Suk Ling Ma

Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis.

Study Design. A genetic association study to comprehensively investigate variations of melatonin receptor 1B gene polymorphism by a set of tagging single nucleotide polymorphisms (tagSNPs) derived from the International Hapmap project. Objectives. To determine whether melatonin receptor 1B (MTNR1B) gene polymorphisms are associated with the predisposition and/or disease severity of adolescent idiopathic scoliosis (AIS). Summary of Background Data. Linkage studies suggested a genetic predisposition for AIS. In addition, evidence showed that AIS might be related to melatonin deficiency and dysfunction of melatonin signaling pathway. Locating in one of the chromosomal regions linked to AIS, MTNR1B gene is a potential candidate gene for AIS. Methods. This study was carried out in 2-stage case-control analysis: 1) initial screening (472 cases and 304 controls) and 2) separate replication test (342 cases and 347 controls) to confirm results in the screening. In the first screening stage, 5 tagSNPs were selected to cover most of the genetic variation in the MTNR1B gene. In the second stage, SNPs showing association in the screening stage were studied in a separate replication sample set to confirm the association. Genotyping was performed by PCR-RFLP. Results. The first stage showed a putative association between rs4753426 and AIS, which was confirmed in the replication sample set. By meta-analysis, the frequency of C allele of this SNP locating in the promoter was significantly higher in the cases than controls (P = 0.006 aftermeta-analysis). Subjects with the CC genotype had an odds ratio of 1.29 for AIS. Another SNP rs741837 in promoter region, being moderate linkage disequilibrium with rs4753426, was also marginally associated with AIS. Conclusion. Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene.

The association between promoter polymorphism of the interleukin-10 gene and Alzheimer's disease

The importance of the role of inflammation has been suggested in the pathogenesis of Alzheimers disease (AD). Interleukin-10 (IL-10) is an anti-inflammatory cytokine that may modulate the progression of the disease through the inhibition of the action of pro-inflammatory cytokines. In this study, three polymorphisms in the regulatory region of the IL-10 gene (-1082, -819 and -592) in 95 Chinese AD patients and 117 age-matched healthy Chinese subjects were investigated. We found that among the Chinese population, the A and C alleles at the -592 position are strongly linked to the T and C alleles at the -819 position, respectively. A strong association with AD was found for these two IL-10 polymorphisms, which are in complete linkage disequilibrium (-592C and -819C), and the odds ratio of AD is 4.03 (95% CI 1.23-13.23; p = 0.011). The functional significance of the IL-10 genotype was further supported by the significant association between plasma IL-10 concentrations and genotypes that were found in an independent sample of 160 healthy male volunteers. No interaction effect between the ApoE and IL-10 genotypes is found. Therefore, we concluded that the functional polymorphisms of the IL-10 gene act as a risk factor for AD.

Apolipoprotein E ε4 Allele Is Associated with Vascular Dementia

Background/Aims: The apolipoprotein E (ApoE) exon 4 polymorphism has been associated with vascular dementia (VaD) risk. Since not all studies confirm this finding, we explored this association in a case-control study. Methods: We genotyped ApoE in 144 VaD patients and 251 controls. Results: VaD patients were more likely than controls to have ApoE Ε3/Ε4 or Ε4/Ε4 genotypes: 23.6% versus 15.1%, odds ratio (OR) = 1.7, p = 0.036. This association remained significant after adjustment for age, sex, hypertension and diabetes by multiple logistic regression: OR = 1.9, p = 0.030. The association of Ε3/Ε4 or Ε4/Ε4 genotypes with VaD was strong among people with hypertension (OR = 2.9, p = 0.007) or diabetes (OR = 6.5, p = 0.011). The association was absent among people without hypertension (OR = 1.1, p = 0.79) or diabetes (OR = 1.3, p = 0.43). Conclusion: This interaction with hypertension and diabetes should be examined in other studies to confirm or refute this observation.

Prolyl isomerase Pin1 promotes amyloid precursor protein (APP) turnover by inhibiting glycogen synthase kinase-3β (GSK3β) activity: novel mechanism for Pin1 to protect against Alzheimer disease.

