Cholesteryl ester transfer protein polymorphism D442G associated with a potential decreased risk for Alzheimer's disease as a modifier for APOE epsilon4 in Chinese.

There is compelling evidence indicating that reduction of high-density lipoprotein (HDL) level is associated with increased risk of Alzheimer's disease (AD). It is known that the levels of HDL are regulated by cholesteryl ester transfer protein (CETP) and several single nucleotide polymorphisms (SNPs) in the CETP gene have been shown to be associated with the levels of HDL. Therefore, it is assumed that the CETP gene is a reasonable candidate for modifying the susceptibility in AD. In the present study, we investigated the association of four CETP SNPs (D442G, L296Q, Taq1B and I405V) with the risk for sporadic AD in Northern Han-Chinese. One hundred and seven AD cases and 115 age and gender-matched controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. The frequency of DG genotype (P=0.035) or G allele (P=0.038) for the CETP (D442G) polymorphism was greater in control subjects than in AD patients. The age- and sex-adjusted odds radio for DG vs. DD genotype was 0.202 (95% CI 0.043-0.958, P=0.044). When the sample was stratified by APOE epsilon4 carrier status, the same tendency (P=0.042 for DG genotype, P=0.046 for G allele) was observed in the presence of APOE epsilon4, but not in the absence of APOE epsilon4 (P=0.284 for DG genotype, P=0.298 for G allele). However, these results became not statistically significant after correcting for multiple testing (Bonferroni) because of limited number of our sample. Our current results suggest that G allele of CETP D442G may have a potential protective effect against the development of AD, especially in APOE epsilon4 carriers, in Northern Han-Chinese, possibly through regulating the HDL level in the brain.

[PINK1 IVS5-5 G>A polymorphism may contribute to the risk of late onset Parkinson disease in Chinese].

OBJECTIVE: To investigate the possible association of IVS5-5G>A polymorphism, positioned in the upstream region of exon 5 of PINK1 gene with the risk for sporadic late onset Parkinson disease (LOPD) in Chinese. METHODS: Intronic regulatory sequence analysis was performed using the web-based in-silico analysis. The authors performed an association study using a case-control series (comprising 382 LOPD patients and 336 controls, Chinese of Han ancestry). Genotyping was performed by PCR-based denaturing high performance liquid chromatography (DHPLC) combined with sequencing analyses. Allele and genotype frequencies were compared by the Chi-square test. RESULTS: In-silico analysis showed that the intronic IVS5-5G>A polymorphism was located within acceptor site of exon 5 and may be the functional single polymorphism (SNP) in the regulatory region with impact on the splicing of PINK1 gene. Those result yielded statistical significant evidence for the association of PINK1 IVS5-5G>A polymorphism with risk for typical PD in Chinese Han population (OR=1.95, 95%CI: 1.29-2.94, P=0.0012). Homozygote of A allele may have increased risk for LOPD (OR=2.45, 95%CI: 1.27-4.72, P=0.009). CONCLUSION: The authors provide the first evidence that the common genetic variation PINK1 IVS5-5G>A may contribute to the risk of LOPD in Chinese population.

[Polymorphisms of neural nicotinic cholinergic receptor alpha 4 gene of Chinese].

OBJECTIVE: To screen for polymorphisms in alpha 4 subunit (principal subunit of nAChR) gene (CHRNA4). METHODS: DNA was extracted from leukocytes of all subjects including 100 healthy senior people and 100 patients with Parkinson's disease (PD). The exons and adjacent intron regions of CHRNA4 were amplified with PCR. SNPs were screened by denatured high performance liquid chromatography (DHPLC) techniques and restriction fragment length polymorphisms. Potential mutations were confirmed by sequencing. RESULTS: Total 10 polymorphisms were detected and identified in coding and adjacent intron regions of nAChR alpha 4 gene, that are 420C/T (0.873/0.127), 870C/T (0.828/0.172), 1440A/C (0.858/0.142), 1860C/T (0.738/0.262), 1890C/T (0.605/0.395), intron 5 +14T/C (0.553/0.447), intron 2 +22G/A (0.873/0.127), intron 3 +182 Del22bp (0.813/0.187), 1758C/T and 1809C/T (reference for coding sequence is GenBank SNPs 000744), of which the last three are novel mutations. PD patients appeared higher frequency of deletion in intron 3+182(0.235) than normal controls (0.140)(P=0.015). CONCLUSION: nAChR alpha 4 gene is polymorphic. PD patients take higher frequency of intron3+182 Del 22 bp.

Association between acyl-coenzyme A: cholesterol acyltransferase gene and risk for Alzheimer's disease in Chinese.

There is a compelling body of evidence indicating an association between cholesterol and Alzheimer's disease (AD). Acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), an endoplasmic-reticulum-resident enzyme that catalyses the formation of cholesteryl esters (CEs) from cholesterol and long-chain fatty acids, modulates the generation of beta amyloid peptide (Abeta). A single nucleotide polymorphism rs1044925 in the sterol O-acyltransferase 1 (SOAT1), the gene encoding ACAT1, has been reported to be association with an increased risk for sporadic AD (SAD) in European population. In the present study, we examined the association of the SOAT1 rs1044925 polymorphism with SAD in our northern Han-Chinese (107 cases, 118 age and gender-matched controls) sample using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. There was no genotypic (chi(2)=0.030, OR 0.942, 95% CI=0.478-1.857) or allelic (chi(2)=0.021, OR 0.955, 95% CI=0.508-1.794) association between SAD and controls, even when the data were stratified by APOEvarepsilon4 carrier status. Our results indicate that the polymorphism rs1044925 in the 3'UTR of SOAT1 gene does not affect the risk of SAD in the northern Han-Chinese.

