Association of NAD(P)H:Quinone Oxidoreductase 1 Polymorphism and Alzheimer’s Disease in Chinese

Several lines of evidence support a role of oxidative stress in the pathology of Alzheimer’s disease (AD). NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyzes the two-electron reduction of quinones, preventing their participation in redox cycling and subsequent generation of reactive oxygen species. We examined association between the NQO1 C609T gene polymorphism and sporadic AD in a Chinese population comprising 311 AD patients and 330 controls. Our results showed a higher T-allele frequency in the AD cases compared with the controls. The difference was close to but did not reach statistically significant level [p = 0.059; odds ratio (OR) T versus C = 1.236; 95% confidence interval (95% CI), 0.992–1.540]. A significantly low C/C genotype frequency in the AD cases compared with the controls was detected (p = 0.025; OR C/C versus C/T + T/T = 0.674; 95% CI, 1.049–2.098) and APOE ε4 status analysis revealed significant difference in the APOE ε4 non-carriers (p = 0.036; OR = 0.633; 95% CI, 1.027–2.427). In the ≥65 years samples, significantly low C/C frequency in the AD cases in comparison with the controls was observed in the APOE ε4 non-carriers (p = 0.045; OR = 0.595; 95% CI, 1.010–2.794). These results indicated that the C/C genotype had a possible protective effect against AD development, and the T allele might be a weak risk factor for late onset AD. J-T Bian and H-L Zhao contributed equally to the work.     

Association Between the G1001C Polymorphism in the GRIN1 Gene Promoter and Schizophrenia in the Iranian Population

Schizophrenia is a complex genetic disorder to which genetic variation in the glutamatergic signaling pathways is believed to play a substantial role in the etiology of the disease. Association studies have implicated the N-methyl-d-aspartate receptor subunit gene, GRIN1, as a candidate gene for schizophrenia. In this report, we used a case control study to establish the possible association between the G1001C polymorphism in the GRIN1 gene promoter region and schizophrenia in an Iranian cohort of 200 unrelated patients and 200 controls. The allelic and genotypic frequencies of the polymorphism were determined using polymerase chain reaction restriction fragment length polymorphism. Data analysis using logistic regression and the Mantel–Haenszel chi-square test revealed a strong association between the G1001C polymorphism and schizophrenia (CG genotype: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.34–3.48, P = 0.001 and CC genotype: OR = 29.10, 95% CI 3.40–565.78, P < 0.001). Furthermore, the C allele is significantly associated with an increasing risk of schizophrenia. An erratum to this article can be found at     

Dopamine receptor D3 genetic polymorphism (rs6280TC) is associated with rates of cognitive impairment in methamphetamine-dependent men with HIV: preliminary findings

Macrophages are one of HIV-1’s principal targets and chiefly responsible for translocating HIV into the central nervous system (CNS). Previous research suggested an increase in macrophages being infected by HIV in the presence of methamphetamine (METH) or increased extracellular dopamine (DA). Experimental studies indicate that this is mediated by DA receptors, including DA receptor D3 (DRD3), which is expressed in macrophages. A single nucleotide polymorphism (SNP) of the DRD3 gene (rs6280TC) modulates its dopamine binding affinity, resulting in the possibility that inheriting a variant of this SNP increases macrophage susceptibility to HIV infection in the presence of METH and DA, particularly in the CNS where METH is sequestered, leading to cognitive impairment (CI). Thus, we conducted a retrospective clinical investigation to evaluate whether rs6280TC is associated with CI among HIV-positive METH users. We stratified 310 males by HIV serostatus (HIV-positive, -negative) and METH dependence (METH-positive, -negative) and then by rs6280TC genotype (CC, CT, and TT). Genotypic groups within each of four HIV/METH groups were compared for rates of CI. We hypothesized that only HIV-positive/METH-positive carriers of the C allele, which increases the DRD3’s binding to DA, would be more likely to develop CI. Cochran–Armitage test for trends in proportions yielded significant (p < 0.05) association between three genotypes and impairment rates in the hypothesized order, but only among HIV-positive/METH-positive subjects. The results also confirmed that C allele carriers (CC and CT, 53.3%) in this group had higher impairment rates (p = 0.05) than TT carriers (33.3%). These findings support the theory that rs6280TC influences the frequency of CI in HIV-positive/METH-positive males.     

