Association between presenilin-1 polymorphism and maternal meiosis II errors in Down syndrome

Several lines of evidence suggest a shared genetic susceptibility to Down syndrome (DS) and Alzheimer disease (AD). Rare forms of autosomal-dominant AD are caused by mutations in the APP and presenilin genes (PS-1 and PS-2). The presenilin proteins have been localized to the nuclear membrane, kinetochores, and centrosomes, suggesting a function in chromosome segregation. A genetic association between a polymorphism in intron 8 of the PS-1 gene and AD has been described in some series, and an increased risk of AD has been reported in mothers of DS probands. We therefore studied 168 probands with free trisomy 21 of known parental and meiotic origin and their parents from a population-based material, by analyzing the intron 8 polymorphism in the PS-1 gene. An increased frequency of allele 1 in mothers with a meiosis II error (70.8%) was found compared with mothers with a meiosis I error (52.7%, P < 0.01), with an excess of the 11 genotype in the meiosis II mothers. The frequency of allele 1 in mothers carrying apolipoprotein E (APOE) epsilon4 allele (68.0%) was higher than in mothers without epsilon4 (52.2%, P < 0.01). We hypothesize that the PS-1 intronic polymorphism might be involved in chromosomal nondisjunction through an influence on the expression level of PS-1 or due to linkage disequilibrium with biologically relevant polymorphisms in or outside the PS-1 gene.     

The -48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased Abeta load in brain

Mutations in the presenilin 1 gene (PS1) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), whereas its role in other late onset forms of AD remains unclear. A −48 C/T polymorphism in the PS1 promoter has been associated with an increased genetic risk in early onset complex AD and moreover has been shown to influence the expression of the PS1 gene. This raises the possibility that previous conflicting findings from association studies with homozygosity for the PS1 intron 8 polymorphism might be the result of linkage disequilibrium with the -48 CC genotype. Here we provide further evidence of increased risk of AD associated with homozygosity for the −48 CC genotype (odds ratio=1.6). We also report a phenotypic correlation with Aβ₄₀, Aβ₄₂₍₄₃₎, and total Aβ load in AD brains. The −48 CC genotype was associated with 47% greater total Aβ load (p<0.003) compared to CT + TT genotype bearers. These results suggest that the -48 C/T polymorphism in the PS1 promoter may increase the risk of AD, perhaps by altering PS1 gene expression and thereby influencing Aβ load.


Keywords: Alzheimer; presenilin; promoter; polymorphism     

No association between alpha‐1‐antichymotrypsin polymorphism and Alzheimer's disease in Koreans

To examine the possible involvement of the alpha‐1‐antichymotrypsin gene (ACT) polymorphism in the manifestation of Alzheimer's disease (AD), we analyzed genotypes of the ACT and apolipoprotein E gene (APOE) among 110 Korean patients with probable AD and 209 nondemented controls. No significant difference was obtained in genotypic (χ²=1.98, df=2, P>0.1) and allelic frequencies (χ²=1.61, df=1, P>0.1) of ACT between the AD and control groups. No overexpression of the ACT A/A genotype and ACT A allele was found when we analyzed the late‐onset AD patients and the early‐onset AD patients, separately. Then we stratified the ACT genotypes based on the presence or absence of the APOE ϵ4 allele to evaluate the possible interaction between them. In the APOE ϵ4‐negative subjects, although the ACT A allele tended to be overexpressed in the AD group, the differences in the frequencies of the ACT A allele (χ²=2.79, df=1, P>0.1) and ACT A/A genotype (χ²=0.16, df=1, P>0.1) were not statistically significant. No significant overrepresentations of the ACT A allele (χ²=0.02, df=1, P>0.1) and ACT A/A genotype (χ²=0.17, df=1, P>0.1) were found in the APOE ϵ4‐positive subjects, either. In addition, the status of the ACT genotype did not influence the age‐at‐onset of AD (F=0.03, df=2, P>0.1). Therefore, the ACT polymorphism does not contribute to the development of AD independently or interactively with the APOE ϵ4 allele in Koreans. Am. J. Med. Genet. 91:355–358, 2000. © 2000 Wiley‐Liss, Inc.     