[NQ01 gene polymorphism C609T associated with an increased risk for cognitive dysfunction and sporadic Alzheimer's disease in Chinese].

OBJECTIVE: To investigate the association between the C609T polymorphism of NADP (H): quinoneoxidoreductase 1 (NQ01) gene and decreased cognitive function and sporadic Alzheimer's disease (AD) in a community cohort. METHODS: Polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC) and sequencing were used to determine the genotype of NQ01 in 110 subjects without cognitive dysfunction, 21 with cognitive dysfunction, and 65 AD patients from a community cohort. RESULTS: Significantly different distributions of C/T and T/T genotypes were found between MMSE normal and abnormal subjects (OR=2.8, 95%CI 0.96-8.18, P=0.024), and between AD patients and healthy controls (OR=3.27, 95% CI 1.54-6.94, P=0.001), respectively. The frequencies of T allele of NQ01 C609T were significantly higher in MMSE abnormal subjects and AD patients (P=0.034 and 0.005) as compared to normal controls. CONCLUSION: The C609T polymorphism of NQ01 gene may be a genetic risk factor for cognitive dysfunction and sporadic AD in Chinese population.

[New polymorphism (IVS3-20 T-->C) of the parkin gene associated with the early-onset Parkinson's disease in Chinese].

OBJECTIVE: To investigate the association between a new polymorphism (IVS3-20 T>C GenBank accession number: AY463003) in intro 3 of the parkin gene and the risk for Parkinson's disease (PD) in Chinese, particularly the relation between this polymorphism and the age of onset of PD patients. METHODS: PD was diagnosed according to the criteria of Core Assessment Program for Intracerebral Transplantations(CAPIT). All patients and controls were examined by two neurologists and were of the Han ethnic background. Polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC) and sequencing were used to determine the genotype of each subject. RESULTS: A total of 312 PD patients (including 99 early-onset PD patients and 213 late-onset PD patients) and 236 controls were studied. The C/C homozygote was not found in this study. Chi-square analysis revealed that the frequencies of the C allele and T/C genotype were higher in total PD group but were not statistically different from those of the control group (P=0.6350 and 0.6331, respectively). After being stratified by age of onset, the frequency of T/C genotype was significantly higher (OR=3.52, 95%CI 0.97-13.13) in PD group with an onset age at or below 45 years old (7.07%), compared with that in the control group (2.12%). Similarly, C allele was much higher (OR=3.42, 95%CI 0.96-12.57, P=0.0276) in the early-onset PD group (3.90%) than that in the control group (1.06%). The linear trend analysis showed that both the T/C genotype and C allele increased significantly in the PD group with the increase of the onset age [chi-square(trend of Genotypes)=4.414, P=0.036; chi-square(trend of Alleles)=4.344, P=0.037]. On the other hand, there was no difference in the frequencies of allele and genotype between the late-onset PD patients and controls. CONCLUSION: The above results suggest that the parkin IVS3-20 T>C polymorphism might be a genetic risk factor for early-onset PD in Chinese.

[Relationship between the Fnu4HI site polymorphism of monoamine oxidase A gene and Parkinson's disease].

OBJECTIVE: To study the association between the polymorphism of human monoamine oxidase type A (MAO-A) gene and Parkinson's disease(PD). METHODS: Fnu4HI restriction fragment length polymorphism(RFLP) and PCR-RFLP were used to detect the mutation of MAO-A gene. The frequencies of alleles and genotypes at the MAO-A Fnu4HI locus on the X chromosome in different PD group were compared with those of the control group. RESULTS: It was found that the frequencies of G allele in the patients with PD and controls were 0.613 and 0.527 respectively, P=0.039 "the frequencies of TT genotype were 0.303 and 0.415(P=0.014), and the frequencies of GG genotype were 0.564 and 0.451 respectively(P=0.021). When the patients were divided into two groups by age-onset, significant difference in the allelic and genotypic frequencies was observed only between early-onset PD group and control group. And when the PD patients were grouped by sex, significant difference was observed only between male PD group and male control group (the frequencies of G allele being 0.669 and 0.500 respectively, P=0.005). CONCLUSION: This study revealed significant differences between PD group and control group in allelic and genotypic frequencies. The findings supported the hypothesis about an association between MAO-A gene and PD, suggesting that age at onset of PD and gender predisposition might be related to the putative association, and Fnu4HI SNP be a risk factor for PD.

[Association between NAD(P)H: quinone oxidoreductase and apolipoprotein E gene polymorphisms in Alzheimer's disease].

OBJECTIVE: To assess the association between NAD(P)H: quinone oxidoreductase 1 (NQO1) C609 T allele and apolipoprotein E (ApoE) polymorphism and sporadic Alzheimer disease (SAD). METHODS: The polymorphisms of NQO1 and ApoE gene were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 92 SAD patients and 108 normal controls, all of Han nationality. RESULTS: The frequencies of mutant T allele and T/C + T/T genotype at nucleotide position 609 of NQO1 gene were 56% and 89% respectively in the patients with SAD, significantly higher than those in the controls (45% and 71% respectively) with an odds ratio of 1.56 (for mutant T allele) and of 3.301 (for genotype) respectively. The frequency of the ApoE2 allele was significantly lower in the SAD patients than in the controls (chi(2) = 3.753, P < 0.05) and the frequency of ApoE4 was higher in the SAD patients, however, without a statistically significant difference (chi(2) = 1.863, P = 0.172). No significant interaction was found between NQO1 C609T and ApoE polymorphisms in SAD patients. CONCLUSION: NQO1 C609T may be an independent genetic risk factor for SAD in Chinese.