Association between the RAGE G82S polymorphism and Alzheimer’s disease

The receptor for advanced glycation end products (RAGE) is associated with several pathological states including Alzheimer’s disease (AD) pathology, while its soluble form (sRAGE) acts as a decoy receptor. We have tested for association of AD with a functional single-nucleotide polymorphism (SNP) in the RAGE gene (G82S; rs2070600), a SNP associated with increased ligand affinity of RAGE. Analysis of a Chinese cohort (276 cases; 254 controls) showed a higher prevalence of the RAGE 82S allele and GS + SS genotype in the patients [82S vs. 82G: P = 0.017, odds ratio (OR) = 1.431; GS + SS vs. GG: P = 0.025, OR = 1.490]. Further stratification analysis revealed that the association of the RAGE G82S polymorphism with AD was significant in early onset AD stratum. Moreover, plasma sRAGE levels were lower in AD than in normal elderly controls, and the presence of the risk allele was associated with further plasma sRAGE reduction and a fast cognitive deterioration. The present study provides preliminary evidence that the RAGE G82S variant is involved in genetic susceptibility to AD.     

Gene–gene interaction between CARD8 and interleukin-6 reduces Alzheimer’s disease risk

Journal of Neurology -     

Association of the RAGE G82S polymorphism with Alzheimer’s disease

The receptor for advanced glycation end-products (RAGE) has been implicated in several pathophysiological processes relevant to Alzheimer’s disease (AD), including transport and synaptotoxicity of AD-associated amyloid β (Aβ) peptides. A recent Chinese study (Li et al. in J Neural Transm 117:97–104, 2010) suggested an association between the 82S allele of the functional single nucleotide polymorphism (SNP) G82S (rs2070600) in the RAGE-encoding gene AGER and risk of AD. The present study aimed to investigate associations between AGER, AD diagnosis, cognitive scores and cerebrospinal fluid AD biomarkers in a European cohort of 316 neurochemically verified AD cases and 579 controls. Aside from G82S, three additional tag SNPs were analyzed to cover the common genetic variation in AGER. The 82S allele was associated with increased risk of AD (P _c = 0.04, OR = 2.0, 95% CI 1.2–3.4). There was no genetic interaction between AGER 82S and APOE ε4 in producing increased risk of AD (P = 0.4), and none of the AGER SNPs showed association with Aβ₄₂, T-tau, P-tau₁₈₁ or mini-mental state examination scores. The data speak for a weak, but significant effect of AGER on risk of AD.     

Vascular risk and genetics of sporadic late-onset Alzheimer’s disease

Summary. In recent years, it is becoming apparent that genes may play an important role in the development of late-onset Alzheimers disease (LOAD), and genetic studies could unravel new clues. Based on a growing vascular hypothesis for the pathogenesis of LOAD and other dementias, there is increasing interest for environmental and genetic vascular factors. Polymorphisms in different susceptibility genes already implicated in vascular disease risk are now also being suggested as possible genetic markers for increased risk of developing LOAD; however, many of these studies have shown conflicting results. Thus far, the apolipoprotein E (APOE) gene seems to be the only vascular susceptibility factor that is agreed to play a role in the multifactorial pathogenesis of AD although emerging genetic and biological evidence is now strengthening the case for additional inclusion of angiotensin I-converting enzyme 1 (ACE1) into this category. This review will focus on the current knowledge on genetic and nongenetic vascular factors likely to be involved in LOAD, with special emphasis placed on the APOE and ACE1 genes.     

Association between CLU gene rs11136000 polymorphism and Alzheimer’s disease: an updated meta-analysis

Large-scale genome-wide association studies (GWAS) identified that the single nucleotide polymorphism rs11136000 in Clusterin (CLU) gene was associated with risk of Alzheimer’s disease (AD) in Caucasian ancestry. However, recent studies reported either a weak association or no association between rs11136000 polymorphism and AD in Asian populations. Therefore, we performed a meta-analysis to explore whether rs11136000 polymorphism is associated with susceptibility to AD in Asian populations. A total of 17 articles including 26 studies with 19,829 cases and 30,900 controls, which were identified by searching PubMed, MEDLINE, and AlzGene up to Nov 2016, were collected for this meta-analysis. The significant association between rs11136000 and AD in the pooled population was found under all the models. In subgroup analysis, we identified significant association in Asian population under the additive mode (OR?=?0.90, 95% CI?=?0.85–0.96) but not in the recessive model (OR?=?0.80, 95% CI?=?0.53–1.21) and the dominant model (OR?=?0.94, 95% CI?=?0.86–1.03). Our analysis further supports previous findings that the rs11136000 polymorphism C allele is associated with AD susceptibility. To our knowledge, this is the new largest meta-analysis to access to the association of CLU rs11136000 polymorphism with AD risk.     

