Chuanfang Zhang

Association of MTHFR gene polymorphism C677T with susceptibility to late-onset alzheimer’s disease

Increased total plasma homocysteine (t-Hcy) levels are found to be associated with Alzheimer’s disease (AD). Because the methylenetetrahydrofolate reductase (MTHFR) gene encodes a key enzyme that influences the metabolism of homocysteine, it has been considered as a possible genetic risk factor for AD. Although the MTHFR gene C677T polymorphism has a significant impact on reducing enzyme activity and increasing t-Hcy concentrations, the association between the C677T polymorphism and AD remains inconclusive. To determine whether the MTHFR gene C677T polymorphism contributes to the risk for late-onset AD (LOAD) in Chinese, we have investigated 104 sporadic LOAD patients and 130 healthy controls. The strong associations of the TT genotype and T-allele with LOAD (p=0.001, OR=5.73 95% CI 1.85–17.72, and p=0.002, OR=1.89 95% CI 1.25–2.86) were found. After stratifying by apolipoprotein E allele 4 (APOE ɛ4) status, increased LOAD risks associated with the TT genotype only in the APOE ɛ4 noncarriers (χ2=8.92, df=1, p=0.003) and with the T-allele in either group (χ2=5.18, df=1, p=0.023 and χ2=5.53, df=1, p=0.019) were seen. These results suggest that as an APOE ɛ4 allele-dependent risk factor, the MTHFR gene C677T polymorphism is involved in developing LOAD in Chinese.

Association between a T/C polymorphism in intron 2 of cholesterol 24S-hydroxylase gene and Alzheimer's disease in Chinese

A polymorphism (T/C) in intron 2 of the cholesterol 24-hydroxylase (CYP46) gene has recently been reported to be associated with the risk for late-onset Alzheimers disease (LOAD). To investigate possible involvement of the CYP46 gene and apolipoprotein E (APOE) gene polymorphisms in the manifestation of LOAD, we analyzed 99 sporadic LOAD patients and 113 healthy controls of China. We found an obvious association between CYP46 TT genotype and LOAD (OR = 2.98, 95% CI 1.64-5.44, P < 0.001). A clear increase of the risk to develop LOAD was also observed in subjects carrying both the CYP46 TT genotype and the APOE epsilon4-allele (OR = 12.94, 95% CI 4.26-39.32, P < 0.001). Our data reveal that the polymorphism of CYP46 intron 2 is implicated in the susceptibility to LOAD and a strong synergistic interaction between CYP46 TT homozoygots and APOE epsilon4 carrier status on the risk of LOAD.

Association of the HTR6 polymorphism C267T with late-onset Alzheimer's disease in Chinese

Serotonergic neurotransmitter system has been implicated in the pathogenesis of Alzheimers disease (AD). 5-Hydroxytryptamine (5-HT)(6) receptor is mainly expressed in the brain areas involved in cognitive processes. And 5-HT(6) receptor gene (HTR6) variants may be a genetic risk factor for late-onset Alzheimers disease (LOAD). To assess whether HTR6 increases the risk for LOAD, we carried out an association study between the HTR6 polymorphism C267T and sporadic LOAD in Mainland Chinese. An association of C/T genotype with LOAD (OR = 2.10, P = 0.014) was observed. And no statistical difference was found between cases and controls after stratification for APOE epsilon4 status. These data suggest that the HTR6 polymorphism C267T possibly involved in the susceptibility to LOAD as an APOE epsilon4-allele independent risk factor of LOAD.

Association study between late-onset Alzheimer's disease and the transferrin gene polymorphisms in Chinese.

To investigate the possible involvement of the transferrin (TF) gene polymorphism in the manifestation of Alzheimers disease (AD), we analyzed the TF and apolipoprotein E (APOE) genotypes of 67 sporadic late-onset AD patients and 131 normal elderly controls in the Chinese population. Our data showed that the TF C1 homozygosity carriers had an increased risk of AD in subjects > or =75 years of age, showing that homozygosity for the TF C1 allele was associated with an approximately three-fold increased risk (OR=3.57, 95% CI, 1.24-10.27, P=0.014). No synergic effects were found between the APOE epsilon 4 allele and TF gene polymorphisms.

