Analysis of seven maternal polymorphisms of genes involved in homocysteine/folate metabolism and risk of Down syndrome offspring.

PURPOSE: We present a case-control study of seven polymorphisms of six genes involved in homocysteine/folate pathway as risk factors for Down syndrome. Gene-gene/allele-allele interactions, haplotype analysis and the association with age at conception were also evaluated. METHODS: We investigated 94 Down syndrome-mothers and 264 control-women from Campania, Italy. RESULTS: Increased risk of Down syndrome was associated with the methylenetetrahydrofolate reductase (MTHFR) 1298C allele (OR 1.46; 95% CI 1.02-2.10), the MTHFR 1298CC genotype (OR 2.29; 95% CI 1.06-4.96), the reduced-folate-carrier1 (RFC1) 80G allele (1.48; 95% CI 1.05-2.10) and the RFC1 80 GG genotype (OR 2.05; 95% CI 1.03-4.07). Significant associations were found between maternal age at conception > or = 34 years and either the MTHFR 1298C or the RFC 180G alleles. Positive interactions were found for the following genotype-pairs: MTHFR 677TT and 1298CC/CA, 1298CC/CA and RFC1 80 GG/GA, RFC1 80 GG and methylenetetrahydrofolate-dehydrogenase 1958 AA. The 677-1298 T-C haplotype at the MTHFR locus was also a risk factor for Down syndrome (P = 0.0022). The methionine-synthase-reductase A66G, the methionine-synthase A2756G and the cystathionine-beta-synthase 844ins68 polymorphisms were not associated with increased risk of Down syndrome. CONCLUSION: These results point to a role of maternal polymorphisms of homocysteine/folate pathway as risk factors for Down syndrome.     

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.     

Common variation in GRB-associated Binding Protein 2 (GAB2) and increased risk for Alzheimer dementia

GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onset Alzheimer dementia (AD) risk in carriers of the APOE epsilon4 allele in a genome-wide association analysis. We aimed to investigate this association in a well-characterized Belgian late-onset AD patient/control group: 528 Belgian AD patients (mean onset age 79.0+/-5.2 years, 70.2% females) and 601 ethnically matched control individuals (mean age 61.9+/-15.3 years, 57.1% females) were genotyped for 10 SNPs across the GAB2 locus. For 2 SNPs the most common genotype was associated with risk for AD, with the most significant result for rs4945261 [OR 1.49 (95%CI 1.04-2.15)]. After stratification by presence or absence of APOE epsilon4 these associations were present in APOE epsilon4 carriers only. When assessing the effect of APOE and rs4945261 in one model, rs4945261 did not show a main effect, but the joint risk effect of rs4945261-GG and APOE epsilon4 on AD was significant (OR 3.87, 95%CI 2.66-5.63; p=1.0E-12), with a deviation of 1.87 from the multiplicative model of interaction. Haplotype analyses showed evidence of association in the total (global p(sim) 0.04) and APOE epsilon4+ (global p(sim) 0.02) but not in the APOE epsilon4 - group (global p(sim) 0.6). The association was driven by a higher frequency of the major haplotype in patients. Our data independently replicate an association between GAB2 and late-onset AD, which appears to be limited to APOE epsilon4 carriers.     

Low erythrocyte folate status and polymorphic variation in folate-related genes are associated with risk of neural tube defect pregnancy

Previous studies have shown conflicting findings in linking polymorphic variation in folate-related genes to the risk of neural tube defect pregnancy. Recent evidence points to maternal genotype being important in determining NTD risk. A case-control study was undertaken in 97 mothers of NTD cases from the northern region of the UK. Pregnant controls (n = 190) from a regional DNA bank and non-pregnant controls (n = 100) from the same geographical area were recruited. MTHFR 677C >T, MTHFR 1298A >C, MTRR 66A >G, SHMT 1420C >T, CbetaS 844ins68, and RFC-1 80G >A allele and genotype frequencies were determined and odds ratios (OR) calculated. Erythrocyte folate levels for cases and controls were also measured and a comparison made of median erythrocyte folate levels stratified according to genotype. The MTHFR 677C >T variant was not shown to be an independent NTD risk factor in mothers of NTD-affected pregnancy. A second polymorphism in MTHFR, 1298A >C, was less frequently observed in mothers of NTD cases (OR [95% CI]=0.57 [0.33, 0.97]). Possession of compound 1298A >C and 677C >T variants elevated risk of NTD pregnancy considerably (TT/AC+TT/CC vs CC/AA OR [95% CI]=6.56 [1.10, 39.33]). Erythrocyte folate levels were persistently lower in NTD mothers (p = 0.001) despite assays being conducted many years after the index pregnancy (17.6+/-12.6 years). Erythrocyte folate levels were depressed in the presence of the MTHFR 677C >T variant.     

