Allelic association at the D14S43 locus in early onset Alzheimer's disease

The D14S43 marker is closely linked to the major gene for early onset autosomal dominant Alzheimer's disease on chromosome 14. Allelic frequencies at the D14S43 locus were compared in 113 familial and isolated cases of early onset Alzheimer's disease (<60 years of age at onset) (EOAD) and 109 unaffected individuals of the same geographic origin. Allele 7 was significantly (P = 0.033) more frequent in type 1 EOAD patients (13.2%), defined by the presence of at least another first degree relative with EOAD, than in controls (4.1%). Since an autosomal dominant gene is probably responsible for type 1 patients, allelic association may reflect linkage disequilibrium at the D14S43 locus. This would mean that some patients share a common ancestral mutation. However, since multiple tests were carried out, this result must be interpreted with caution, and needs confirmation in an independent sample. © 1995 Wiley-Liss, Inc.     

ApoE4在阿尔茨海默病中的研究进展

载脂蛋白E(apolipoprotein E,ApoE)是一种脂质转运蛋白,在中枢神经系统的神经元中丰富表达,而ApoE4是其中的一种亚型.研究表明ApoE4是阿尔茨海默病(Alzheimer's disease,AD)的危险因素之一,会提高AD的发生率及降低其发病年龄.深入研究ApoE4的结构特性及在AD中的作用机制,有望使其成为诊治AD的靶点.     

Association of apolipoprotein E allele ϵ4 with late-onset sporadic Alzheimer's disease

Apolipoprotein E, type ?4 allele (ApoE ?4), is associated with late-onset sporadic Alzheimer's disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for?4 allele frequencies). These data support the involvement of ApoE?4 allele as a very important risk factor for the clinical expression of AD. © 1994 Wiley-Liss, Inc.     

Association of an apolipoprotein CII allele with familial dementia of the Alzheimer type

In order to identify the genetic locus responsible for familial dementia of the Alzheimer type (DAT), we are studying 10 families in which DAT appears to be inherited as an autosomal dominant trait. Genotypes for a TaqI restriction fragment length polymorphism (RFLP) at the apolipoprotein CII locus were determined for the following groups: affected and unaffected DAT family members, DAT subjects with no family history of the disease, and normal control subjects. The control group included 103 individuals from our study and 123 from the study of Wallis et al. (Hum. Genet., 68 (1984) 286). The frequency of the TaqI fast (F) allele in the affected familial DAT subjects (0.64 ± 0.08) differed significantly from that for the control group (0.39 ± 0.02) (Z = 2.87, P <0.005). In contrast, the F-allele frequency for the unaffected family members was 0.31 ± 0.09, which was similar to that of the combined control group (Z = 0.78, P > 0.40). Subsequently, genotypes were determined for two other polymorphisms at the Apo CII locus: a BanI RFLP and a Bgll RFLP. For these two polymorphisms, the allele frequencies for the familial DAT subjects differed from the unaffected control groups but the differences were smaller and not statistically significant. These data suggest a previously unrecognized association between the Apo CII TaqI F-allele and familial DAT.     

E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles

A single base substitution of a glutamic acid to an alanine codon 280 was found in the presenilin-1 (PS-1) gene on chromosome 14 in affected individuals in each of seven Colombian early-onset Alzheimer's disease (AD) kindreds. The mutation segregated with disease in kindreds tested. In the largest kindred (C2), the maximum two-point lod score between the mutation and AD was Z = 8.14 at θ = 0. The presence of a single mutation and the common geographic origin, with all families from the state of Antioquia, suggest a founder effect in this population. This finding is supported by the observation of a rare haplotype inherited with AD in all kindreds. These kindreds form the largest collection of AD cases with the same PS-1 mutation and the same educational, environmental, and ethnic background in which to study the phenotypic effect of putative risk factors, such as the ϵ4 allele of apolipoprotein E (ApoE) or head trauma. Of the few AD cases having a history of head trauma, the age of onset was not lowered. No effect of ApoE genotype on the age of onset was detected. Previous investigations of the effect of ApoE genotype on the age of onset were confounded by small patient numbers, familial clustering of ApoE genotypes, and combining data from unrelated families with different mutations. Hum Mutat 10:186–195, 1997. © 1997 Wiley-Liss, Inc.     

