk of AD in our population and our in vitro findings suggest that it is a functional variant and predisposes to apoptosis.     

Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial disorder with possible involvement of several genetic and environmental factors. For late-onset AD (LOAD), the epsilon4 allele of apolipoprotein E (APOE) has been identified as a major susceptible gene. However, the observation that APOE epsilon4 accounted for approximately one half of the genetic variance of LOAD prompted many researchers to undertake genome surveys to identify other susceptible genes. Recently, several candidate genes such as alpha-1 antichymotrypsin (ACT) and alpha-2 macroglobulin (A2M) were reported to be associated with LOAD. To evaluate the possible association between these genes and LOAD in Korean population, we genotyped ACT A/T and A2M 5-bp deletion (exon 18) polymorphisms in 89 LOAD cases and 50 age-matched healthy controls. The frequencies of ACT A and A2M 5-bp deletion alleles in LOAD and controls were 0.39 vs. 0.37, and 0.05 vs. 0.05, respectively. Although APOE epsilon4 clearly showed higher frequency in LOAD (0.34) than that in controls (0.09), giving an odds ratio of 5.14 (95% confidence interval, 2.31-11.76), neither ACT nor A2M showed statistically significant difference between LOAD and controls regardless of APOE carrier status. Our results do not support previously reported association of ACT and A2M with LOAD, at least in Korean population.     

Lack of association between rs597668 polymorphism near EXOC3L2 and late-onset Alzheimer's disease in Han Chinese

Recently, an international genome-wide association study (GWAS) additionally found rs597668 near EXOC3L2/BLOC1S3/MARK4 was a new genome-wide significance locus associated with late-onset Alzheimer's disease (LOAD) in Caucasians. Follow-up replication studies were conducted almost exclusively in Caucasians, and the effects of the risk locus in other populations are as yet unknown. This study investigated the GWAS-associated locus near EXOC3L2 in 1205 unrelated Northern Han Chinese subjects comprising 598 LOAD patients and 607 healthy controls matched for gender and age. The results showed no significant differences in the genotypic or allelic distributions of rs597668 polymorphism between LOAD cases and healthy controls (genotype: P = 0.653; allele: P = 0.603), even after stratification for apolipoprotein E (APOE) ?4 status and statistical adjustment for age, gender and APOE ?4 status. This study suggests that the rs597668 polymorphism near EXOC3L2 may not play a major role in the susceptibility to LOAD in the Northern Han Chinese population.     

Association between haplotype −88G/25G in A2M with Alzheimer's disease

Alpha 2-Macroglobulin gene (A2M) has been recognized as a candidate gene for late-onset Alzheimer's disease (AD), but the association between several polymorphisms in A2M gene and risk for AD remained controversial. Moreover, little is known regarding the effects of polymorphisms in A2M promoter region on AD susceptibility. Our study aimed to detect polymorphisms in A2M promoter region, and then evaluate their relationship to sporadic AD (SAD). One single nucleotide polymorphism (−88A/G) in proximal promoter region was found by sequencing, and further analyzed with an established 25T/G polymorphism in 179 SAD patients and 179 age-gender-matched controls. Allele A in −88A/G polymorphism was more prevalent in cases, with a 1.7-folded risk for SAD (OR = 1.74, 95%CI 1.05–2.91, P = 0.031), while G allele in 25T/G was less prevalent in cases, with a 43% reduced risk for SAD (OR = 0.57, 95%CI 0.36–0.89, P = 0.013). After adjusted the effects of age, gender and APOE?4 allele status in logistic regression model, the protective effects of −88G and 25G on SAD still remained. Individuals who carried haplotype −88G/25G had a significant 44% reduced risk for SAD compared to those who did not carry (OR = 0.56, 95%CI 0.34–0.94, P = 0.027), while haplotype −88A/25T carriers had an increased risk for SAD compared to those who did not carry (OR = 1.77, 95%CI 1.06–2.96, P = 0.027). Our study supports that haplotype −88G/25G might play a protective role in the development of SAD, and the protective effects of −88G and 25G were independent of APOE?4 allele.     

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 β (Aβ) 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.     

HLA rs3129882 variant in Chinese Han patients with late-onset sporadic Parkinson disease

Recently, the rs3129882 variant in intron 1 of HLA-DRA was found to be associated with late-onset sporadic Parkinson disease (PD) in Americans of European ancestry. To evaluate whether the same variant is related to PD in Chinese population, we investigated late-onset sporadic PD patients of Chinese Han ethanicity in Mainland China. We found significant difference in genotypic and allele distribution between patients and control subjects (χ² = 6.446, p = 0.040 for genotypic distribution; χ² = 5.762, p = 0.016 for allele distribution), suggesting this variant is associated with late-onset sporadic PD in Chinese Han population.     

Ubc9 gene polymorphisms and late-onset Alzheimer's disease in the Korean population: A genetic association study

Ubiquitin-conjugating enzyme E2I (Ubc9) ligates small ubiquitin-related modifier (SUMO) to target proteins, resulting in changes of their localization, activity, or stability. Sumoylation of amyloid precursor protein (APP) was reported to be associated with decreased levels of beta amyloid (Aβ) aggregates, suggesting that sumoylation may play a role in the pathogenesis of Alzheimer's disease (AD). We investigated the association between genetic variations of Ubc9 gene (UBE2I) and late-onset Alzheimer's disease (AD). Five single nucleotide polymorphisms (SNPs) in UBE2I were genotyped in the DNA samples of 312 AD patients, 347 subjects with mild cognitive impairment (MCI), and 489 cognitively healthy controls. The genotype distribution of a polymorphism in intron 7 (rs761059) differed between AD cases and controls, with an adjusted odds ratio (OR) of 1.45 (p = 0.046, 95% CI: 1.01–2.08). One haplotype (ht2 CAGAG) was found in 14.0% of the AD patients and in 11.1% of the controls (p = 0.04, OR = 1.43. 95% CI; 1.01–2.01). Stratification by the ApoE-?4 allele gave no significant difference between the groups. When the samples were stratified by gender, the genotypes of two SNPs (rs8052688, rs8063) were significantly associated with the risk of MCI among women. Our investigation suggests that UBE2I polymorphisms might be associated with a risk of AD and MCI.