Association of Toll-like Receptor 2 Polymorphisms with National Institute of Health Stroke Scale Scores of Ischemic Stroke Patients

Toll-like receptor 2 (TLR2) has been shown to have an important role in the postischemic inflammatory response and to contribute to ischemic brain damage. In this study, we investigated whether coding region single nucleotide polymorphisms (SNPs) of the TLR2 gene were associated with ischemic stroke (IS) and with clinical phenotypes in IS patients. We genotyped two SNPs (rs3804099 [Asn199Asn] and rs3804100 [Ser450Ser]) using direct sequencing in 202 IS patients and 291 control subjects. No SNPs of the TLR2 gene were found to be associated with IS. However, in analysis of clinical phenotypes, we found that rs3804099 was associated with the National Institute of Health Stroke Scale (NIHSS) scores of IS patients in codominant (TC vs. TT, p = 0.0005; CC vs. TT, p = 0.0007) and dominant models (TC/CC vs. TT, p = 0.0001). Also, rs3804100 revealed significant association in codominant (TC vs. TT, p = 0.0002; CC vs. TT, p = 0.008) and dominant models (TC/CC vs. TT, p < 0.0001). In allele frequency analysis, we also found that the C alleles of rs3804099 and rs3804100 were associated with higher NIHSS scores (p = 0.0003 in rs3804099; p = 0.0001 in rs3804100). Our results suggest that TLR2 may be related to severe IS.     

Polymorphisms of RANTES and IL-4 Genes in Cerebral Infarction

Chemoattractant peptides (chemokines) and cytokines have been shown to play a key role in the inflammatory development and progression of cerebrovascular disease. The effect of polymorphisms in regulated upon activation, normal T cells expressed, and secreted (RANTES) and interleukin-4 (IL-4) genes on cerebral infarction (CI) is evaluated in this study. Patients with CI (n = 320) and healthy controls (n = 481) were genotyped for RANTES-403 and IL-4 variable number of tandem repeat (VNTR) polymorphisms using polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism. A significant difference was observed between the CI group and controls in subjects with the RANTES AA genotype in IL-4 A3− carriers (18.6% vs. 13.1%, P = 0.035, odds ratio = 1.5, 95% confidence interval = 1.03–2.25). These findings suggest that the RANTES G-403A allele increased the relative risk for CI in the subjects without the IL-4 VNTR allele 3.     

ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: a meta-analysis

Introduction

The ABCB1 C3435T polymorphism limits oral bioavailability of clopidogrel and may influence prognosis of patients treated with clopidogrel. Several studies have examined the association between the C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients, but the results were inconsistent. To assess the role of the C3435T polymorphism in the impact on clinical outcomes, a meta-analysis was conducted.

Methods

6 studies with 10,153 subjects were included in this meta-analysis. Fixed- or random-effects model was chosen according to heterogeneity. Publication bias was evaluated by fail-safe numbers.

Results

The association of the C3435T polymorphism with risk of overall recurrent ischemic events in clopidogrel treated patients was not statistically significant for all genetic models (OR = 1.13, 95%CI: 0.78-1.64, P = 0.51; OR = 1.15, 95%CI: 0.99-1.33, P = 0.07; OR = 1.19, 95%CI: 0.81-1.76, P = 0.37). Significant association was identified between the C3435T polymorphism and risk of short-term recurrent ischemic events (OR = 1.55, 95% CI: 1.09-2.20, P = 0.01; OR = 1.41, 95% CI: 1.06-1.87, P = 0.02; OR = 1.77, 95% CI: 1.19-2.63, P = 0.005). No statistically significant association between the C3435T polymorphism and stent thrombosis (OR = 0.79, 95% CI: 0.47-1.32, P = 0.37) or bleeding (OR = 0.98, 95% CI: 0.79-1.21, P = 0.82) was identified. The results may be affected by publication bias.

