Apolipoprotein E: risk factor for Alzheimer disease.

The apolipoprotein E gene (APOE) has three common alleles (epsilon 2, epsilon 3, and epsilon 4) that determine six genotypes in the general population. In this study, we examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-epsilon 4 allele. We show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-epsilon 4/epsilon 3 genotype being the most common in the AD group and the APOE-epsilon 3/epsilon 3 being the most common in the control group. In the AD group, homozygosity for epsilon 4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two epsilon 4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-epsilon 4, was 3.6 (95% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-epsilon 4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). Our data, which are in agreement with recent reports, suggest that the APOE-epsilon 4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population.     

老年痴呆关联基因的研究进展

阿尔茨海默类痴呆（AD）是老年痴呆中最常见的一种,它以渐进性的神经功能退化并伴随着整体认知能力的下降为特征。早发性AD主要是由β-淀粉样前体蛋白（APP）基因和早老素基因突变引起,而与晚发性AD发病明显相关的只有载脂蛋白E-ε4 ( APOE-ε4)等位基因。但是APOE-ε4等位基因对AD发病既非充分又非必要,而且只能解释少于50%的AD的遗传变异。所以有必要进一步寻找与AD的关联基因。 Abstract:Dementia of the Alzheimer type (AD) is the leading cause of dementias for the elders.It is a progressively neurodegenerative disorder characterized by global cognitive decline.While most of the rare early-onset AD can be explained by mutations in APP gene and presenilin genes,the genetic etiology of the more common late-onset AD is only partly explained by the APOE-ε4 genotype.But the APOE-ε4 allele is neither necessary nor sufficient to cause disease and it can only account for less than one-half of the genetic variance of AD.Thus,more genes involved in AD are our special attention.     

Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.     

Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City.

Apolipoprotein-E epsilon 4 (APOE-epsilon 4) has been consistently associated with Alzheimer disease (AD) and may be responsible for an earlier age at onset. We have previously reported a diminished association between APOE-epsilon 4 and AD in African Americans. Using a new method, which allows inclusion of censored information, we compared relative risks by APOE genotypes in an expanded collection of cases and controls from three ethnic groups in a New York community. The relative risk for AD associated with APOE-epsilon 4 homozygosity was increased in all ethnic groups (African American relative risk [RR]=3.0; 95% confidence interval [CI]=1.5-5.9; Caucasian RR=7.3, 95% CI=2.5-21.6; and Hispanic RR=2.5, 95% CI=1.1-5.7), compared with those with APOE-epsilon 3/epsilon 3 genotypes. The risk was also increased for APOE-epsilon 4 heterozygous Caucasians (RR=2.9, 95% CI=1.7-5.1) and Hispanics (RR=1.6, 95% CI=1.1-2.3), but not for African Americans (RR=0.6, 95% Ci=0.4-0.9). The age distribution of the proportion of Caucasians and Hispanics without AD was consistently lower for APOE-epsilon 4 homozygous and APOE-epsilon 4 heterozygous individuals than for those with other APOE genotypes. In African Americans this relationship was observed only in APOE-epsilon 4 homozygotes. These results confirm that APOE genotypes influence the RR of AD in Caucasians and Hispanics. Differences in risk among APOE-epsilon 4 heterozygote African Americans suggest that other genetic or environmental factors may modify the effect of APOE-epsilon 4 in some populations.     

Polymorphisms in the promoter region of ESR2 gene and breast cancer susceptibility

Genetic variations like single nucleotide polymorphisms (SNPs) in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to affect breast cancer susceptibility. In this study we tested the hypothesis that polymorphisms in the promoter of ESR2 gene may be associated with increased risk for breast cancer. We analyzed three SNPs in the promoter region of human ESR2 gene by means of allele-specific tetra-primer PCR. A total of 318 sporadic breast cancer cases and 318 age-matched controls were included in the study. With regard to homozygous genotypes, women with sporadic breast cancer more frequently carried the CC genotype of ESR2 promoter SNP rs2987983 (OR 1.99, p = 0.005). Calculation of allele positivity demonstrated that presence of T allele of this SNP was more frequent in healthy women. Our data suggest that a SNP in the promoter region of ESR2 gene might be able to affect breast cancer risk. These results further support the emerging hypothesis that ERβ is an important factor in breast cancer development.     