No association between the intronic presenilin 1 polymorphism and Alzheimer's disease in the Chinese population

Wragg et al. [1996: Lancet 347:509-512] recorded an association between the intron-based presenilin 1 (PS1) genotype 1/1 and late-onset Alzheimer's disease (AD). This study was performed to determine if there is a similar association in the Chinese population. Ninety-one AD cases, 50 multiinfarct dementia (MID) patients, and 73 age-matched normal controls were recruited. Genotyping of PS1 and apolipoprotein E (APOE) was performed by the methods of polymerase chain reaction and restriction fragment length polymorphism. In AD, MID, and normal controls PS1 allele 1 frequency was 0.6703, 0.5600, and 0.6301, respectively; PS1 allele 2 frequency was 0.3297, 0.4400, and 0.3699, respectively. No association was detected between these diseases and any PS1 allele or genotype. There was only a nearly significant negative association between MID and PS1 genotype 1/1 in the subgroup population bearing APOE allele E4 (odds ratio = 0.2753, P = 0.0776). Our results do not support the conclusion that the intronic PS1 polymorphism is associated with Alzheimer's disease.     

ApoE ϵ3‐haplotype modulates Alzheimer beta‐amyloid deposition in the brain

ApoE ?4 allele increases the risk of late‐onset Alzheimer disease (AD) as well as the amount of beta‐amyloid deposition in the brain. Because half of AD patients do not have ApoE ?4, it is important to search for other determinants of ApoE that modify AD risk. We tested whether the haplotype background of the most common ApoE allele, ?3, influences brain amyloid deposition or the risk of neuropathologically verified AD in a population‐based sample of elderly Finns. To exclude the effects of ApoE protein polymorphism we focused these analyses on subjects homozygous for ?3. Haplotypes were defined using polymorphisms at positions ? 491 and ? 219 of the ApoE promoter and at position +113 of intron‐1. We found that ?3‐haplotypes containing the promoter allele ? 219T were associated with reduced amyloid deposition and reduced risk of neuropathologically verified AD as compared to ?3‐haplotypes containing ? 219G. The functional polymorphism(s) responsible for the haplotypic difference remains to be identified. These results indicate that there is significant allelic variation in the ApoE gene region, which modulates brain amyloid deposition and AD risk, independent of the ApoE protein polymorphism. © 2002 Wiley‐Liss, Inc.     

Gene diagnosis of Alzheimer's disease and Parkinson's disease

Alzheimer's disease(AD) is the most common form of neurodegenerative diseases that causes intellectual dysfunction. AD is a genetically heterogenous disorder. Over 100 mutations have been identified in three causative genes, i.e. amyloid protein precursor(APP), presenilin 1(PS1) and presenilin 2(PS2) genes, for early-onset autosomal dominant familial AD(FAD). Apolipoprotein E(APOE) gene has been identified as susceptibility gene for late-onset FAD. The missense mutations in the causative genes lead to abnormal APP processing with overproduction of total A beta protein or A beta 42(43) isoform. The epsilon 4 allele of APOE gene is a genetic risk factor for sporadic AD as well as FAD. Parkinson's disease(PD) is another common form of neurodegenerative disease that causes movement dysfunction. Three genes, i.e. alpha-synuclein (SNCA), parkin(PARK2), and ubiquitin carboxy-terminal hydrolase L1(UCHL1) genes, have been identified as causative genes for familial PD. The B mutation of CYP2D6 gene(CYP2D6*4 allele) is a genetic risk factor for PD. Lewy body(LB), that is an intracellular inclusion body characteristic of PD, is widely distributed in the cerebral cortex of 20 to 30% of AD patients. This disease entity is called as Lewy body variant(LBV) of AD. LBV shares the genetic risk factor with AD and PD, i.e. APOE epsilon 4 allele and CYP2D6 B mutation. Gene diagnosis is possible for familial AD and PD. APOE and CYP2D6 genotyping is also applicable to the future prediction of AD and PD, respectively.     