Genetic association of BACE1 gene polymorphism C786G with late-onset Alzheimer’s disease in Chinese

Abstractβ-Amyloid (Aβ) peptides are derived from the end oproteolytic processing of amyloid precursor protein (APP) and play a key role in the pathogenesis of Alzheimer’s disease (AD). β-Site APP-cleaving enzyme 1 ([BACE1] also known as β-secretase) is responsible for cleaving APP to generate neurotoxic Aβ peptides in patients with AD. The BACE1 gene is located on chromosome 11q23.3, near the recently identified region with increased lod scores for AD. The biological functional and genetic association studies indicated that the BACE1 gene might be a genetic risk factor for late-onset Alzheimer’s disease (LOAD). To investigate an association between the BACE1 C786G polymorphism and sporadic LOAD in Chinese, we examined 105 LOAD patients and 130 healthy controls. Our results showed higher frequency of the 786G-allele in LOAD patients (38.6%) than that in controls (28.5%), and a statistical significance was observed for an association of the G-allele with LOAD (odds ratio [OR]=1.58, 95% confidence interval [CI] 1.07–2.23, p=0.02). We also found a synergetic interaction between the G-allele and apolipoprotein E allele 4 (APOE ε4) status on the risk of LOAD (OR=1.91, 95% CI 1.23–2.95, p=0.003). These results suggest that BACE1 gene polymorphism C786G might act as an APOE ε4 allele-dependent risk factor for developing LOAD in Chinese.

The haplotype identified in LEPR gene is associated with type 2 diabetes mellitus in Northern Chinese

Leptin receptor (LEPR) plays an important physiological role in energy metabolism. The study addressed the relationship between leptin receptor gene variations and type 2 diabetes mellitus (T2DM). Three single nucleotide polymorphisms (SNPs) of LEPR gene, Arg109Lys (A/G), Asn656Lys (C/G) and Pro1019Pro (C/T) were detected in a northern population in China. Totally, 317 patients with T2DM and 282 healthy controls were recruited randomly from urban communities in Harbin area in the Northeast of China. All polymorphisms were genotyped by Sequenom SNP detection system in both case and control groups. Linkage disequilibria analysis showed moderate linkage disequilibria between the pair-wise SNPs for all three SNPs. Then, we identified the haplotype covering the three SNPs (AGC) with higher risk of T2DM (OR=1.69 (1.09-2.61)), and showed that there existed significant difference between cases and controls (9.8% vs. 6.0%, P=0.02). We also observed significant difference in frequencies of the heterozygous haplotype combination (GGT/AGC), that is 17.0% vs. 8.2% in cases and controls, respectively (P=0.001). It further supported the evidence that the haplotype (AGC) was associated with T2DM. So, AGC haplotype in LEPR gene could be a risk factor associated with T2DM in Northern Chinese.

Analysis of the relationship between three coding polymorphisms in LEPR gene and obesity in northern Chinese

SUMMARY To determine the effect of variants in LEPR gene on obesity in northern Chinese, three coding polymorphisms Arg109Lys (A/G), Asn656Lys (C/G) and Pro1019Pro (C/T) were investigated for association with overweight and obesity. By a case control design, 248 overweight or obese subjects and 351 lean normal controls were recruited in Harbin region in north China. All three polymorphisms were genotyped by Sequenom single nucleotide polymorphism (SNP) detection system in both cases and controls. Genotypes for all three polymorphisms were in Hardy-Weinberg equilibrium in control subjects. Both groups had similar distribution of alleles and genotypes created by the three coding polymorphisms of LEPR gene. No differences in frequencies of genotypes or alleles between cases and controls for any polymorphism individually were found by χ(2) analysis (p = 0.444, p = 0.507 and p = 0.662, respectively). Further, when the haplotypes of three polymorphisms were assessed, no association for any haplotype of three polymorphisms was revealed. In the present study, the three coding polymorphisms in LEPR gene were firstly investigated in a population of northern Chinese. It was suggested that the three coding polymorphisms in LEPR gene were unlikely to have major effects on susceptibility to obesity in northern Chinese.:

The Ser311Cys variation in the paraoxonase 2 gene increases the risk of type 2 diabetes in northern Chinese

Four hundred and thirty four unrelated patients of T2DMwere recruited, from Beijing (228) and Harbin (206) regions(with an average age of 49.7 ±13.2, 204 males and 230 fe-males). Diabetes was diagnosed based on the American Dia-betesAssociation(ADA)fastingplasmacriteria(2005). Sub-jects were defined as diabetic, either through an oral glucosetolerance test (OGTT) using 75 g glucose load (dissolved in250 ml water) or receiving anti-diabetic treatment by oral