Infants' MTHFR polymorphisms and nonsyndromic orofacial clefts susceptibility: A meta-analysis based on 17 case-control studies

Methylenetetrahydrofolate reductase (MTHFR), an important enzyme in folate metabolism, is thought to be involved in the development of nonsyndromic orofacial clefts (NSOC). However, conflicting results have been achieved when evaluating the associations between infants' MTHFR C677T and A1298C polymorphisms and the risk of NSOC. To obtain more precise estimations of these associations, a meta-analysis recruiting 17 case-control studies was performed. Among Asians we found that CT heterozygote, TT homozygote, and CT/TT of infants' MTHFR C677T variant could contribute to elevated risks of NSOC, compared with CC wild-type homozygote (OR?=?1.741, 95% CI?=?1.043-2.907 for CT vs. CC, OR?=?2.311, 95% CI?=?1.313-4.041 for TT vs. CC, and OR?=?1.740, 95% CI?=?1.051-2.882 for CT/TT vs. CC, respectively). Similar effect was also observed on MTHFR 677T T allele, when using C allele as a reference in Asians (OR?=?1.420, 95% CI?=?1.191-1.693, for T allele vs. C allele). Furthermore, in stratified analysis by types of disease, CT/CC was suggested to confer decreased susceptibility to CL/P under recessive genetic model (OR?=?0.854, 95% CI?=?0.730-1.000). For MTHFR A1298C, the MTHFR 1298C allele in the case group of Caucasians was significantly lower than that in the control group, suggesting a protective effect against NSOC in Caucasian populations (OR?=?0.711, 95% CI?=?0.641-0.790, for C allele vs. A allele). In conclusion, the meta-analysis provided confirmative evidences that infants' MTHFR C677T and A1298C polymorphisms were involved in the development of NSOC. ? 2012 Wiley Periodicals, Inc.     

载脂蛋白E、白细胞介素-1α基因多态性与成都地区阿尔茨海默病的关联分析

目的　探讨载脂蛋白E(apolipoprotein E,APOE)和白细胞介素 - 1α(interleukin- 1α,IL- 1α)基因多态性与成都地区阿尔茨海默病 (Alzheimer's disease,AD)的关系。方法　用聚合酶链反应 -限制性片段长度多态性技术检测成都地区流行病学调查中诊断为 AD的 114例患者和 113名健康老年人 APOE基因和 IL - 1α基因多态性。结果　中度、重度 AD组含 APOEε4基因型频率 (2 8.6 % )显著高于轻度 AD组 (18.5 % )和正常对照组 (14 .2 % ) ,其中中度、重度 AD组与正常对照组差异有显著性 (OR=2 .4 ,95 % CI:1.1～5 .5 )。将ε4等位基因频率与ε2和ε3等位基因频率之和比较 ,中度、重度 AD组与正常对照组的差异有显著性 (OR=2 .6 ,95 % CI:1.3～ 5 .3)。 AD患者组和正常对照组 IL - 1α基因型和等位基因频率分布相似 ,差异无显著性 (P>0 .0 5 )。结论　 APOEε4等位基因与中、重度 AD相关联 ,是中、重度 AD的易感因素。 IL - 1α基因多态性与中国成都地区 AD患者无关联。     

The C677T methylenetetrahydrofolate reductase mutation is not associated with Alzheimer's disease.

The methylenetetrahydrofolate reductase (MTHFR) gene has been recently considered as a candidate gene for Alzheimer's disease (AD). MTHFR is a key enzyme in the metabolism of homocysteine and elevated levels of that amino acid have been associated to Vascular Dementia and AD. A T-->C transition at codon 677 produces a thermolabile type of the enzyme. However, contrasting results on the distribution of the MTHFR C677T common polymorphism in AD have been published. We analyzed the distribution of the MTHFR and apolipoprotein E (APOE) polymorphisms in Italian patients with sporadic AD. The distribution of the C677T polymorphism did not differ in AD and controls. Our data suggest that the MTHFR polymorphism does not contribute to genetic susceptibility in Italian sporadic AD and does not mitigate the effect of ApoE epsilon4 allele on AD risk.     