Background: Increased amyloid precursor protein (APP) contributes to Alzheimer disease (AD), but how its protein stability is regulated is unclear. Results: Pin1 inhibits glycogen synthase kinase-3β (GSK3β) and thereby reduces APP phosphorylation and promotes its protein turnover. Conclusion: Pin1 promotes APP protein turnover by inhibiting GSK3β activity. Significance: This study provided a novel mechanism for Pin1 to protect against AD. Alzheimer disease (AD) is characterized by the presence of senile plaques of amyloid-β (Aβ) peptides derived from amyloid precursor protein (APP) and neurofibrillary tangles made of hyperphosphorylated Tau. Increasing APP gene dosage or expression has been shown to cause familial early-onset AD. However, whether and how protein stability of APP is regulated is unclear. The prolyl isomerase Pin1 and glycogen synthase kinase-3β (GSK3β) have been shown to have the opposite effects on APP processing and Tau hyperphosphorylation, relevant to the pathogenesis of AD. However, nothing is known about their relationship. In this study, we found that Pin1 binds to the pT330-P motif in GSK3β to inhibit its kinase activity. Furthermore, Pin1 promotes protein turnover of APP by inhibiting GSK3β activity. A point mutation either at Thr-330, the Pin1-binding site in GSK3β, or at Thr-668, the GSK3β phosphorylation site in APP, abolished the regulation of GSK3β activity, Thr-668 phosphorylation, and APP stability by Pin1, resulting in reduced non-amyloidogenic APP processing and increased APP levels. These results uncover a novel role of Pin1 in inhibiting GSK3β kinase activity to reduce APP protein levels, providing a previously unrecognized mechanism by which Pin1 protects against Alzheimer disease.

A PIN1 polymorphism that prevents its suppression by AP4 associates with delayed onset of Alzheimer's disease

Alzheimers disease (AD), the most common form of dementia, is characterized by the presence of neurofibrillary tangles composed of tau and senile plaques of amyloid-beta peptides (Aβ) derived from amyloid precursor protein (APP). Pin1 is a unique prolyl isomerase that has been shown to protect against age-dependent neurodegeneration by acting on phosphorylated tau and APP to suppress tangle formation and amyloidogenic APP processing. Here we report a functional polymorphism, rs2287839, in the Pin1 promoter that is significantly associated with a 3-year delay in the average age at onset (AAO) of late-onset AD in a Chinese population. More significantly, the Pin1 polymorphism rs2287839 is located within the consensus binding motif for the brain-selective transcription factor, AP4 (CAGCTG) and almost completely abolishes the ability of AP4 to bind and suppress the Pin1 promoter, as shown by chromatin immunoprecipitation, electrophoretic mobility shift assay, and promoter luciferase assay. Moreover, overexpression or knockdown of AP4 resulted in an 80% reduction or 2-fold increase in endogenous Pin1 levels, respectively. Thus, AP4 is a novel transcriptional repressor of Pin1 expression and the Pin1 promoter single nucleotide polymorphism (SNP) identified in this study that prevents such suppression is associated with delayed onset of AD. These results indicate that regulation of Pin1 by AP4 plays a critical role in determining age at onset of AD and might be a novel therapeutic target to delay the onset of AD.

Association between tumor necrosis factor-α promoter polymorphism and Alzheimer’s disease

Tumor necrosis factor-α (TNFα) gene polymorphisms have been reported to be associated with Alzheimer’s disease (AD) in Caucasian populations. Three TNFα polymorphisms (−857, −863, and −1,031) were studied in a Chinese population. A high-risk TNFα haplotype (−1,031C-863C-857C) with an odds ratio of 2.54 (95% CI 1.37 to 4.79) for AD was identified. No interaction effect of APOE and TNFα genotypes was found, but both acted as important risk factors for AD.

Low-density lipoprotein receptor-related protein 8 (apolipoprotein E receptor 2) gene polymorphisms in Alzheimer's disease

Apolipoprotein E (ApoE) isoforms affect the risk of developing Alzheimers disease (AD). ApoE-associated risk may be related to its binding to and clearance by cell surface receptors, such as the members of the low-density lipoprotein (LDL) receptor family. Previous studies had shown association of LDL receptor-related protein (LRP) and AD, therefore we speculated that another member of this LDL receptor family, LRP8 (also called apolipoprotein E receptor 2 or ApoER2), which is predominantly expressed in brain, might be associated with Alzheimers disease. To explore this hypothesis, we screened exons 2-19 of the LRP8 gene in a total of 204 AD and 184 elderly control subjects for polymorphisms using the conformation-sensitive gel electrophoresis method. Our results revealed four sequence alterations: two predicted to result in amino acid changes (E46D and R952Q), one in an intron (IVS9 + 7G > A), and one synonymous polymorphism (2622T > C). The latter was found in four AD patients (2.0%) and 11 controls (6.0%), a significant difference (P = 0.042). Further study is needed to confirm this possible association of LRP8 with AD.