阿尔茨海默病与载脂蛋白E基因-427C/T多态性的关联研究

目的 探讨上海地区汉族人群载脂蛋白E(apolipoprotein E，apoE)基因启动子区—427C／T多态性与Alzheimer病(Alzheimer's disease，AD)发病风险的关系。方法 采用聚合酶链反应和限制性片段长度多态性方法，在104例AD患者和110名正常人中检测了apoE基因—427C／T各基因型及基因频率的分布。按比值比(odds ratio，0R)作疾病关联分析。结果 (1)AD患者与正常对照人群之间不存在—427C／T各等位基因和基因型频率分布的差异(P＞0．05)；(2)按apoE ε4基因分层后，无论是ε4型人群还是非ε4人群都不存在AD患者与正常老人间多态分布的差异(P＞0．05)；(3)在—427C／T 3种基因型中，仅T／T型AD与apoE ε4等位基因呈正关联(OR＝3．94，95％CI：2．206—7．038，x^2＝21．48，P＜0．05)。结论 上海地区汉族人群中，apo E基因—427C／T多态不是AD的疾病易感因子。     

HLA-DRB1基因多态性与克山病及其核心家系的关系研究

目的探讨HLA-DRB1基因多态性在我国北方克山病地区的分布特征及其与克山病核心家系的关联和连锁。方法采用聚合酶链反应-序列特异性寡核苷酸探针(polymerase chain reaction-sequence specific oligonucleotide probing,PCR-SSOP)技术,对118例克山病(Keshan disease,KD)患者HLA-DRB1基因进行分型,其中潜在型KD63例,慢型KD55例,65名正常人为对照;采用单倍型相对风险(haplotype based haplotype relative risk,HHRR)和传递不平衡检验(transmission disequilibrium test,TDT)方法对该基因在18个KD核心家系中的分布进行关联和连锁分析。结果(1)在KD患者和对照人群中,HLA-DRB1位点共检出13种等位基因;(2)DR7等位基因在KD组中的分布频率显著低于对照组(P<0.01,OR=0.1695);(3)DR7等位基因在慢型KD中的分布频率显著低于对照组(P<0.01,OR=0.091),而在潜在型KD中的分布频率与对照组比较差异无统计学意义;(4)DR15等位基因与KD显著关联(χ2=9.32,P<0.01),并与KD易感位点连锁(χ2=7.40,P<0.01)。结论KD可能存在遗传易感性,HLA-DRB1的DR7等位基因可能是KD保护性基因,携带DR7等位基因的KD患者可能不易发展为慢型KD,DR15等位基因可能与KD易感基因连锁。     

Allele doses of apolipoprotein E type ϵ4 in sporadic late-onset Alzheimer's disease

Apoliprotein E, type ?4 allele (ApoE-?4) is associated with late-onset sporadic Alzheimer's disease (AD). We have found that the cumulative probability of remaining unaffected over time decreases for each dose of ApoE-?4 in sporadic, late-onset French AD. The effect of genotypes on age at onset of AD was analyzed using the product limit method, to compare unaffected groups during aging. © 1995 Wiley-Liss, Inc.     

Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease

Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.     

α2-巨球蛋白基因I1000V多态性与散发阿尔茨海默氏病的关联研究

目的近年来有研究发现α2-巨球蛋白基因(α2-macroglobulin，A2M)Ile1000Val多态与阿尔茨海默氏病(Alzheimer’s disease，AD)发病有关联，但也有相悖的研究结果报道。因此．我们利用较大的样本，观察了A2M基因Ile1000Val多态在广州及成都地区汉族老年人中的分布，并探讨其与散发AD的相关性。方法以广州地区257例散发AD患者和242名正常老年人、成都地区112例散发AD患者和113名正常老年人为对象进行病例一对照研究。用聚合酶链反应一限制性片段长度多态性方法分析A2M基因11000V多态性和载脂蛋白E基因(apolipoprotelnE，apoE)多态性。结果(1)在两地合并样本中，AD患者与对照组中等位基因A2M-1000V的频率分别为7．7％与8．7％，广州与成都地区AD患者与对照组中A2M基因I1000V多态的分布差异无统计学意义。(2)散发AD无论按是否伴有apoE—ε4或按发病年龄分成不同亚组后，A2M基因I1000V多态的分布在病例组与对照组之间差异无统计学意义。结论广州与成都汉族人群中A2M基因I1000V多态与散发AD不具有关联。     

Initial results of a genome survey for novel alzheimer's disease risk genes: association with a locus on the X chromosome