Maternal gene polymorphisms involved in folate metabolism as risk factors for Down syndrome offspring in Southern Brazil

This study aimed to investigate the role of maternal polymorphisms, as well as their risk genotypes combinations of MTR A2756G, MTRR A66G, CBS 844ins68, and RFC A80G, involved in folate/homocysteine metabolism, as possible risk factors for Down syndrome (DS) in Southern Brazil. A case-control study was conducted with 239~mothers of DS children and 197~control mothers. The investigation of polymorphisms was performed by PCR and PCR-RFLP. The distribution of genotypic variants was similar in both groups when they were analyzed separately. An investigation of combined risk genotypes showed that the risk of having a DS child for one, two or three risk genotypes was 6.23, 6.96 and 5.84 (95%CI 1.48-26.26; 1.69-28.66; 1.37-24.86), respectively. The combined MTRR 66G and MTHFR 677T alleles were significantly more common among mothers of children with DS than among control mothers (OR 1.55; IC 95% 1.03-2.35). The results show that individual polymorphisms studied in this work are not associated with DS; however, the effects of the combined risk genotypes among MTR, MTRR, CBS and RFC genes are considered maternal risk factors for DS offspring in our population.     

Reduced folate carrier polymorphism (80A-->G) and neural tube defects

Transport of folates in mammalian cells occurs by a carrier-mediated mechanism. The human folate carrier (RFC-1) gene has been isolated and characterized. Within this gene, a common polymorphism, 80A-->G, changing a histidine to an arginine in exon 2 (H27R), was recently identified. Defects in folate metabolism, such as defective carrier molecules, could be implicated in the etiology of neural tube defects (NTDs). In the present case-control study, we recruited 174 Italian probands with nonsyndromic NTD, 43 mothers, 53 fathers and 156 control individuals and evaluated the impact of RFC-1 variant on NTD risk. A statistically significant risk was calculated for the 80GG genotype of the NTD cases (OR=2.35; 95% CI 1.21-4.58) and mothers (OR=2.74; 95% CI 0.92-8.38). On the contrary, the heterozygous genotype of the mothers and both heterozygous and homozygous genotypes of the fathers did not seem to be significant NTD risk factors. Furthemore, according to the multifactorial inheritance of NTDs, we demonstrated that the combined genotypes for MTHFR 1298A-->C and RFC-1 80A-->G polymorphisms of cases resulted in greater NTD risk than heterozygosity or homozygosity for RFC-1 80A-->G variant alone. Conversely, our data provide no evidence for an association between NTD phenotype and combined MTHFR C677T/RFC-1 A80G genotypes. Moreover, here we describe the combinations of the two MTHFR polymorphic sites (677CT and 1298AC) with RFC-1 genotypes. We found that both patients and controls could have at most quadruple-mutation combinations. Interestingly, 27% (7/26) of the mothers and 18.75% (30/160) of the cases genotyped presented four mutant alleles in comparison with 8.5% (11/129) of the controls. Finally, the frequency of NTD cases and mothers carrying combined heterozygosity for the two MTHFR polymorphisms and RFC-1 80GG homozygosity (677CT/1298AC/80GG) (cases=11.3%; mothers 11.5%) was increased compared with controls (1.6%). Altogether, our findings support the hypothesis that RFC-1 A80G variant may contribute to NTD susceptibility in the Italian population.     

Polymorphisms of methylenetetrahydrofolate reductase and methionine synthase genes and bladder cancer risk: a case–control study with meta-analysis

Folate deficiency due to the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) variants leads to carcinogenesis by affecting DNA synthesis, repair, and methylation. We hypothesized that the MTHFR C677T, A1298C, and MS A2756G polymorphisms are associated with risk of bladder cancer. In a case-control study of 239 bladder cancer cases and 250 cancer-free controls, we found that the MTHFR 677TT genotype was statistically significantly associated with an increased risk of bladder cancer compared with the 677CC genotype (OR = 2.06, 95% CI = 1.16-3.64). Furthermore, the TA haplotype was associated with a significantly increased bladder cancer risk (OR = 1.38, 95% CI = 1.05-1.81) than was the most common haplotype, CA (e.g., CA denotes MTHFR 677C -1298A). We also found that the combined genotypes with 4-6 variant (risk) alleles (i.e., MTHFR 677T, 1298A, and MS 2756G alleles) were associated with an increased risk of bladder cancer (OR = 1.62, 95% CI = 1.03-2.53) compared with those with 0-3 variants, and this increased risk was more pronounced among subgroup of older people (OR = 1.71, 95% CI = 1.03-2.83). A meta-analysis of seven studies did not show a significant risk of bladder cancer in the MTHFR polymorphisms. The MTHFR polymorphisms and their haplotypes appear to jointly contribute to risk of bladder cancer.     

Association of genetic variants of ABCA1 with Alzheimer's disease risk.