Association study of polymorphisms in the cyclooxygenase-2 gene and Alzheimer’s disease risk in Chinese

To determine if polymorphisms (?765G/C, ?1195G/A and 8473T/C) of the cyclooxygenase-2 (COX-2) gene can be associated with Alzheimer disease (AD). The frequency of the polymorphisms was determined in 244 cases and 226 controls. The results revealed that the distributions of COX-2 ?765G/C and 8473T/C polymorphisms were statistically not significant between AD cases and controls. The genotype distributions and allele frequencies of COX-2 ?1195G/A polymorphism in the cases were statistically significantly different from the controls (P < 0.05). The A/A distribution and A allele frequency were significantly lower in the AD group. COX-2 ?1195AA carriers showed a one-third lower risk of developing AD as compared to those with ?1195GG and GA genotypes (OR = 0.3, 95 % CI 0.194–0.465, P = 0.000). This study suggested that ?1195G/A polymorphism of the COX-2 gene is associated with the risk of AD, and the A allele represents a protective factor in patients with AD.     

Association of tau gene polymorphism with Parkinson’s disease

Abstract. We investigated the segregation of the dinucleotide GT repeat polymorphism in the intron between exons 9 and 10 of the tau gene in 300 patients with Parkinsons disease (PD) and in 197 normal controls. The A3 allele was more frequent in cases than in controls (30% versus 16%, p<0.001), and individuals carrying at least one A3 allele in their genotype had an increased risk of developing PD (odds ratio 2.78, 95% confidence interval 1.81–4.29). No significant differences were found between patients by considering the age at onset and the presence of family history or dementia. Our findings suggest a possible involvement of the tau gene in the pathogenesis of PD.     

APOE and LRPAP1 gene polymorphism and risk of Parkinson’s disease

Epidemiologic findings suggest that lipids and alteration in lipid metabolizing protein/gene may contribute to the development of neurodegenerative disorders. The aim of the current study was to determine the serum lipid levels and genetic variation in two lipid metabolizing genes, low-density lipoprotein receptor-related protein-associated protein (LRPAP1) and apolipoprotein E (APOE) gene in Parkinson’s disease (PD). Based on well-defined inclusion and exclusion criteria, this study included 70 patients with PD and 100 age-matched controls. LRPAP1 and APOE gene polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism, respectively. Fasting serum lipid levels were determined using an autoanalyser. The logistic regression analysis showed that high levels of serum cholesterol [odds ratio (OR) = 1.101, 95 % confidence interval (CI_95%) = 1.067–1.135], LRPAP1 I allelic variant alone (OR = 2.766, CI_95% = 1.137–6.752) and in combination with APOE ε4 allelic variant (OR = 4.187, CI_95% = 1.621–10.82) were significantly associated with increase in PD risk. Apart from that, the high levels of LDL cholesterol appears to have a protective role (OR = 0.931, CI_95% = 0.897–0.966) against PD. The LRPAP1 I allelic variant may be considered a candidate gene for PD, predominantly in patients having the APOE ε4 allelic variant.     

Interleukin-18 −137 G/C and −607 C/A polymorphisms and Alzheimer’s disease risk: a meta-analysis

The ?137 G/C and ?607 C/A polymorphisms in interleukin-18 (IL-18) gene have been reported to be associated with Alzheimer’s disease (AD) risk, but the results are inconclusive. Considering a single study may lack the power to provide reliable conclusion, we performed a meta-analysis to investigate the association between the IL-18 ?137 G/C and ?607 C/A polymorphisms and AD susceptibility. A comprehensive literature search of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases were conducted before September 1, 2015. The pooled odds ratio (OR) with 95 % confidence intervals (CIs) were calculated. Five eligible studies with a total of 1536 subjects were finally included in this meta-analysis. For the IL-18 ?137 G/C polymorphism, a significantly decreased risk was detected in patients carrying the C allele of ?137 G/C in all study subjects in allele model (C vs. G: OR = 0.816, 95 % CI = 0.680–0.980, p = 0.029). Moreover, stratification by ethnicity indicated markedly association between the ?137 G/C C allele and AD risk in Asians. For the IL-18 ?607 C/A polymorphism, a significantly decreased risk was found in patients carrying the A allele of ?607 C/A in all study subjects in dominant model (AA + CA vs. CC: OR = 0.696, 95 % CI = 0.529–0.915, p = 0.010). However, the results suggested no significant association between the ?607 C/A polymorphism and AD susceptibility when stratified by ethnicity. Our present meta-analysis suggests that the C allele carrier of IL-18 ?137 G/C was associated with decreased risk for AD in Asians. Further well-designed case–control studies with larger sample size and more ethnic groups are needed to confirm these conclusions.     

