Endothelin-Converting Enzyme-1 Promoter Polymorphisms and Susceptibility to Sporadic Late-Onset Alzheimer's Disease in a Chinese Population

Endothelin converting enzyme (ECE-1) is a candidate Alzheimer disease susceptibility gene. It was previously reported that western individuals homozygous for the C-338A polymorphism (AA) within the ECE1 gene promoter region are at reduced risk of developing late onset Alzheimer disease (LOAD). A further polymorphism, T-839G, is present within the ECE1 promoter region but a potential association with LOAD has not been studied. We therefore studied possible associations between these ECE1 polymorphisms and LOAD in a Chinese population. Subjects comprised 376 Chinese LOAD patients and 376 age- and sex-matched controls; all subjects were typed for the ECE1 C-338A and the T-839G polymorphisms. We report that the frequency of the 338A allele was decreased in LOAD patients compared to controls (adjusted OR =0.73; 95% CI=0.54–0.98; P=0.03). There was no significant association between T-839G genotype and LOAD, however the combined 839T/338A haplotype was significantly associated with decreased risk of LOAD (OR=0.73; 95% CI=0.57–0.93; P=0.01). This study argues that the ECE1 338A allele is protective against LOAD in a Chinese population.     

A haplotype of the methylenetetrahydrofolate reductase gene is protective against late-onset Alzheimer's disease

Epidemiological studies have shown that elevated plasma homocysteine (Hcy) levels play an important role in the pathogenesis of Alzheimer's disease (AD). In spite of the evidence that a C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene elevates plasma Hcy levels, the impact of the C677T polymorphism on the development of AD is controversial. Here, we performed a genetic case-control study in a Japanese population to investigate whether three polymorphisms of the MTHFR gene, C677T (Ala222Val), A1298C (Glu429Ala), and A1793G (Arg594Gln), are associated with the development of late-onset AD (LOAD). In our study, the MTHFR gene had four major regional haplotypes: Haplotype A (677C-1298A-1793G), Haplotype B (677T-1298A-1793G), Haplotype C (677C-1298C-1793G), and Haplotype D (677C-1298C-1793A). The frequency of Haplotype C in LOAD was significantly lower than that in control group. Furthermore, the benefit conferred by the presence of at least one Haplotype C was stronger in LOAD patients who lacked the ApoE 4 allele (OR=0.293; 95% CI=0.115-0.744; P=0.010). The results indicate that Haplotype C of the MTHFR gene is protective against the development of LOAD.     

The H+ allele of the lipoprotein lipase (LPL) HindIII intronic polymorphism and the risk for sporadic late-onset Alzheimer's disease

A sample of 243 Italian patients affected by the sporadic late-onset form of Alzheimer's disease (AD) was studied for the HindIII intronic polymorphism of the lipoprotein lipase (LPL) gene and compared with a sample of 148 healthy subjects. Since this polymorphism has been reported to be associated with CAD and because the two pathologies share common aspects, we decided to study it in AD too. We found a difference in the allele distribution, in that the H+ allele was more frequent in patients (0.782) than in controls (0.720); this difference was not quite significant (P = 0.059). The odds ratio from the logistic regression analysis for the H+ carrying genotypes was 2.7 (95% CI = 1.01-7.21; P = 0.048). When the separate genotypes H+H+ and H+H- were entered into the analysis, only H+H+ was found to significantly increase the risk with respect to H-H- (P = 0.029). This means that carrying this allele significantly increases the risk of developing AD, and the risk is mostly associated with the H+H+ genotype.     

Investigation of the effect of brain-derived neurotrophic factor (BDNF) polymorphisms on the risk of late-onset Alzheimer's disease (AD) and quantitative measures of AD progression

BDNF is a functional candidate gene for AD, owing to its role in neuronal development and survival. The Val66Met (G196A), along with another C270T polymorphism has been associated with AD, however, the effects seem to be inconsistent across studies. We examined the association of the G196A and C270T polymorphisms with sporadic late-onset AD (LOAD) in a large American White cohort of 995 AD cases and 671 controls and an American Black cohort of 64 AD cases and 45 controls. We also examined the association of these polymorphisms with quantitative measures of AD progression, including age at onset (AAO), disease duration and Mini-Mental State Examination (MMSE) scores. No significant difference in allele, genotype or estimated haplotype frequencies was observed between AD cases and controls within the American White and Black cohorts for the G196A and C270T polymorphisms. However, the frequency of the 196*A allele was significantly lower in American Black subjects compared to Whites. While MMSE scores were significantly lower in C270T/CT carriers compared to C270T/CC subjects only among American Blacks, no such effect was observed among American Whites. The BDNF polymorphisms did not affect AAO or disease duration measures in American Whites or Blacks. Our finding does not support any association between the BDNF/G196A or C270T polymorphism and the risk of sporadic LOAD among American Whites or Blacks. The significant effect of the C270T polymorphism observed on MMSE scores among American Blacks needs to be further explored in a larger cohort.     