ABCA1 plays key roles in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain. To evaluate the relationship between ABCA1 genetic variants and Alzheimer's disease (AD), independently or in concert with the APOE epsilon4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (C-14T and C-477T) in a group of 372 Spanish AD patients and 440 controls. The ABCA1 219K, 883I, 1587R haplotype was significantly associated with AD, conferring a risk of 1.78 (P = 0.007). The ABCA1 C-14T polymorphism modified the risk of AD in an APOE epsilon4 allele-dependent fashion: in APOE epsilon4 carriers, homozygous for the ABCA1 -14T allele had 3.7 times higher risk of developing AD (OR = 13.99) than carriers of the ABCA1 -14CC and CT genotypes (OR = 3.79). These data suggest that the development of AD might be influenced by either a qualitative change of the ABCA1 protein caused by coding region variants (219K, 883I, and 1587R), or by a quantitative change in ABCA1 expression caused by promoter region variant (-14T) in concert with the APOE epsilon4 allele.     

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 --491 TT apolipoprotein E promoter polymorphism is associated with reduced risk for sporadic Alzheimer's disease

Homozygosity for the A allele of the -491 A/T apolipoprotein E (APOE) promoter polymorphism has recently been reported to be associated with sporadic Alzheimer's disease (AD). Two hundred and fifty one patients with AD and an equal number of controls derived from the same region in a Spanish population, were genotyped for -491 A/T and epsilon2/epsilon3/epsilon4 APOE polymorphisms. We did not detect an elevated -491 AA genotype frequency when comparing AD cases to controls. In contrast, persons homozygous for the T allele were at a significantly reduced risk of AD (odds ratio of 0.10, P=0.006). Multiple logistic regression analysis indicated that the -491 TT polymorphism added information on the risk of AD which was independent of that of the APOE epsilon4 allele.     

Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study

Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three common isoforms: APOE2, -3 and -4. The varepsilon4 allele of the APOE gene ( APOE ) coding for the APOE4 isoform is associated with an increased risk of myocardial infarction (MI) and of Alzheimer's disease (AD). Recently, several polymorphisms in the APOE regulatory region have been reported. Some of these have been associated with AD and modified APOE allelic mRNA expression in AD brains. Here, we have investigated whether three of these promoter polymorphisms (-491AT, -427CT and -219GT) can also modify cardiovascular risk. The hypothesis was tested in a large multicentre case-control study of MI, the ECTIM Study, on 567 cases and 678 controls. Among the three APOE promoter polymorphisms tested, only the-219T allele was associated with a significantly increased risk of MI (OR = 1.29, 95% CI: 1.09-1.52, P < 0.003) and the effect was shown to be independent of the presence of the other mutations, including the APOE epsilon2/epsilon3/epsilon4 polymorphism. Moreover, the-219T allele greatly decreased the APOE plasma concentrations in a dose-dependent manner ( P < 0.008). These data indicate that the-219GT polymorphism of the APOE regulatory region emerges as a new genetic susceptibility risk factor for MI and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases.     

Association between MTHFR 1298A>C polymorphism and spontaneous abortion with fetal chromosomal aneuploidy

PROBLEM Polymorphisms in genes involved in folate metabolism are commonly associated with defects in folate-dependent homocysteine metabolism, which can result in DNA hypomethylation and chromosome nondisjunction. This prospective study aimed to investigate the associations between MTHFR 677C>T, MTHFR 1298A>C, MTR 2756A>G, MTRR 66A>G, and CBS 844ins68 polymorphisms and spontaneous abortion (SA) with fetal chromosomal aneuploidy. METHOD OF STUDY Subjects included 33 SA with normal fetal karyotype, 24 SA with fetal chromosomal aneuploidy and 155 normal controls. Polymorphisms were genotyped by PCR-RFLP and QF-PCR analysis. RESULTS The frequencies of MTHFR 1298AC and combined 1298AC/CC genotypes were higher in SA with fetal chromosomal aneuploidy than in controls. The 1298C allele frequency was also significantly higher in SA with fetal chromosomal aneuploidy than in controls. Moreover, the 1298C allele frequency was higher in SA with fetal chromosomal aneuploidy than in SA with normal fetal karyotype. The combined 1298AC/CC genotype was significantly associated with the risk of SA with fetal chromosomal aneuploidy compared with that of the 1298AA genotype (adjusted OR = 2.93, 95% CI: 1.11-7.69). There was no association between SA with fetal chromosomal aneuploidy and other polymorphisms. CONCLUSIONS Our findings indicate that MTHFR 1298A>C polymorphism may be an independent risk factor for SA with fetal chromosomal aneuploidy.     

