Interleukin-1 gene cluster polymorphisms and risk of Alzheimer’s disease in Chinese Han population

Summary. Interleukin-1 (IL-1) has been implicated as a key cytokine in Alzheimers disease (AD) pathogenesis. IL-1 gene polymorphisms, especially IL-1A C(^–889)T polymorphism, have been suggested to be associated with AD risk and onset age. To determine if IL-1 polymorphisms are genetic risk factors for developing AD in Chinese Mainland population, we analyzed IL-1A (^–889), IL-1B (^–511) and IL-1RN variable number of tandem repeat (VNTR) polymorphisms in a sample of 145 sporadic AD patients and 181 healthy controls. Our data revealed that the three polymorphisms in IL-1 gene cluster might not play a key role in AD pathogenesis in Chinese Mainland Han population.     

Association of polymorphisms in the LRP1 and A2M genes with Alzheimer’s disease in the Northern Chinese Han population

Low-density lipoprotein receptor-related protein1 (LRP1) and alpha-2-macroglobulin (A2M) are candidate genes for sporadic Alzheimer’s disease (SAD). It is not clear whether the LRP1 exon 3 and A2M exon 24 polymorphisms are associated with SAD. In the present study, we used direct sequencing to genotype the LRP1 C766T (rs1799986) polymorphism in exon 3 and the A2M I1000V (rs669) polymorphism in exon 24 in 364 patients with SAD and 291 healthy control subjects from the Northern Chinese Han population. The distributions of LRP1 genotypes (chi-squared [χ²] = 7.25, degrees of freedom [d.f.] = 2, p = 0.027) and alleles (χ² = 8.154, d.f. = 1, p = 0.004) were significantly different between patients and controls who were apolipoprotein E (APOE) ε4 positive. The T allele and TT+TC genotype were associated with a reduced risk of developing SAD (T allele: odds ratio [OR] = 0.541, 95% confidence interval [CI] = 0.368–0.859, p = 0.005; TT+TC genotype: OR = 0.613, 95% CI = 0.315–0.725, p = 0.012). There was no statistically significant difference in allele and genotype frequencies between patients with SAD and control subjects for the A2M I1000V polymorphism, even after stratification by age of onset, gender, and APOE ε4 status. We found an interaction between LRP1 and APOE genotypes (p = 0.001), but no interaction between LRP1 and A2M genotypes. Our results suggest that the T allele of the LRP1 C766T polymorphism is associated with a decreased risk of SAD in APOE ε4 carriers from the Northern Han Chinese population.     

Genetic analysis of BDNF and TrkB gene polymorphisms in Alzheimer’s disease

According to previous biochemical and genetic findings, brain–derived neurotrophic factor (BDNF), via activation of its tyrosine kinase receptor B (TrkB), is considered as a plausible candidate for contributing to Alzheimers disease (AD). To examine the genetic association of BDNF and TrkB genes with AD, we genotyped multiple single nucleotide polymorphisms (SNPs) within these genes among 375 Finnish AD patients and 460 control subjects. Single locus and multi–loci haplotype association analyses of BDNF and TrkB gene SNPs did not reveal significant differences between unstratified AD and control groups. In the case of BDNF SNPs, different allele and haplotype frequencies were observed when 160 sporadic AD cases were compared with 460 control subjects. However, these differences did not remain statistically significant after multiple corrections. We conclude that BDNF and TrkB genes are not contributing significant risk effect among Finnish AD patients.An earlier version of this article has been published with a typographic error in the published online date.     

Association study of cholesterol-related genes in Alzheimer’s disease

Alzheimer’s disease (AD) is a genetically complex disorder, and several genes related to cholesterol metabolism have been reported to contribute to AD risk. To identify further AD susceptibility genes, we have screened genes that map to chromosomal regions with high logarithm of the odds scores for AD in full genome scans and are related to cholesterol metabolism. In a European screening sample of 115 sporadic AD patients and 191 healthy control subjects, we analyzed single nucleotide polymorphisms in 28 cholesterol-related genes for association with AD. The genes HMGCS2, FDPS, RAFTLIN, ACAD8, NPC2, and ABCG1 were associated with AD at a significance level of P ≤ 0.05 in this sample. Replication trials in five independent European samples detected associations of variants within HMGCS2, FDPS, NPC2, or ABCG1 with AD in some samples (P = 0.05 to P = 0.005). We did not identify a marker that was significantly associated with AD in the pooled sample (n = 2864). Stratification of this sample revealed an APOE-dependent association of HMGCS2 with AD (P = 0.004). We conclude that genetic variants investigated in this study may be associated with a moderate modification of the risk for AD in some samples. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Association of VEGF gene polymorphisms with sporadic Parkinson’s disease in Chinese Han population