Association between a T/C polymorphism in intron 2 of cholesterol 24S-hydroxylase gene and Alzheimer's disease in Chinese

A polymorphism (T/C) in intron 2 of the cholesterol 24-hydroxylase (CYP46) gene has recently been reported to be associated with the risk for late-onset Alzheimer's disease (LOAD). To investigate possible involvement of the CYP46 gene and apolipoprotein E (APOE) gene polymorphisms in the manifestation of LOAD, we analyzed 99 sporadic LOAD patients and 113 healthy controls of China. We found an obvious association between CYP46 TT genotype and LOAD (OR = 2.98, 95% CI 1.64-5.44, P < 0.001). A clear increase of the risk to develop LOAD was also observed in subjects carrying both the CYP46 TT genotype and the APOE epsilon4-allele (OR = 12.94, 95% CI 4.26-39.32, P < 0.001). Our data reveal that the polymorphism of CYP46 intron 2 is implicated in the susceptibility to LOAD and a strong synergistic interaction between CYP46 TT homozoygots and APOE epsilon4 carrier status on the risk of LOAD.     

α3—巨球蛋白基因多态性与Alzheimer病的关联研究

目的：观察α2-巨球蛋白基因（α2-macroglobulin,A2M) 内含子17一种五核苷酸缺失突变在广州地区汉族老年人中的分布,探讨其与晚发Alzheimer病（AD）的相关性。方法：以97例晚发AD患者和111名健康老年人为对照进行病例－对照研究。用聚合酶链反应－限制性片段长度多态性方法分析A2M缺失／插入多态性和载脂蛋白E（apolipoproteinE,apoE)基因多态性。结果：（1）A2M基因缺失突变在晚发AD患者中的频率为2．6％,在正常老年人中的频率为2．7％,在所有受试者中未检测到A2M突变纯合体,晚发AD患者和健康老年人之间不存在A2M等位基因和基因型分布的差异,A2M基因多态性与晚发AD无关联。（2）晚发AD患者中apoE等位基因ε4频率显著升高（Z＝3．32,P＜0．01）。晚发AD与ε3／ε4基因型正关联（RR＝2．62,χ^2=6.89,P＜0．01）,和等位基因ε4正关联（RR＝2．67,χ^2=10.71,P＜0．01）。（3）晚发AD无论是否伴有apoE-ε4均与A2M不存在相关性。结论：广州汉族人群中A2M基因缺失突变多态性与晚发AD不具有关联。     

Methylenetetrahydrofolate reductase polymorphism, type II diabetes mellitus, coronary artery disease, and essential hypertension in the Czech population

Increased plasma concentrations of homocysteine have been found in patients with coronary artery disease (CAD) and essential hypertension (EH) and in patients with diabetic complications. The 677C/T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism is related to the MTHFR enzyme activity and to the plasma homocysteine concentration. This study was designed to investigate an association of this polymorphism with CAD, EH, and type II diabetes mellitus in the Czech population. The MTHFR genotypes were assessed by the polymerase chain reaction-based methodology in a sample of 1199 unrelated Caucasian subjects with CAD, EH, type II diabetes, or a combination of these diseases, and in healthy subjects. Allele frequencies of the MTHFR polymorphism differed considerably between women with and without type II diabetes mellitus (P = 0.00069), with a higher frequency of the C allele in the diabetic women. In addition, the MTHFR T allele frequency was significantly higher in normotensive subjects with CAD compared with normotensive subjects without this disease (P = 0.020). Both associations were confirmed by multiple logistic regressions. In conclusion, while the C allele of the 677C/T MTHFR polymorphism is associated with type II diabetes mellitus in women, the T allele is associated with CAD only in normotensive subjects of Czech origin.     

Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease

Experimental data have shown an upregulated expression of toll-like receptors, particularly toll-like receptor 4 (TLR4), in neurodegeneration. The Asp299Gly polymorphism of the TLR4 gene has been associated with an attenuated receptor signalling and a blunted inflammatory response. In the present study, we sought to determine whether this common genetic variant could influence susceptibility to late-onset Alzheimer's disease (LOAD) in an Italian population sample. A cohort of 277 LOAD patients and 300 cognitively healthy controls were genotyped for the TLR4 Asp299Gly polymorphism using restriction isotyping. The frequency of the minor 299Gly allele was significantly higher in the controls than in the LOAD cases (7.2% versus 3.1%, respectively, P=0.003). Additionally, the frequency of the variant genotypes (Asp/Gly and Gly/Gly) was 13.0% in the controls and 5.4% in LOAD patients (P=0.002). After adjustment for age, gender, and the APOE varepsilon4 carrier status, the odds ratio for the development of LOAD associated with the Asp/Gly and Gly/Gly versus Asp/Asp genotype was 0.37 (95% CI: 0.20-0.69, P=0.002). Our data further support a role for innate immunity in neurodegeneration and give the first evidence that the TLR4 Asp299Gly variant may be protective toward the development of LOAD.     

Interleukin-6 promoter polymorphism and late-onset Alzheimer's disease in the Finnish population

Recently, the involvement of the inflammatory response in Alzheimer's disease (AD) has received considerable attention. The gene encoding for interleukin-6 (IL-6) is interesting since IL-6 has been reported not only to be involved in immune functions but also in AD. We investigated whether the IL-6-174 G/C polymorphism is associated with late onset AD (LOAD) in the Finnish subjects. The G allele was over-represented in ApoE4-LOAD patients but remained unimportant in all and in the ApoE E4 carriers. Interestingly, the G allele frequency was lower in our population in both AD patients and in controls compared to Southern European populations.     

Association between the TNFalpha-308 A/G polymorphism and the onset-age of Alzheimer disease

Local inflammatory processes associated with amyloid plaques would contribute to the progression of late-onset Alzheimer disease (LOAD). Tumor necrosis factors alpha (TNF(alpha)) and beta (LT(alpha)) are inflammatory cytokines involved in the local immune response occurring in the central nervous system of LOAD patients. Genetic variation at these genes could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 315 LOAD patients and 400 healthy controls for DNA-polymorphisms in the genes encoding TNF(alpha) (-308 G/A, -238G/A) and LT(alpha) (Asn26Thr). Carriers of -308A showed a mean age at onset 3 years younger than noncarriers of this allele (P = 0.019). Our data suggest an effect of the TNF(alpha)-308 polymorphism on the age at onset of late AD. This represents additional evidence of the importance of genetic variation at the proinflammatory components in the origin and progression of this common neurodegenerative disease.     

Relationship between the -374T/A RAGE gene polymorphism and angiographic coronary artery disease

The receptor for advanced glycation end products (RAGE) is thought to play a critical role in diabetic atherosclerosis. Accordingly, a functional -374T/A polymorphism in RAGE gene promoter has been associated with macrovascular complications in type 1 diabetic patients. However, the extent to which this common variant influences the risk of coronary artery disease (CAD) in the general population remains to be determined. We genotyped the -374T/A RAGE polymorphism in 259 non-diabetic individuals, of whom 175 had angiographically documented coronary artery disease (CAD patients) and 84 had normal coronary angiography (CAD-free control subjects). Homozygosity for the -374A allele was found in 9.7% of the CAD patients versus 22.6% of the CAD-free subjects (p=0.005). By means of a multiple logistic regression analysis, the AA genotype of the -374T/A polymorphism was shown to be independently associated with a reduced risk of CAD (adjusted odds ratio 0.33, 95% CI 0.15 to 0.73; p=0.006). Our observations suggest that the -374T/A polymorphism of the RAGE gene may reduce susceptibility to CAD, thus exerting a protective effect on coronary risk. Future pathophysiological studies may be worthwhile to clarify the mechanisms behind this association.     

Interleukin-1A polymorphism is not associated with late onset Alzheimer's disease

Over the past few years, association studies have proposed a number of potential genetic risk factors for Alzheimer's disease (AD). With the exception of the varepsilon4 allele of the apolipoprotein E gene, whose association with the late onset type of AD (LOAD) has been confirmed, the relative significance of most of these associations is still in question. A polymorphism in the interleukin-1A gene (IL-1A2) has been suggested as a risk factor for the early onset as well as for LOAD. In this study, the distribution of IL-1A alleles was examined in a cohort of predominantly LOAD patients and in control individuals. No significant difference was detected in genotype or allele frequencies (odds ratios of 0.929 and 0.743, respectively; P>0.5). We conclude that IL-1A genotype is not a major risk factor for LOAD.     