Allelic association but only weak evidence for linkage to the apolipoprotein E locus in late-onset Swedish Alzheimer families

An association between the ϵ4 allele of the apolipoprotein E gene (APOE) and late-onset Alzheimer's disease (AD) was recently demonstrated. In order to confirm the association and to gauge the ability of standard genetic linkage methods to identify susceptibility genes, we investigated 15 Swedish late-onset AD families. We found an association of familial AD to the APOE ϵ4 allele (P = 0.01) but no indication of linkage to the APOE region using 2-point linkage analysis, and only weak evidence using the affected pedigree-member (APM) method. Our results confirm an APOE ϵ4 association with late-onset familial AD and indicate that susceptibility genes can easily be missed when using standard lod score and APM genetic linkage analysis. © 1996 Wiley-Liss, Inc.     

Memory performance and the apolipoprotein E polymorphism in a community sample of middle‐aged adults

The apolipoprotein E genotype (APOE) is an established risk factor for Alzheimer disease, with the age‐at‐onset occurring earlier in individuals having at least one APOE ϵ4 allele, relative to the APOE ϵ3 or APOE ϵ2 isoforms. Moreover, nondemented older adults with the APOE ϵ4 allele also show diminished cognitive performance, particularly on tests of learning and memory, and an accelerated decline in memory performance with increasing age. The current investigation extends the study of the APOE ϵ4 allele and cognitive performance to healthy, middle‐aged adults. A community sample of 220 non‐Hispanic Caucasian men and women, aged 24–60 (average age = 46), were genotyped for the APOE polymorphism and completed a battery of neuropsychological tests. Multivariate analyses were conducted on measures of verbal learning and memory (e.g., learning a list of words and recalling them 30 min later), visual memory (e.g., reproducing a previously copied figure from memory), and attention span (e.g., repeating long lists of digits), after adjustments for age, and estimated IQ. Results indicated that performance on learning and memory tasks was significantly poorer in adults having any APOE ϵ4 allele, relative to adults with APOE ϵ2 and ϵ3 genotypes (P < .01). Attention span did not differ by genotype. These findings, the first in a sample of middle‐aged adults, suggest that the APOE polymorphism is a marker for age‐related decline in memory (detectable prior to overt, clinical manifestations of memory loss), and/or a marker for individual differences in memory ability across the life span. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:707–711, 2000. © 2000 Wiley‐Liss, Inc.     

Maternal and neonatal interleukin-1 receptor antagonist genotype and pregnancy outcome in a population with a high rate of pre-term birth

Problem We evaluated associations between a length polymorphism in intron 2 of the gene coding for IL‐1ra (gene symbol IL1RN) and pregnancy outcome in a population with a high rate of preterm birth. Method of study Subjects were pregnant women in Maceio, Brazil and their newborns. DNA was tested for IL1RN genotypes and alleles by gene amplification using primer pairs that spanned the polymorphic region. Every subject completed a detailed questionnaire. Results The frequency of allele 2 (IL1RN*2) carriage was elevated in mothers with a spontaneous preterm birth (SPTB) in the current pregnancy (P = 0.02) and also with a prior preterm delivery (P = .01). Both SPTB with intact membranes (P = 0.01) and SPTB preceded by pre‐term pre‐mature rupture of membranes (P = .03) were associated with IL1RN*2 carriage. A previous fetal demise was more than twice as prevalent in mothers positive for two copies of IL1RN*2. Conclusion Maternal carriage of IL1RN*2 increases susceptibility to inflammation‐triggered spontaneous pre‐term birth.     