Recent evidence indicates that vascular endothelial growth factor (VEGF) is capable of protecting dopaminergic (DA) neurons. Parkinson’s disease (PD) is a progressive neurodegenerative disease caused by the degeneration of nigrostriatal dopaminergic neurons. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in PD, we performed a case–control study including 400 PD patients and 400 healthy-matched controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) analysis and DNA sequencing were used to detect the rs699947, rs2010963 and rs3025039 polymorphisms of the VEGF gene in cases and controls. Our study revealed that T allelic frequency of rs3025039 polymorphism was significantly higher in PD subjects (OR 1.497, 95 % CI 1.099–2.040, P = 0.013) than that in controls. Significant association for rs3025039 could be found in additive model (TT vs. CT vs. CC: OR 1.489, 95 % CI 1.018–2.177, P = 0.040) and dominant model (TT + CT vs. CC: OR 1.538, 95 % CI 1.068–2.216, P = 0.021). Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Moreover, it also demonstrated a significant association in the subgroup of late-onset PD (LOPD). However, for rs699947 and rs2010963 polymorphisms, genotype or allele frequencies did not differ between groups. No significant association could be found between rs699947 and rs2010963 polymorphism and PD risk. None of the observed haplotypes showed significant association with PD. Therefore, these results suggested that the VEGF gene might be associated with risk of developing sporadic PD in Han Chinese and the rs3025039 polymorphism may be a risk factor for sporadic PD.     

Brain-derived neurotrophic factor gene polymorphisms and Alzheimer’s disease

Summary. Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for Alzheimers disease (AD). Recently, three studies reported an association between two single-nucleotide polymorphisms (SNP) – i.e., C270T and G196A – in the BDNF gene and AD. This attempt to confirm these associations in a larger AD sample included examination of the linkage disequilibrium of these two SNPs. Comparison of 487 Japanese AD subjects with 471 cognitively normal elderly controls showed higher frequencies of the G allele (60.5 vs. 55.5%, p=0.028) and of both the GG and GA genotypes (85.8 vs. 79.8%, p=0.025) of the G196A polymorphism in AD subjects than in controls and higher frequency of the T allele of the C270T polymorphism in AD subjects who were negative for apolipotrotein E4 (2.0 vs. 4.4%, p=0.035) or positive for AD family history (2.8 vs. 7.1%, p=0.046). These findings suggest that BDNF gene polymorphisms play some role in the development of AD.     

Mitochondrial DNA polymorphisms and the risk of Parkinson’s disease in Taiwan

Summary A critical role of mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD). The association of mitochondrial DNA (mtDNA) polymorphisms 9055G/A, 10398G/A and 13708G/A with PD has been controversial. In this study we analyzed whether these three genetic polymorphisms are associated with PD in a cohort of 416 PD cases and 372 ethnically matched controls. The allele frequency distribution of any of these three analyzed polymorphisms was not significantly different between the cases and the controls. None of the six haplotypes derived influences risk of PD. Notably, after stratification by age, individuals over 70 years of age carrying the haplotype 9055G-10398A-13708G demonstrated a significant decrease in risk of developing PD (OR = 0.44, 95% CI = 0.24–0.80, p = 0.008). These results suggest that the mtDNA haplotype 9055G-10398A-13708G plays a role in PD susceptibility among Taiwanese people older than 70 years of age.     

Association study of TREM2 polymorphism rs75932628 with late-onset Alzheimer’s disease in Chinese Han population

Abstract

Objective:

We conducted a case–control study to investigate whether TREM2 polymorphism (rs75932628-T) was associated with late onset Alzheimer’s disease in Chinese Southern Han population.