Different implication of NEDD9 genetic variant in early and late-onset Alzheimer's disease

Alzheimer's disease (AD) is a complex and multifactorial progressive neurodegenerative disease. Recently, two studies reported inconsistent results on a possible involvement of the NEDD9 (neural precursor cell expressed, developmentally down-regulated 9, 6p25-p24) as a candidate gene for the risk of developing AD and/or Parkinson's disease (PD). We analyzed the distribution of the rs760678 SNP polymorphism in 735 Italian subjects: 214 unrelated sporadic late-onset AD patients (LOAD, 64.5% females, mean age-at-onset 71.8 ± 5.2 years), 135 early-onset AD patients (EOAD, 57.3% females, mean age-at-onset 57.5 ± 5.5 years) and 386 healthy controls (68.9% females, mean age 83.4 ± 17.9 years; SD). We observed a statistically significant difference between LOAD patients and controls according to genotypes (P = 0.016) and allele frequency (P = 0.007); CC genotype was more frequent in LOAD cases (44.4%) than controls (36.0%). No difference after stratification of the data in terms of gender and status of the APOE ?4 allele was observed. In conclusion, our data do support an implication of the NEDD9 allelic variant in late-onset AD, with an independent effect of the apolipoprotein E (APOE) ?4 allele in the risk of developing AD.     

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.     

Lipoprotein lipase gene PvuII polymorphism serum lipids and risk for coronary artery disease: meta-analysis

Our aim was to determine whether lipoprotein lipase gene PvuII polymorphism can be considered as an independent risk factor for coronary artery disease (CAD) by conducting a meta-analysis of all available published trials, including our own study. In 7 seperate studies, 3289 subjects were screened for this substitution; meta-analysis included only some of these individuals. Among the 7 studies, 6 were performed on white subjects, whereas 1 was on patients with Saudi Arabic descent.Subgroup analysis indicated that individuals with PvuII substitution does not have an increased risk for CAD. The LPL-PvuII genotype and allele frequency distributions did not differ significantly between CAD patients and healthy controls. There was no difference in the distribution of LPL-PvuII genotypes between the healthy subjects and the patients with CAD. However, no significant differences in lipid variables (triglyceride and HDL-cholesterol) were determined for the PvuII polymorphisms in the patients with CAD. No significant differences were found in serum triglyceride and HDL-cholesterol levels for LPL-PvuII genotypes when the control and CAD groups were pooled. In conclusion, LPL-Pvu II polymorphism cannot be used as independent genetic risk factor for CAD.     

Association of plasma nitric oxide concentration and endothelial nitric oxide synthase T-786C gene polymorphism in coronary artery disease

Nitric oxide (NO) is synthesized from l-arginine by endothelium nitric oxide synthase (NOS3) and plays important roles in many physiologic and pathologic processes. NO involved in the pathogenesis of coronary atherosclerosis. In the present study we hypothesized that polymorphisms of NOS gene might be associated with increased risk of coronary artery disease (CAD) and plasma NO concentrations. The eNOS gene polymorphism was investigated in 241 unrelated CAD patients with positive coronary angiograms and 261 ages matched control subjects without a history of symptomatic CAD. The NOS3 gene polymorphisms were analyzed by RFLP. Plasma NO, lipid profile and other risk factors were also assessed. The genotype frequencies for T-786C polymorphism differed significantly between CAD patients and controls (p=0.041). The mean plasma NO(x) concentrations showed significant differences according to genotypes of T-786C polymorphism in total population only. The mean plasma NO(x) increased in those individuals that are homozygote for C allele in promoter compared with those individuals are heterozygote for this allele and homozygote for T allele in total population and Controls, but no in CAD patients. The present study provides evidences that T-786C polymorphism of the NOS3 gene is associated with CAD. T-786C polymorphism was not associated with increased plasma NO in CAD patients.     

Association between the TNFα‐308 A/G polymorphism and the onset‐age of Alzheimer disease

Local inflammatory processes associated with amyloid plaques would contribute to the progression of late‐onset Alzheimer disease (LOAD). Tumor necrosis factors α (TNFα) and β (LTα) are inflammatory cytokines involved in the local immune response occurring in the central nervous system of LOAD patients. Genetic variation at these genes could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 315 LOAD patients and 400 healthy controls for DNA‐polymorphisms in the genes encoding TNFα (‐308 G/A, ‐238G/A) and LTα (Asn26Thr). Carriers of ‐308A showed a mean age at onset 3 years younger than noncarriers of this allele (P = 0.019). Our data suggest an effect of the TNFα‐308 polymorphism on the age at onset of late AD. This represents additional evidence of the importance of genetic variation at the proinflammatory components in the origin and progression of this common neurodegenerative disease. © 2002 Wiley‐Liss, Inc.     

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.