Investigation of glutathione S-transferase M1 and T1 deletions in lung cancer

Glutathione S-transferases (GSTs) M1 and T1 are known to be polymorphic in humans. Both polymorphisms are due to gene deletions which are responsible for the existence of null genotypes. Previous studies have suggested that GST genotypes may play a role in determining susceptibility to a number of unrelated cancers, including lung cancer. The GSTM1 and GSTT1 polymorphisms were determined by PCR-based analysis in 75 lung cancer patients and 55 controls. The unconditional logistic regression analysis was used to calculate ORs and 95% CI. The frequencies of GSTM1 and GSTT1 null genotypes were 37.3 and 22.7% in lung cancer patients and 27.3 and 16.4% in controls, respectively. When analyzed by histology the GSTM1 null genotype was more prevalent in squamous-cell carcinoma and adenocarcinoma patients. Whereas, GSTT1 null genotype frequency was lower in small-cell lung cancer patients than controls. But these differences were not statistically significant. According to smoking status, null genotype for both gene are associated with an increase in risk for lung cancer. Our results suggest that GSTM1 and GSTT1 polymorphisms may play a role in the development of lung cancer for some histological subtypes and modifies the risk of smoking-related lung cancer.     

中国人群中肿瘤坏死因子α-308 A/G基因多态和α2-巨球蛋白基因缺失多态与晚发性阿尔茨海默病无相关性

晚发性阿尔茨海默病 (LOAD)是老年痴呆中最常见的一种 ,它是一种病因复杂、由遗传因素和环境等其他因素共同作用引起的老年期疾病。服用非甾类抗炎类药物能延缓或防止LOAD的发病说明炎症反应可能参与LOAD病理 ,肿瘤坏死因子 (TNF)是炎症反应中主要的细胞因子 ,并且能增加 β 淀粉样肽 (Aβ)的产生说明其可能是LOAD的易感基因。α2 巨球蛋白 (A2M)是一种血清蛋白酶抑制剂 ,它是低密度脂蛋白受体相关蛋白 (LRP)主要的配体 ,并且能与Aβ结合并介导其降解和清除 ,说明它可能是另一个LOAD的易感基因。在 6 7名晚发性阿尔茨海默病人和 14 2名正常对照中比较了载脂蛋白E基因 (APOE)、TNF启动子区 (- 30 8A G)多态和A2M一 5bp核苷酸缺失 (I D)多态 (A2M 2 )与LOAD发病风险的关系。结果显示 ,APOEε4等位基因在AD病人组中显著高于对照组 (χ2=11 6 6 ,P <0 0 1) ,而TNF(- 30 8A G)多态和A2M缺失多态的基因型和等位基因在LOAD病人组和对照组中都无显著差别 (P >0 1)。按年龄和APOEε4等位基因分组同样无相关性 ,说明TNF 30 8A G位点的多态与A2M缺失不是中国人群的晚发性老年痴呆的风险因子     

Deficiency in mitochondrial aldehyde dehydrogenase increases the risk for late-onset Alzheimer's disease in the Japanese population

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) deficiency is caused by a mutant allele in the Mongoloids. To examine whether genetic constitutions affecting aldehyde metabolism influence the risk for late-onset Alzheimer's disease (LOAD), we performed a case-control study in the Japanese population on the deficiency in ALDH2 caused by the dominant-negative mutant allele of the ALDH2 gene (ALDH2*2). In a comparison of 447 patients with sex, age, and region matched nondemented controls, the genotype frequency carrying the ALDH2*2 allele was significantly higher in the patients than in the controls (48.1% vs 37.4%, P = 0.001). Logistic regression analysis indicates that carriage of the ALDH2*2 allele is an independent risk for LOAD of the epsilon4 allele of the apolipoprotein E gene (APOE-epsilon4) (P = 0.002). Moreover, the odds ratio for LOAD in carriers of the ALDH2*2 allele was almost twice that in noncarriers, irrespective of status with regard to the APOE-epsilon4 allele. Among patients homozygous for the APOE-epsilon4 allele, age at onset of LOAD was significantly lower in those with than without the ALDH2*2 allele. In addition, dosage of the ALDH2*2 allele significantly affected age at onset of patients homozygous for the APOE-epsilon4 allele. These results indicate that the ALDH2 deficiency is a risk for LOAD, synergistically acting with the APOE-epsilon4 allele.     