Methods:

PCR-restriction fragment length polymorphism assay was performed to genotype rs75932628 in 279 cases with late onset Alzheimer’s diseases patients and 346 control subjects in Shanghai and Nanjing.

Results:

There was no rs75932628-T variant detected in our sample. However, APOE?4 was shown closely associated with the risk of Alzheimer’s disease (Chi-square?=?60·288, P?=?0·000).

Conclusion:

Our study suggested that TREM2 (rs75932628-T) was rare in Chinese Han population. Further association studies with large samples are needed to further study the association of TREM2 with late-onset Alzheimer’s disease.     

Association between NMDA receptor subunit 2b gene polymorphism and Alzheimer’s disease in Chinese Han population in Shanghai

Objective

N-methyl-D-aspartate (NMDA) receptor has been indicated to be involved in the pathogenesis of Alzheimer’s disease (AD). The NMDA receptor subunit 2b (NR2B) has attracted more attention due to its characteristic distribution and selective reduction in AD brain. The present study aimed to explore the association between NMDA gene polymorphism and AD.

Methods

A total of 63 AD patients and 68 normal controls in Shanghai city were employed in this study. Genotype of C2664T variant (rs1806201) in the exon13 of GRIN2B gene was determined by gene sequencing.

Results

Among AD patients, 15 (23.6%) subjects were identified as C/C genotype, and 35 (55.6%) were identified as C/T genotype. The left 13 (20.6%) subjects were identified as T/T genotype. In normal controls, 15 (22.1%) subjects were identified as C/C genotype, 39 (57.4%) as C/T genotype and 14 (20.6%) as T/T genotype. The distribution frequency of neither GRIN2B C2664T genotype (P=0.895) nor allele (P=0.790) was significantly different between AD patients and normal controls, even when the subjects were stratified by gender and age of disease onset in AD patients.

Conclusion

The results suggest that there is no relation between GRIN2B C2664T polymorphism and AD in Chinese Han population of Shanghai City.

     

Follow-up study of variants of the GIGYF2 gene in Chinese patients with Parkinson’s disease

The Grb10-interacting GYF protein-2 gene (GIGYF2) is a PARK11 gene that reportedly has a causal role in familial Parkinson’s disease (PD) among populations from Italy and France. However, no comprehensive study of the GIGYF2 gene has been conducted among PD patients from mainland China. In our previous study, the GIGYF2 gene was directly sequenced, and nine missense variants and 14 polymorphisms were identified. For these 14 polymorphisms, in the present study we performed a case–control analysis for 300 PD patients and 200 healthy controls from mainland China. The c.297T>C p.Ala99Ala polymorphism was associated with increased risk with respect to the pathogenesis of sporadic PD. In conclusion, within the Chinese population, the c.297T>C p.Ala99Ala polymorphism of the GIGYF2 gene may be associated with an increased risk of developing PD.     

Association study of polymorphisms in LRP1, tau and 5-HTT genes and Alzheimer’s disease in a sample of Colombian patients

Summary. Analysis of genetic susceptibility factors for Alzheimer’s disease (AD) in populations with different genetic and environmental background may be useful to understand AD etiology. There are few genetic association studies of AD in Latin America. In the present work, we analyzed polymorphisms in 3 candidate genes; the LDL receptor related protein-1, the microtubule-associated protein Tau and the serotonin transporter genes in a sample of 106 Colombian AD patients and 97 control subjects. We did not find a significant allelic or genotypic association with any of the three polymorphisms analyzed using different statistical analysis, including a neural network model or different sample stratifications. To date, APOE polymorphisms are the only genetic risk factors identified for AD in the Colombian population. It may be factible that future combination of high-throughput genotyping platforms and multivariate analysis models may lead to the identification of other genetic susceptibility factors for AD in the Colombian population.     