As the initial step in a systematic genome survey, 16 simple sequence tandem repeat polymorphisms that span the X chromosome at an average spacing of 10 cM were examined for allelic associations with typical-onset Alzheimer's disease (AD). The efficiency of this survey was substantially enhanced by genotyping pools of genomic DNA from 50 autopsy-confirmed AD cases and 50 autopsied controls who were similar in sex ratio, race, and age at death. The frequency of the DXS1047 202-bp allele was twice as common among AD cases (0.45 ± S.E. 0.06) than controls (0.22 ± S.E. 0.05), a finding that was reproduced in an independent and geographically disparate sample. Consistent with Hardy-Weinberg equilibrium, the proportion of women with AD who carried the 202-bp allele, 73% was nearly double that observed for men with AD, 38%. However, the frequency of the 202-bp allele was similar for men and women and the presence of this allele did not affect the age at onset of dementia in either sex. Furthermore, the frequency of the DXS1047 202-bp allele in AD cases and controls was unaffected by the APOE genotype, indicating that these two loci modulate AD risk independently. Finally, the frequency of the 202-bp allele among 50 autopsy-confirmed cases of Parkinson's disease (0.29 ± S.E. 0.06) was indistinguishable from the control value, reflecting relative specificity for this allelic association with AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:98–107, 1998. © 1998 Wiley-Liss, Inc.     

Analysis of association and linkage for the interleukin-4 and interleukin-4 receptor alpha; regions in Swedish atopic dermatitis families

BACKGROUND: Atopic dermatitis (AD) is caused by genetic and environmental factors that interact to determine disease susceptibility and severity. Several lines of evidence suggest that the IL-4 gene and the IL-4-receptor alpha (IL-4Ralpha) gene are involved in the development of atopic diseases. OBJECTIVE: The objective of this study was to evaluate the possible involvement of the chromosomal regions 5q31 and 16p12, which include the genes coding for the IL-4 and the IL-4Ralpha in AD. METHODS: We conducted linkage analysis and association studies using the microsatellite markers D16S298 and D16S403 and a single nucleotide polymorphism in the promoter region of the IL-4 gene (- 590C/T) in 406 Swedish families with at least two siblings affected with AD, in total 1514 individuals. RESULTS AND CONCLUSION: We report linkage (P < 0.005) to the - 590C/T polymorphism in the promoter of the IL-4 gene for the semiquantitative trait severity score of AD. Neither linkage nor association was found to the IL-4Ralpha chromosomal region.     

The gene for apolipoprotein C-ll is closely linked to the gene for apolipoprotein E on chromosome 19

We have used a common TaqI restriction fragment length polymorphism (RFLP) near the human apolipoprotein C-II (apoC-II) gene to study linkage with apolipoprotein E (apoE). The inheritance of the apoC-II RFLP was followed in seven families that were segregating for apoE protein variants. No recombinants were observed in 20 informative meioses, giving an overall lod score of > 4.0 at recombination fraction 0. We have also observed apparent linkage disequilibrium between apoE and the apoC-II RFLP. Taken together these results demonstrate that these two apolipoprotein genes are closely linked and confirm that the gene for apoC-II is on human chromosome 19.     

Cortical Alzheimer Type Pathology Does Not Influence tau Pathology in Progressive Supranuclear Palsy

Alzheimer disease (AD) is characterized by numerous senile plaques (SP) in addition to widespread neocortical neurofibrillary tangles (NFT). Some elderly have pathologic aging (PA), which is characterized by numerous SP composed of diffuse amyloid deposits with few or no NFT confined to the limbic lobe. Both AD and PA represent a range of Alzheimer type pathology (ATP). Some cases of progressive supranuclear palsy (PSP) have concurrent ATP, but the relationship between ATP and PSP has not been addressed. In this study, a consecutive series of PSP cases were divided into three groups according to the degree of concurrent ATP – pure PSP, PSP/PA and PSP/AD. Braak NFT stage was significantly greater in PSP/AD compared with both PSP/PA and PSP. Among the pathologic variables studied in middle frontal, superior temporal and motor cortices, there were no differences between PSP and PSP/PA except for SP. In PSP/AD, there was greater neuronal tau pathology (pretangles, NFT and neuropil threads) in middle frontal and superior temporal cortices, probably a reflection of ATP since there was no comparable increase in PSP-related glial tau pathology in these regions. The APOEɛ4 allele frequency was significantly higher in PSP/PA and PSP/AD than in PSP. These results strongly argue that ATP in PSP represents independent disease processes even when present in the same brain.     