ACE I/D polymorphism in Alzheimer’s disease

Angiotensin-converting enzyme (ACE) has been reported to show altered activity in patients with neurological diseases. The recent studies found that a 287 bp insertion/deletion (I/D) polymorphism of the ACE gene may be associated with susceptibility to Alzheimer’s disease (AD) but the results have been heterogenous between studies in Europe. In the present study we examined for the first time the association of ACE I/D polymorphism along with APOE genotype in 70 sporadic AD and 126 control subjects in Slovak Caucasians (Central Europe). An increased risk for AD was observed in subjects with at least one APOE*E4 allele (OR=3.99, 95% CI=1.97–8.08). No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and patients for ACE gene. Gene-gene interaction analysis showed increase of the risk to develop AD in subjects carrying both the ACE DD genotype and the APOE*E4 allele (OR=10.32, 95% C.I. 2.67–39.81).     

Genetic Analysis of Interleukin-1A C(-889)T Polymorphism with Alzheimer Disease

Neuroinflammation has been implicated in the etiology of Alzheimer’s disease (AD). Many studies have suggested that C(-889) T promoter polymorphism in one of the proinflammatory cytokine interleukin-1 (IL-1) encoding gene IL-1A may be associated with AD pathogenesis. To determine whether the polymorphism contributes to the risk for late-onset AD (LOAD) in Chinese, we carried out our investigation in 344 sporadic LOAD patients and 224 healthy controls. No statistical significant association was obtained between IL-1A C(-889) T polymorphism and LOAD and no statistical difference was found between cases and controls after stratification for apolipoprotein E allele 4 (APOE ε4) status. The results reveal that it is not likely that the IL-1A C(-889) T polymorphism is involved in AD pathogenesis in the Chinese population. Further studies of the associations between other IL-1A genetic polymorphisms and AD should be performed in a larger population and biologic functional analysis of IL-1A gene is required to verify the underlying roles of IL-IA in LOAD.     

Association of genetic polymorphisms in vitamin D receptor gene and susceptibility to sporadic prostate cancer

Genetic and environmental factors are involved in prostate cancer (PCa) etiology. Single nucleotide polymorphisms (SNPs) may contribute to the PCa pathogenesis. The goal of this study is to determine the role of vitamin D receptor (VDR) gene polymorphisms and haplotypes in the development and progression of sporadic PCa. One hundred and thirty-three PCa patients and 157 age-matched healthy controls were genotyped for the Apa I (rs7975232), Bsm I (rs1544410) and Taq I (rs731236) polymorphisms in VDR gene by using polymerase chain reaction-restriction fragment length polymorphism. An association was observed between the Apa I polymorphism and PCa predisposition (P = 0.03). When compared with AA genotype, there was a highly notable difference in the frequencies of the Aa (P = 0.02), aa (P = 0.026) and Apa I 'a' allele carriers (Aa + aa) (P = 0.009) genotypes. Furthermore, we found a statistical difference in the allele frequencies of the Apa I polymorphism between the sporadic PCa patients and control subjects (P = 0.013). The genotype distribution for the Bsm I and Taq I polymorphisms were similar between cases and controls (P > 0.05). No clinically significant relationship was found between the three-locus haplotypes and development of sporadic PCa. The genotype frequencies for the three polymorphisms of the VDR gene within subgroups of PCa (defined by tumor stage, Gleason score, PSA levels) were also analyzed, but no statistically noteworthy difference was observed (P > 0.05). As far as we know, this is the first study which investigates the relationship between VDR genotypes and sporadic PCa in the Turkish population. Our findings suggest that the VDR ApaI (rs7975232) polymorphism may play a role in the development of sporadic PCa.     

Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E epsilon 4.

Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility.     