PAI-1基因和MTHFR基因多态性与复发性早期自然流产的关系

目的探讨纤溶酶原激活剂抑制物1(plasminogenactivatorinhibitor1,PAI1)基因和亚甲基四氢叶酸还原酶(methylenetetrahydrofolatereductase,MTHFR)基因多态性与复发性早期自然流产(recurrentearlyspontaneousabortion,RESA)的相关性。方法选取127例RESA非妊娠患者和117名健康非妊娠妇女,应用聚合酶链反应限制性片段长度多态性分析技术检测PAI1基因-675位4G/5G多态性和MTHFR基因C677T位点多态性。结果(1)患者组PAI1基因4G/4G基因型频率(45.7%)和4G等位基因频率(66.1%)显著高于对照组(17.1%和46.6%)(P<0.01),与5G/5G基因型比较,4G/4G型患者发生RESA的相对风险率的比数比(oddsratio,OR)为4.8,95%的可信区间(confidenceinterval,CI):2.23～10.35;(2)MTHFR基因T/T基因型和T等位基因频率患者组(43.3%和66.5%)显著高于正常对照组(21.4%和52.6%)(P<0.01),与C/C基因型比较,T/T型患者发生RESA的相对风险率为OR=3.2,95%CI:1.40～7.30;(3)RESA患者若同时兼有4G/4G和T/T基因型时,发生自然流产的相对风险率明显增加,OR=6.20,95%CI:2.62～14.67。结论PAI1基因4G/5G多态性和MTHFR基因C677T位点多态性与不明原因RESA密切相关,易感基因型4G/4G型和T/T型对RESA的发生具有协同作用。     

Methylenetetrahydrofolate Reductase C677T polymorphism and breast cancer risk in Moroccan women

Background

Methylenetetrahydrofolate (MTHFR) enzyme plays an important role in folate metabolism which is involved in DNA methylation, repair, and synthesis.

Objective

We investigated if the MTHFR C677T polymorphism modulates the risk of developing breast cancer in Moroccan women.

Methods

Genotyping was performed by PCR-RFLP method on a sample of 96 patients with breast cancer and 117 controls.

Results

A positive correlation was found between the MTHFR C677T polymorphism and progesterone receptors expression (p= 0.04). According to menopausal status, the heterozygous CT (OR = 2.29 and P = 0.03) was statistically significant in pre-menopausal women. There was a significant association between C677T polymorphism and breast cancer risk in both additive (OR = 2.2, 95% CI = 1.24–3.86, p = 0.007) and dominant (OR = 2.10, CI 95% = 1.21–3.64, p = 0.008) models. In addition, the T allele were associated with a high breast cancer risk (OR = 1.59, 95% CI = 1.04–2.44, p = 0.03).

Conclusion

In the light of our preliminary study, 677T allele and 677CT MTHFR genotype may represent a genetic determinant increasing breast cancer risk in Moroccan women. A larger study including a larger sample size and more information is needed to confirm our conclusions.     

The CDC2 I-G-T haplotype associated with the APOE epsilon4 allele increases the risk of sporadic Alzheimer's disease in Sicily

The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.     

Association between haplotype −88G/25G in A2M with Alzheimer's disease

Alpha 2-Macroglobulin gene (A2M) has been recognized as a candidate gene for late-onset Alzheimer's disease (AD), but the association between several polymorphisms in A2M gene and risk for AD remained controversial. Moreover, little is known regarding the effects of polymorphisms in A2M promoter region on AD susceptibility. Our study aimed to detect polymorphisms in A2M promoter region, and then evaluate their relationship to sporadic AD (SAD). One single nucleotide polymorphism (−88A/G) in proximal promoter region was found by sequencing, and further analyzed with an established 25T/G polymorphism in 179 SAD patients and 179 age-gender-matched controls. Allele A in −88A/G polymorphism was more prevalent in cases, with a 1.7-folded risk for SAD (OR = 1.74, 95%CI 1.05–2.91, P = 0.031), while G allele in 25T/G was less prevalent in cases, with a 43% reduced risk for SAD (OR = 0.57, 95%CI 0.36–0.89, P = 0.013). After adjusted the effects of age, gender and APOE?4 allele status in logistic regression model, the protective effects of −88G and 25G on SAD still remained. Individuals who carried haplotype −88G/25G had a significant 44% reduced risk for SAD compared to those who did not carry (OR = 0.56, 95%CI 0.34–0.94, P = 0.027), while haplotype −88A/25T carriers had an increased risk for SAD compared to those who did not carry (OR = 1.77, 95%CI 1.06–2.96, P = 0.027). Our study supports that haplotype −88G/25G might play a protective role in the development of SAD, and the protective effects of −88G and 25G were independent of APOE?4 allele.