Association between interleukin-1α C(−889)T polymorphism and Alzheimer’s disease: a meta-analysis including 12,817 subjects

Epidemiological studies have evaluated the association between interleukin-1 (IL-1)α C(?889)T polymorphism and Alzheimer’s disease (AD), but the results remain inconclusive. This meta-analysis was, therefore, designed to clarify these controversies. Systematic searches of electronic databases Embase, PubMed, and Web of Science as well as hand searching of the references of identified articles and the meeting abstracts were performed. Statistical analyses were performed using software Review Manager (Version 5.1.2) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were calculated. A total of 28 publications including 29 studies were involved. There was a significant association between IL-1α C(?889)T polymorphism and AD (for T allele vs. C allele: OR = 1.14, 95 % CI = 1.07–1.21; for T/T vs. C/C: OR = 1.39, 95 % CI = 1.18–1.63; for dominant model: OR = 1.13, 95 % CI = 1.04–1.22; and for recessive model: OR = 1.39, 95 % CI = 1.20–1.60). Significant association was found for Asians, Caucasians, and early-onset Alzheimer’s disease (EOAD) but for late-onset Alzheimer’s disease (LOAD). This meta-analysis indicates that there is a significant association between IL-1α C(?889)T polymorphism and AD as well as EOAD.     

Association between polymorphism in the promoter region of <Emphasis Type="Italic">Interleukin 6</Emphasis> (-174 G/C) and risk of Alzheimer’s disease: a meta-analysis

Studies of the relationship between Alzheimer’s disease (AD) and polymorphism in the promoter region of Interleukin 6 (IL-6) -174 G/C have reported inconsistent results. To assess the association between IL-6 -174 G/C promoter polymorphism and AD risk, a meta-analysis containing 3,101 AD cases and 3,860 controls from 18 case–control studies was performed. There were 16 studies involving Europeans and 2 studies involving non-Europeans. The combined results showed significant differences in recessive model [CC versus GC + GG, odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.54–0.90] and heterozygote comparison (CC versus GC, OR = 0.76, 95% CI = 0.60–0.96) on the basis of all studies. On subgroup analysis by ethnicity, similarly significant differences in recessive model (CC versus GC + GG) were found in both Europeans and non-Europeans, but significant difference in heterozygote comparison (CC versus GC) was found only in non-Europeans. In conclusion, there were statistically significant differences in genotype distribution of IL-6 -174 G/C between AD cases and controls in recessive model (CC versus GC + GG). Genotype CC of IL-6 -174 G/C could decrease the risk of AD. Further studies with large sample size, especially in subgroup analysis, should be done.     

A novel ARC gene polymorphism is associated with reduced risk of Alzheimer’s disease

Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid β (Aβ) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute Aβ application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and Aβ(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c)?=?0.005; OR?=?0.74; 95?% CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.     

Association between G2385R and R1628P polymorphism of LRRK2 gene and sporadic Parkinson’s disease in a Han-Chinese population in south-eastern China

The G2385R and R1628P polymorphisms of the leucine-rich repeat kinase 2 (LRRK2) gene have been reported to be associated with Parkinson’s disease (PD), but no data are available on Han-Chinese population of south-eastern China. This study aimed to investigate whether G2385R and R1628P variants are associated with sporadic PD in this population. Total 1,060 subjects were enrolled; including 550 unrelated healthy controls and 510 patients with sporadic PD. Genotyping of polymorphisms was performed by PCR–restriction fragment length polymorphism analysis. All variant samples were sequenced for further confirmation. The results showed that the A allele of the G2385R variant was significantly enriched in sporadic PD patient group (4.8 %) when compared with control group [1.1 %; odds ratio (OR) 4.58, 95 % confidence interval (CI) 2.42–8.65, P < 0.01]. However, no significant difference in the frequency of the C allele of R1628P polymorphism variant was observed between cases and controls (2.8 vs. 1.7 %, OR 1.67, 95 % CI 0.93–2.99, P = 0.08). In conclusion, this study provides the first evidence that G2385R polymorphism is a risk factor for sporadic PD in Han-Chinese population of south-eastern China.