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。     

No evidence for linkage to the type 1 or type 2 neurofibromatosis loci in Noonan syndrome families

A linkage analysis has been performed on 6 two-generation families with classical Noonan syndrome to determine whether the shydrome is linked to neurofibromatosis type 1 on chromosome 17q or to neurofibromatosis type 2 on chromosome 22q. A significantly negative location score was obtained between 10cM centromeric to and 15 cM telomeric from the neurofibromatosis type 1 locus. A significantly negative lod score was obtained with a marker mapping within the region where neurofibromatosis type 2 is thought to be located. These data indicate that Noonan syndrome is not tightly linked to either neurofibromatosis type 1 or type 2. © 1993 Wiley-Liss, Inc.     

Allelic frequencies at the ACE and LRPAP1 loci suggest age-related relationships in a Northern Italian population

The present work attempts to determine the distribution of ACE and LRPAP1 genotypes and allele frequencies in a sample of the population of north-western Italy and to examine the age-related association of these polymorphisms. ACE D allele frequency found in this work further confirms data obtained in previous studies of Northern Italian populations. Regarding the LRPAP1 gene, high frequencies of the deleted allele in European populations were also confirmed. In order to analyse the relationship between ACE and LRPAP1 gene polymorphisms and age, the sample was subdivided into four age groups: 1–30 (n?=?99), 31–50 (n?=?165), 51–79 (n?=?146) and 80–100 years old (n?=?57). For the ACE gene, significant difference in D/D genotype frequency was found only between the younger and the 51–79 age groups (p?<?0.05), the latter showing the lower frequency value. Significant differences were found, for both the I/D and D/D LRPAP1 genotypes, between the first and the second age group (p?<?0.02) and between the first and the third age group (p?<?0.01), with the 51–79 age group showing the higher D/D and the lower I/D genotype frequency values.     

F-fluorodeoxyglucose positron emission tomography,aging, and apolipoprotein E genotype in cognitively normal persons

Our objective was to examine associations between glucose metabolism, as measured by ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET), and age and to evaluate the impact of carriage of an apolipoprotein E (APOE) ε4 allele on glucose metabolism and on the associations between glucose metabolism and age. We studied 806 cognitively normal (CN) and 70 amyloid-imaging-positive cognitively impaired participants (35 with mild cognitive impairment and 35 with Alzheimer's disease [AD] dementia) from the Mayo Clinic Study of Aging, Mayo Alzheimer's Disease Research Center and an ancillary study who had undergone structural MRI, FDG PET, and ¹¹C-Pittsburgh compound B (PiB) PET. Using partial volume corrected and uncorrected FDG PET glucose uptake ratios, we evaluated associations of regional FDG ratios with age and carriage of an APOE ε4 allele in CN participants between the ages of 30 and 95 years, and compared those findings with the cognitively impaired participants. In region-of-interest (ROI) analyses, we found modest but statistically significant declines in FDG ratio in most cortical and subcortical regions as a function of age. We also found a main effect of APOE ε4 genotype on FDG ratio, with greater uptake in ε4 noncarriers compared with carriers but only in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature meta-ROI. The latter consisted of voxels from posterior cingulate and/or precuneus, lateral parietal, and inferior temporal. In age- and sex-matched CN participants the magnitude of the difference in partial volume corrected FDG ratio in the AD-signature meta-ROI for APOE ε4 carriers compared with noncarriers was about 4 times smaller than the magnitude of the difference between age- and sex-matched elderly APOE ε4 carrier CN compared with AD dementia participants. In an analysis in participants older than 70 years (31.3% of whom had elevated PiB), there was no interaction between PiB status and APOE ε4 genotype with respect to glucose metabolism. Glucose metabolism declines with age in many brain regions. Carriage of an APOE ε4 allele was associated with reductions in FDG ratio in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature ROIs, and there was no interaction between age and APOE ε4 status. The posterior cingulate and/or precuneus and lateral parietal regions have a unique vulnerability to reductions in glucose metabolic rate as a function both of age and carriage of an APOE ε4 allele.     

The role of the apolipoprotein E polymorphism in the prediction of coronary artery disease age of onset

We investigated the role of the apolipoprotein (Apo) E polymorphism in the prediction of CAD age of onset in a sample of unrelated living male (n = 65) and female (n = 54) Caucasian subjects diagnosed with CAD. Cumulative distributions of age at the first diagnosis of CAD were estimated for each Apo E genotype and tested for homogeneity using the log-rank test. The Apo e33 genotype was used as a reference group for all hypothesis tests. Analyses were performed separately in males and females. We found evidence suggesting that the presence of the Apo s32 genotype in males is associated with a significantly earlier CAD age of onset. These results suggest that the Apo E polymorphism may be a gender-specific predictor of CAD age of onset.