Influenza infections and risk of Alzheimer’s disease

Influenza may cause neuropsychiatric disorders, including confusion, delirium, convulsions, and encephalopathy. We conducted a case-control study to evaluate the association between diagnosed influenza and the risk of developing Alzheimer’s disease (AD) using the UK-based Clinical Practice Research Datalink (CPRD). We identified 19,463 patients who developed an incident AD diagnosis between 1998 and 2013 and matched them 1:1 to dementia-free controls on age, sex, general practice, calendar time and number of years of recorded history. We calculated adjusted odds ratios (aORs) with 95% confidence intervals (CIs) of developing AD in association with previous influenza infections and stratified by number of infections prior to the AD diagnosis date. Patients with a previous influenza infection were not at an increased risk of developing AD as compared to those with no previous infection (aOR, 95% CI 0.94, 0.87–1.02) overall. Nor was increasing number of infections related to an increased risk of developing AD; the aOR (95% CI) for those with 1, 2, or ⩾3 episodes was 0.98 (0.90–1.07), 0.70 (0.56–0.88), and 0.92 (0.63–1.34), respectively. Presence of an underlying chronic inflammatory disease in those with an influenza infection did not increase the risk of developing AD (aOR, 95% CI 0.83, 0.71–0.96), either, and there was no association between the severity of influenza infections (based on recorded neurological or bacterial complications) and the risk of AD. In conclusion, considering the limitations of this large observational study, we found no association between influenza infections and the risk of developing AD.     

Novel polymorphisms of the amyloid precursor protein (APP) gene in Chinese/Taiwanese patients with Alzheimer’s disease

We aimed to determine if the amyloid precursor protein (APP) gene polymorphism is present in Chinese/Taiwanese patients with Alzheimer’s disease (AD). This is a 3-year prospective assessment of the genotypes of the APP gene among Chinese/Taiwanese patients with AD. The sample consisted of 50 AD patients and 50 unaffected controls. Participants were recruited from the practices of the authors. Controls were comprised of 45 unrelated healthy subjects and 5 unaffected family members of AD patients. Data were collected in a university-based research unit of a tertiary medical center. Sequencing of the APP gene from exon 15 to exon 18 was performed on the peripheral blood of the patients and the unaffected controls after their informed consent was obtained. Among 50 AD subjects, 11 (7 men, 4 women) had APP gene polymorphisms. Mean age of onset was 72 years (range 65–82 years). Polymorphism of APP gene with A to C substitution at nucleotide position (nt) 284490 (A284490C) was found in 8 AD patients, at nt 284493 (A284493C) in 5, T284497C in 3 patients, and T284500C in 1 patient. These single nucleotide substitutions of the APP gene corresponded to the amino acid substitutions I718L, L720S, and V710G. These polymorphisms were not found in the unaffected controls. The mutations were confirmed by StyI restriction enzyme digestion assay using the subclone from polymerase chain reaction (PCR) products of the mutated APP gene. Thus, APP gene polymorphisms at codon 718 (I > L), 720 (L > S), and 710 (V > G) can be found in certain Chinese/Taiwanese patients with Alzheimer’s disease.     

TMEM106B and APOE polymorphisms interact to confer risk for late-onset Alzheimer’s disease in Han Chinese

Recent large genome-wide association studies have found variants in TMEM106B (top SNP rs1990622) as a strong risk factor for frontotemporal lobar degeneration. Moreover, the TMEM106B risk variant is also implicated in the pathologic presentation of Alzheimer’s disease (AD). Here, we evaluated the association between TMEM106B rs1990622 polymorphism and late-onset AD (LOAD) in a Northern Han Chinese population consists of 1,133 LOAD patients and 1,159 controls. Our data demonstrate that TMEM106B and APOE interact to increase AD risk.     

Association between interleukin-6 gene promoter −572C/G polymorphism and the risk of sporadic Alzheimer’s disease

Inflammation is a key component of Alzheimer’s disease (AD), and we have examined the effect of two polymorphisms (−174G/C and −572C/G) in the promoter of the inflammatory cytokine interleukin-6 (IL-6) gene on risk of AD in 318 AD patients. Significant differences in genotype and allele frequencies of −572C/G IL-6 promoter polymorphism were observed between AD patients and controls. The GG genotype was associated with a decreased risk of developing AD (OR 0.423, 95% CI 0.200–0.894). Similarly, logistic regression analysis revealed that G allele was a protective factor for AD (OR 0.732, 95% CI 0.567–0.945). For −174G/C variability, no C variability was found in all the subjects. The frequency of the IL-6 −174G/C promoter polymorphism is very low or no variability in Henan Han population. The −572C/G polymorphism of IL-6 gene promoter region is associated with AD, and G allele is an independent protective factor for AD.