Parkinson's disease and apolipoprotein E: possible association with dementia but not age at onset

Idiopathic Parkinson's disease (PD) is an age-dependent, neurodegenerative condition frequently associated with dementia. Although it is predominantly a sporadic disease, 20-30% of cases are familial, suggesting a complex mode of inheritance. Apolipoprotein E (APOE) allele epsilon4 has been associated with familial and sporadic late-onset senile dementia of the Alzheimer's type. To investigate the role of this gene in the development of dementia associated with PD and age at onset of PD, we evaluated the frequency of APOE gene polymorphism in a sample of PD patients with (n=118) and without (n=167) a family history, as well as matched normal controls (n=96). The PD sample was categorized according to age at onset and presence or absence of dementia. Kaplan-Meier survival analysis was used to plot genotype-specific age at onset distribution curves. Allele frequencies of APOE in PD patients with and without a family history and normal controls were not significantly different. APOE genotypes were also similar between the groups. However, the frequencies of epsilon4 allele and epsilon4/- genotype in the PD group with dementia were more than twofold higher than in normal controls, and the differences were statistically significant. There were no differences in the allele and genotype frequencies of the APOE gene between PD groups with different age at onset. The familial PD had significantly earlier age at onset than sporadic PD (Log-rank test, P=0.027). The age at onset distribution curves for different genotype groups were similar, and their differences were not statistically significant (P=0.38). After the Bonferroni's correction for multiple tests, the positive results are not significant at the P<0.05 level. We conclude that APOE does not play an important role in susceptibility to PD or age at onset of PD, but may play a role in dementia associated with PD in our sample.     

Prevalence of estrogen receptor alpha PvuII and XbaI polymorphism in population of Polish postmenopausal women

Numerous data indicate that polymorphism of estrogen receptor alpha (ERalpha) may predict lipid levels, lipid response to hormone replacement therapy (HRT), myocardial infarction risk, bone fracture risk, bone mineral density (BMD) and changes in BMD over time. In this study we aimed to evaluate distribution of ERalpha PvuII and XbaI genotypes in population of Polish postmenopausal women qualified to different protocols of HRT. Subject of the study were 64 consecutive postmenopausal women aged from 45 to 65 years (mean 56.6) assigned to HRT. ERalpha PvuII and XbaI polymorphism was determined by PCR-restriction fragment length polymorphism (RFLP). The absence of PvuII and XbaI restriction sites were indicated by "P" and "X" and presence by "p" and "x", respectively. PvuII genotype was distributed as follows: PP 17.2% (n=11), Pp 50% (n=32), pp 32.83% (n=21). Frequency of XbaI genotype was: XX 6.25% (n=4), Xx 34.4% (n=22), xx 59.4% (n=38). Four haplotypes with following frequencies were recognized: PX 17.3%, px 47.4%, Px 24.4% and pX 10.9%. Prevalence of estrogen receptor alpha PvuII and XbaI polymorphisms in Polish women is similar to previously studied population.     

新疆维吾尔族、汉族阿尔茨海默病Neprilysin基因单核苷酸多态性研究

摘要目的：探讨新疆地区维吾尔族、汉族脑啡肽酶（Neprilysin,NEP）基因单核苷酸多态性与阿尔茨海默病（Alzheimer’SdiseaseAD）的关系。方法：对新疆地区维吾尔族、汉族≥50岁8284名人群进行AD流行病学调查,参照ADRDA．NINCDS的标准,选取散发性阿尔茨海默病（sporadicAlzheimer’s disease,SAD）患者209例（AD组）与正常对照220例（对照组）,应用聚合酶链反应一限制性片段长度多态性技术（PCR）检测NEP基因多态性,采用病例一对照的关联分析方法对NEP基因rs3736187位点进行基因型和等位基因频率分析。结果：（1）新疆维吾尔族、汉族两民族AD组与对照组间NEP基因基因型频率和等位基因频率分布差异均有统计学意义（P〈0．05）。携带T等位基因个体出现AD的危险性高于携带c等位基因的个体（0R=1．981,P〈0．05）。（2）新疆维吾尔族、汉族不同民族之间比较NEP基因基因型频率和等位基因频率分布差异均无统计学意义（P〉0．05）,而在同一民族中AD组和对照组之间比较NEP基因等位基因频率分布差异均具有统计学意义（P〈0．05）。（3）两个年龄分段（〈65岁及≥65岁）之间NEP基因基因型频率和等位基因频率分布差异均无统计学意义（P〉0．05）,而在同一年龄段内部AD组与对照组间等位基因频率分布差异具有统计学意义（P〈0．05）。（4）男性、女性之间NEP基因基因型频率和等位基因频率分布差异均无统计学意义,而在女性AD组与对照组间等位基因频率分布差异有统计学意义（P〈0．05）。结论：NEP基因rs3736187位点基因型频率和等位基因频率在新疆维吾尔族、汉族两民族间的分布相似;NEP基因的T等位基因是SAD的危险因素,在新疆维吾尔族、汉族两民族及女性SAD的发病中起重要作用。     