Association between presenilin-1 -48C/T polymorphism and Down's syndrome

Individuals with Down's syndrome (DS), i.e., trisomy 21, over 40 years of age, are likely to develop neuropathological changes characteristic of Alzheimer's disease (AD). The involvement of chromosome 21 both in DS and AD suggests a shared genetic susceptibility to these disorders, but genetic determinants are still undefined. The -48C/T polymorphism in the PSEN1 promoter is a possible candidate, since it has recently been associated with an increased risk of early onset AD. Based on the assumption that the excess of dementia in DS might be a consequence of a different distribution of the -48C/T polymorphism, we investigated the association between DS and this polymorphism in patients with trisomy 21 and controls. Overall, 260 DS patients and 197 controls were recruited at the Department of Neurosciences, Tor Vergata University of Rome. Cases and controls had similar age and gender distribution. High molecular weight DNA was extracted from whole blood samples collected in EDTANa(2) and -48C/T genotypes were determined. Genotype and allele frequencies were compared between cases and controls. Cases were less likely than controls to have the CC genotype ( P = 0.05). A significant difference for allele distribution between DS cases and controls was found, with DS showing a lower frequency of the allele C compared with the control population (OR: 0.57; 95% CI: 0.35-0.91; P = 0.01). No significant interaction of PSEN1 with age, gender, ApoE and -850 TNF-alpha polymorphisms was found. The association found suggests that the -48C/T polymorphism in the PSN1 gene promoter, which is involved in the modulation of amyloid beta load in human AD, is associated with DS. However, the biological role of this polymorphism in DS-related dementia remains unclear and merits further investigation.     

Folate gene polymorphisms and the risk of Down syndrome pregnancies in young Italian women

Maternal impairments in folate metabolism and elevated homocysteinemia are known risk factors for having a child with Down syndrome (DS) at a young age. The 80G>A polymorphism of the reduced folate carrier gene (RFC-1) has been recently demonstrated to affect plasma folate and homocysteine levels, alone or in combination with the 677C>T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. We performed the present study on 80 Italian mothers of DS individuals, aged less than 35 at conception, and 111 Italian control mothers, to study the role of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C genotypes to the risk of a DS offspring at a young maternal age. When polymorphisms were considered alone, both allele and genotype frequencies did not significantly differ between DS mothers and control mothers. However, the combined MTHFR677TT/RFC-1 80GG genotype was borderline associated with an increased risk (OR 6 (CI 95%: 1.0-35.9), P = 0.05), and to be MTHF1298AA/RFC-1 80(GA or AA) was inversely associated with the risk (OR 0.36 (CI 95%: 0.14-0.96), P = 0.04). Present results seem to indicate that none of the RFC-1 80G>A, MTHFR 677C>T, and MTHFR 1298A>C polymorphisms is an independent risk factor for a DS offspring at a young maternal age; however, a role for the combined MTHFR/RFC-1 genotypes in the risk of DS pregnancies among young Italian women cannot be excluded.     

Systematic genetic study of Alzheimer disease in Latin America: Mutation frequencies of the amyloid β precursor protein and presenilin genes in Colombia*

Nearly all mutations in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid β precursor protein (APP) genes lead to early‐onset Alzheimer disease (EOAD, onset age at or before 65 years). In order to assess the genetic contribution of these genes in a series of Colombian AD cases, we performed a systematic mutation analysis in 11 autosomal dominant, 23 familial, and 42 sporadic AD patients (34% with age of onset ≤ 65 years). No APP missense mutations were identified. In three autosomal dominant cases (27.2%), two different PSEN1 missense mutations were identified. Both PSEN1 mutations are missense mutations that occurred in early‐onset autosomal AD cases: an I143T mutation in one case (onset age 30 years) and an E280A mutation in two other cases (onset ages 35 and 42 years). In addition, a novel PSEN1 V94M mutation was present in one early‐onset AD case without known family history (onset age 53 years) and absent in 53 controls. The E318G polymorphism was present in five AD cases and absent in controls. In PSEN2, two different silent mutations were detected, including one not reported elsewhere (P129). The majority of the Colombian AD cases, predominantly late‐onset, were negative for PSEN and APP mutations. © 2001 Wiley‐Liss, Inc.     