Conclusions

This meta-analysis failed to show an association between the ABCB1 C3435T polymorphism and risk of overall recurrent ischemic events, stent thrombosis or bleeding in clopidogrel treated patients. However, the association between TT homozygotes of the C3435T polymorphism and risk of short-term recurrent ischemic events may exist, but needs more studies to confirm.     

<Emphasis Type="Italic">PEMT</Emphasis> G523A (V175M) Is Associated with Sporadic Alzheimer's Disease in a Chinese Population

There is evidence that increased concentrations of circulating homocysteine are associated with Alzheimer's disease (AD). Phosphatidylethanolamine N-methyltransferase (PEMT) is an important catalyst involved in the production of homocysteine. We investigated the association of a functional single nucleotide polymorphism (rs7946) in PEMT with sporadic AD risk in a Han Chinese population that included 386 AD patients and 366 controls. PEMT G523A was genotyped by either sequencing or PCR-restriction fragment length polymorphism analysis. The plasma homocysteine concentrations of 210 subjects were determined by high-performance liquid chromatography. Significant higher frequency of the A allele was detected in AD cases than in controls (A vs. G, p = 0.007, OR = 1.482, 95% CI 1.114–1.972). After adjusting for gender, age/age at onset, and APOE ε4 status, logistic analysis showed rs7946 was associated with AD in a dominant model (AA + GA vs. GG, p = 0.007, OR = 1.596, 95% CI 1.138–2.240). When stratified by APOE ε4 status or gender, the significant difference was only observed in the APOE ε4 non-carriers and in the female subjects, respectively. We did not find a relationship of this polymorphism with plasma homocysteine levels. These results suggested that PEMT G523A is associated with AD and that the A allele is an APOE ε4-independent risk factor for AD among Han Chinese women.     

Meta-analysis of the association between the interleukin-1A -889C/T polymorphism and Alzheimer's disease

No clear consensus has been reached on the Interleukin-1A (IL-1A) -889C/T polymorphism and Alzheimer's disease (AD) risk. In this meta-analysis, 27 case-control studies were assessed to evaluate the possible association. Overall, positive associations of the IL-1A -889C/T polymorphism with AD risk were found in allele comparison T vs. C (OR = 1.09, 95% CI = 1.01-1.18), recessive model TT vs. CT + CC (OR = 1.21, 95% CI = 1.01-1.45), and homozygote comparison (TT vs. CC; OR = 1.32, 95% CI = 1.04-1.67). In subgroup analysis stratified by ethnicity, significant associations were demonstrated in Caucasians but not in Asians. In subgroup analysis according to the age of onset, the data showed a significant association in patients with late-onset AD in Caucasians but not in early-onset AD. In conclusion, this meta-analysis supports the idea that IL-1A -889C/T polymorphism is capable of causing AD and LOAD susceptibility in Caucasians but not in Asians.     

The cholesteryl ester transfer protein (CETP) gene and the risk of Alzheimer’s disease

Like the apolipoprotein E (APOE) gene, the most common genetic determinant for Alzheimer’s disease (AD), the cholesteryl ester transfer protein (CETP) is involved in lipid metabolism. We studied the I405V polymorphism of the CETP gene in relation to AD. We genotyped 544 AD cases and 5,404 controls from the Rotterdam study, using a TaqMan allelic discrimination assay. Odds ratios (ORs) for AD were estimated using logistic regression analysis. CETP VV carriers showed significantly increased high-density lipoprotein levels compared to the IV and II carriers. In the overall analysis of AD, the risk of disease for the VV carriers of the CETP polymorphism was non-significantly increased compared to II carriers OR_VV = 1.33, 95% confidence interval (CI) 0.96–1.90 p = 0.08). In those without the APOE*4 allele, the risk of AD for VV carriers was increased 1.67-fold (95% CI 1.11–2.52, p = 0.01). The difference in the relationship between CETP and AD between APOE*4 carriers and APOE*4 non-carriers was statistically significant (p for interaction = 0.04). Our results suggest that the VV genotype of the I405V polymorphism of the CETP gene increases the risk of AD in the absence of the APOE*4 allele, probably through a cholesterol metabolism pathway in the brain.     