Single nucleotide polymorphisms of estrogen receptor alpha in human renal cell carcinoma

Estrogens and their receptors (ERs) have been shown to play a role in various cancers. We hypothesize that polymorphisms and genotypic changes of the ERalpha gene are involved in renal cell carcinoma. To test this hypothesis, DNA samples from 113 cases of human renal cell cancer were analyzed by sequence-specific polymerase chain reaction to determine the genotypic frequency of six different polymorphic loci on ERalpha gene (codon 10 T-->C, codon 87 G-->C, codon 243 C-->T, codon 325 C-->G, codon 594 G-->A, and intron 1 C-->T). The relative risk of variant genotype was calculated by comparison with 200 healthy controls. The results of this study demonstrate that the distribution of genotypes on codon 10 differs between renal cancer patients and healthy normal controls (p<0.05). The relative risk of the genotype 10C/C was calculated as 2.51. No differences in genotypes were observed at all other loci. We also analyzed DNA from pairs of cancerous and normal tissues from 96 cases of human renal cell cancer to characterize genotypic changes at these loci. Genotypic changes were detected in nine cancer samples on exon 1 (codons 10 and 87) of ERalpha, although none were detected at other regions. The present study demonstrates for the first time that codon 10 polymorphism on exon 1 of ERalpha may be involved in renal cancer risk.     

天津地区人群hMLH1和hMSH2基因多态性与散发性结直肠癌易感性的关系

为探讨错配修复基因hMLH1和hMSH2单核苷酸多态性(Single nucleotide polymorphism,SNP)与散发性结直肠癌(Sporadic colorectal caner,SCRC)发病易感性之间的关系,文章采用聚合酶链式反应-变性高效液相色谱方法和序列分析技术,检测了天津地区600例SCRC患者和600例健康对照个体hMLH1394G/C、hMSH2943-1G/A、hMSH21917T/G和hMSH22783C/A的基因型频率分布。结果显示:SCRC患者组hMSH22783C/A3种基因型C/C、C/A、A/A频率(90%、9%、1%)与对照组(95%、4.8%、0.2%)相比差异具有统计学意义(χ2=11.91,P0.01)。与hMSH22783C/C基因型相比,C/A和A/A基因型能增加SCRC发病风险(OR值分别为1.77和11.94,95%CI分别为1.03～3.03和1.38～103.2)。多态性位点联合分析显示,SCRC组与对照组单倍型分布差异有统计学意义(χ2=38.38,P0.01);与394G/943-1G/2783C单倍型相比,394G/943-1G/2783A单倍型显著增加SCRC的发病风险(OR=2.18,95%CI:1.40～3.40)。结果提示hMSH22783C/A多态性可能成为预测SCRC发病风险的独立因素,394G/943-1G/2783A单倍型可能增加SCRC的发病风险。     

Promoter polymorphism in fibroblast growth factor 1 gene increases risk of definite Alzheimer's disease

Fibroblast growth factor 1 (FGF1, also known as acidic FGF) protects selective neuronal populations against neurotoxic effects such as those in Alzheimer's disease (AD) and HIV encephalitis. The FGF1 gene is therefore a strong candidate gene for AD. Using the promoter polymorphism of the FGF1 gene, we examined the relationship between AD and the FGF1 and apolipoprotein E (APOE) genes in 100 Japanese autopsy-confirmed late-onset AD patients and 106 age-matched non-demented controls. The promoter polymorphism (-1385 A/G) was significantly associated with AD risk. The odds ratio for AD associated with the GG vs non-GG genotype was 2.02 (95% CI = 1.16-3.52), while that of s4 vs non-?4 in APOE4 gene was 5.19 (95% CI = 2.68-10.1). The odds ratio for APOEP4 and FGF1 GG carriers was 20.5 (95% CI = 6.88-60.9). The results showed that the FGF1 gene is associated with autopsy-confirmed AD.