Association between the COMT locus and obsessive‐compulsive disorder in females but not males

A polymorphism in the coding region of catechol‐O‐methyltransferase gene (COMT) was previously reported to be associated with obsessive‐compulsive disorder (OCD), particularly in male probands. We attempted to replicate the previous finding using a family‐based genetic design in haplotype relative risk (HRR) and transmission disequilibrium (TDT) analyses. Fifty‐six OCD probands and their parents were genotyped for the COMT locus using established methods. Analysis of allele and genotype frequencies between the proband genotypes and the control (parental nontransmitted) genotypes failed to replicate the previous finding of gender divergence, gave no evidence of overall association, nor was linkage detected by TDT. However, further analysis of the COMT allele frequencies by proband gender gave evidence of a mildly significant association with the low‐activity COMT allele in female probands (P = 0.049), but not in male probands. These findings indicate that COMT may be etiologically relevant to OCD in a gender‐specific manner opposite to that shown in previous studies. © 2001 Wiley‐Liss, Inc.     

阿尔茨海默病患者早老素-1基因与ApoE基因关联分析

目的：探讨早老素－１（ｐｒｅｓｅｎｉｌｉｎ－１,ＰＳ－１）基因第８外显子３’端内含子,Ａｐｏｌｉｐｏｐｒｏｔｅｉｎ Ｅ（ＡｐｏＥ）基因等位基因多态性相互作用在散发性阿尔茨海默病（ｓｐｏｒａｄｉｃ Ａｌｚｈｅｉｍｅｒ’ｓ ｄｉｓｅａｓｅ,ＳＡＤ）发病机理中的作用。方法：应用聚合酶链反应－限制性片段长度多态性方法检测了７５例ＳＡＤ患者和７３名正常老年人的ＰＳ－１基因第８外显子３’端内含子、ＡｐｏＥ基因等位基因多态性分布。结果：ＰＳ－１、ＡｐｏＥ基因多态性与ＳＡＤ发病有明显关联：ＳＡＤ发病与ＰＳ－１基因的等位基因２呈明显负关联,等位基因１呈明显正关联。ＳＡＤ发病与Ｅ２等位基因呈明显负关联,与Ｅ３、Ｅ４等位基因无关联。ＡｐｏＥ基因多态性和ＳＰ－１基因多态性相互作用对ＳＡＤ发病无明显影响。结论：ＰＳ－１基因的等位基因２和     

A novel KIR3DS1*0130107 allele isolated by sequencing from an Asian donor

This novel KIR3DS1 allele officially named as KIR3DS1*0130107 was isolated from DNA samples from Asia using high‐resolution sequenced‐based techniques. KIR3DS1*0130107 differs from the first member of the KIR3DS1*013 subgroup (KIR3DS1*0130101) by a single mutation at position 8922A>G (intron 5), just nine nucleotides away from the start of exon 6.     

Absence of association between Alzheimer disease and the regulatory region polymorphism of the PS2 gene in an Italian population

Alzheimer disease (AD) is the most common neurodegenerative disorder of aging. Identifying novel AD genetic risk factors is important for understanding its pathogenesis. A recent study demonstrated that the deletion of adenosine in the promoter region of the presenilin 2 gene (PS2) is a susceptibility factor for early-onset AD. The objective of our study was to test the possibility that this variation is associated with AD in the Italian population. A case-control association study was performed, using 200 sporadic AD cases and 160 normal controls matched by age, gender and ethnicity. The current study does not support the notion that the polymorphism in the PS2 gene constitutes a risk factor for either late-onset or early-onset AD, which means that other genetic factors play a role in the development of AD in the Italian population.     

Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency

DNA sequence analysis of the protein S gene (PROS1) in 22 Spanish probands with type I or III PS deficiency, has allowed the identification of 10 different mutations and 2 new sequence variants in 15 probands. Nine of the mutations, 8 of which are novel, cosegregate with type I or quantitative PS deficiency in 12 of the 13 pedigrees analyzed. One of these mutations (Q238X) also cosegregates with both type I and III PS‐deficient phenotypes coexisting in a type I/III pedigree. Another mutation identified in a pedigree with these two PS phenotypes is the missense mutation R520G, present in the homozygous form in the type I propositus and in the heterozygous form in his type III relatives. By contrast, no cosegregating PROS1 mutation has been found in any of the six families with only type III phenotypes. Three of these families, as well as the two families with type I and I/III phenotypes where no other PROS1 mutation has been identified, segregate the P allele of the S460P variant, although this allele does not always cosegregate with the deficient phenotype. From these results we conclude that while mutations in PROS1 are the main cause of type I PS deficiency, the molecular basis of the type III phenotype is probably more complex, with many cases not being explained by a PROS1 mutation. Hum Mutat 14:30–39, 1999. © 1999 Wiley‐Liss, Inc.     

VNTR polymorphism of human IL1RN in Chinese Han and She ethnic populations

Interleukin 1 receptor antagonist (IL‐1Ra) is an important anti‐inflammatory molecule encoded by the IL1RN gene. The polymorphism of IL1RN characterized by variable numbers of an 86 bp tandem repeat (VNTR) sequence in intron 2 has been described. Moreover, frequencies of the IL1RN alleles vary among different ethnics. In the present study, we analysed the IL1RN polymorphism in intron 2 in 256 Chinese Han and 252 Chinese She individuals. Four alleles including IL1RN*1, *2, *3 and IL1RN*4 were identified in this study. Data revealed that the distribution of the IL‐1RN genotypes and allele was significantly different between the two Chinese populations (P < 0.001). Among them, 66.8% (171/256) and 86.5% (218/252) were homozygous for the allele IL‐1RN*1 in Chinese Han and She individuals respectively. Homozygosity for allele IL‐1RN*2 was only observed in Chinese Han with the percentage of 0.8% (2/256). Heterozygosity for IL‐1RN*1/2, IL1RN*1/3 and IL1RN*1/4 was 30.9% (79/256), 0.4% (1/256) and 1.2% (3/256) in Chinese Han, whereas only heterozygosity for IL‐1RN*1/2 was found in Chinese She (13.5%, 34/252). Frequencies of the most common allele IL‐1RN*1 and IL‐1RN*2 were 83.0% and 16.2% for Chinese Han and 93.3% and 6.7% for Chinese She respectively. The rare allele IL‐1RN*3 and IL‐1RN*4 was only observed in the Chinese Han population with the frequency of 0.2% and 0.6% respectively. Our findings suggested that the ethnic background plays an important role in IL‐1Ra gene variation in different populations.     

Pathogenic presenilin 1 mutations (P436S & I143F) in early‐onset Alzheimer's disease in the UK

Familial Alzheimer's disease (AD) is an autosomal dominant disorder characterized by memory impairment and multiple cognitive deficits which occurs in mid to late life. Early onset AD has been associated with mutations in three genes, of which presenilin 1 (PS1) mutations are the most frequent. We sequenced the open reading frame from genomic DNA of a series of 21 early onset AD (AD3) UK families in which there were at least two affected individuals in two or more generations with a diagnosis of probable or definite AD. We found PS1 mutations in six of these families with no sequence variation in the remaining 15. The six families contained between them five different mutations of which two, I143F and P436S, have not been found elsewhere. I143F shows incomplete penetration within the affected family. P436S is the most carboxy‐terminal presenilin 1 mutation reported to date. © 1999 Wiley‐Liss, Inc.