Polymorphisms of the cholesterol 24-hydroxylase (CYP46A1) gene and the risk of Alzheimer's disease in a Chinese population.

BACKGROUND An increasing number of studies have suggested a link between cholesterol metabolism and Alzheimers disease (AD), which may be mediated by its effect on amyloid processing. Intracranial cholesterol is primarily eliminated into the bloodstream through conversion into 24-hydroxycholesterol by the enzyme cholesterol 24-hydroxylase (encoded by the CYP46A1 gene). CYP46A1 is an essential gene modulating cholesterol metabolism in the brain. METHOD To investigate whether polymorphisms in the CYP46A1 gene modulate the risk of AD, we studied four common polymorphisms (IVS1-192, IVS2-150, IVS3-128 and IVS4-122) in 182 Chinese AD patients and 179 age-matched healthy Chinese subjects. RESULTS AND CONCLUSION We found that the IVS3-128 polymorphism was associated with the risk of AD (p < 0.05). Subjects homozygous for the C alleles were protected from AD with an adjusted odds ratio (OR) of 1.53 [95% confidence interval (95% CI) 0.98-2.37, p = 0.047]. However, another minor allele, IVS1-192 C, was more prevalent in the AD group and was associated with an increased risk. Haplotype analysis revealed that two of the eight common haplotypes formed by the four polymorphisms were rarely found in the AD group, suggesting a protective effect of these two haplotypes (GTCA and CCTA). The results supported the involvement of the CYP46A1 gene and cholesterol metabolism in the pathogenesis of AD.

Lack of Association of the Interleukin-1β Gene Polymorphism with Alzheimer’s Disease in a Chinese Population

Over the past few years, a number of genetic risk factors for Alzheimer’s disease (AD) have been proposed. IL-1β gene polymorphism such as IL-1β-511 and IL-1β+3953 have been reported to be associated with the risk of AD in a number of studies in a Caucasian population. However, conflicting results have been reported recently which showed that IL-1β was not universally associated with the risk of AD in other populations. In order to validate these associations, we investigated the IL-1β polymorphisms (IL-1β-31, IL-1β-511 and IL-1β+3953) in a Chinese population, which has not been studied before. In our study, the allelic frequencies of IL-1β-31C, IL-1β-511T and IL-1β+3953T for the AD group were 0.49, 0.57 and 0.03, respectively. The allelic frequencies of IL-1β-31C, IL-1β-511T and IL-1β+3953T for the control group were 0.53, 0.61 and 0.03, respectively. No significant difference was detected in the genotypic or allelic frequencies (p > 0.25). We conclude that IL-1β polymorphism is unlikely to be a significant risk factor for AD in the Chinese Population.

Telomere length and cognitive function in southern Chinese community-dwelling male elders

BACKGROUND telomere attrition has been associated with an increased risk of different age-related diseases and is widely accepted as a marker of cellular ageing. On the other hand, it is well known that cognitive function declines with age. The telomere length may therefore act as a marker for the pathway associated with cognitive function. METHODS we examined telomere length and cognitive functions in a community-dwelling Chinese male population aged 65 years and above living in Hong Kong. The telomere length was measured by quantitative real-time PCR in 976 men. Cognitive function was assessed by Chinese (Cantonese) version of Mini-Mental State Exam and Community Screening Interview for Dementia. RESULTS our result showed there was a significant association between telomere length, delayed recall (P = 0.007) and category verbal fluency (P = 0.048). These associations remained significant after adjustment for age and education. Further analysis using a cut-off score for MMSE, three-item recall and word list generation tests suggested that the telomere length was positively correlated with performance in these areas (P = 0.015). CONCLUSION the findings support the association of telomere length and cognitive function and suggested that the telomere length may serve as a biological marker for cognitive decline.