醛固酮合成酶基因多态性和血压、血糖、血脂相互作用与急性脑梗死的易感性

目的研究醛固酮合成酶(CYP11B2)基因-344T/C多态性和血压、血糖、血脂相互作用与急性脑梗死(ACI)易感性的关系。方法采用病例对照研究方法,检测研究对象的血压、血糖和血脂情况,采用聚合酶链反应限制性内切酶长度多态性(PCR-RFLP)方法检测CYP11B2的基因型。结果病例组CYP11B2基因TC和CC基因型的频率显著高于对照组,分别为38.12%和9.97%;相对于TT基因型,暴露于TC和CC基因型人群的OR值分别为1.72和1.88。病例组C等位基因的频率也显著高于对照组,为29.03%;相对于T等位基因,C等位基因的OR值为1.57。此外研究还显示CYP11B2基因TC或CC基因型与血糖、血脂相互作用可增加ACI的易感性,而该基因型与血压无协同作用。结论当个体携带TC或CC基因型时,ACI的易感性增加,该两种基因型与血糖、血脂相互作用,可增加ACI的易感性。     

CYP46A1 T/C polymorphism associated with the APOEε4 allele increases the risk of Alzheimer’s disease

Studies of the relationship between Alzheimer’s disease (AD) and single nucleotide polymorphism (SNP) T/C in intron 2 of the cholesterol-24S-hydroxylase gene (CYP46A1) have reported inconsistent results. To confirm the association between the CYP46A1 T/C polymorphism and AD risk, a meta-analysis containing 4,875 AD cases and 4,874 controls from 21 case–control studies was performed. There were 16 studies involving Europeans, four studies with Asians and one study with Africans. The combined results of overall analysis showed that the CYP46A1 T/C polymorphism increased the risk of AD significantly in recessive model [CC versus CT + TT, odds ratio (OR) = 1.20, 95 % confidence interval (CI) = 1.04–1.38, p = 0.01]. On subgroup analysis by ethnicity, similarly significant differences in recessive model were also found in Europeans. Another analysis of the synergistic effect of the CYP46A1 T/C polymorphism and the ε4 allele of the apolipoprotein E gene (APOE ε4) was performed in eight studies with available stratified information. The results revealed that the presence of APOE ε4 allele could strengthen the effect of CC genotype on AD risk, and the reverse was also true. In conclusion, our meta-analysis has successfully proved that CC genotype of the CYP46A1 T/C polymorphism could increase the risk of AD, and this effect would be weakened in APOE ε4 non-carriers and strengthened in APOE ε4 carriers.     

The association of cystathionine β synthase (CBS) T833C polymorphism and the risk of stroke: a meta-analysis

As results from published studies on the association of Cystathionine β Synthase (CBS) T833C genetic polymorphism with the risk of stroke are inconsistent, we performed a meta-analysis to summarize the possible association. Eligible studies published were searched for in PubMed, Elsevier Science Direct, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), and the Chinese database, Wanfang. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were assessed for the association using fixed- or random-effect model. We identified 10 case-control studies including 2247 cases and 1813 controls for the present meta-analysis. Significant associations between CBS T833C genetic polymorphism and risk of stroke were observed in most genetic models (OR=1.57, 95% CI=1.02-2.41, p=0.039 for TC+CC vs. TT; OR=1.79, 95% CI=1.14-2.82, p=0.012 for CC vs. TT; OR=1.56, 95% CI=1.01-2.40, p=0.044 for TC vs. TT). Moreover, in the subgroup analysis based on ethnicity, significant associations were observed in most genetic models in Chinese but not in Caucasian. This meta-analysis provided evidence that CBS T833C genetic polymorphism was associated with increased risk of stroke, and the C allele probably acts as an important stroke risk factor.     

Polymorphism in the sorbin and SH3-domain-containing-1 (SORBS1) gene and the risk of brain infarction in the Japanese population: the Fukuoka Stroke Registry and the Hisayama study

Background and purpose:  Sorbin and SH3-domain-containing-1 (SORBS1) is an important adaptor protein in insulin-signalling pathway, and its genetic polymorphism may regulate the activity of insulin resistance. We investigated the association between the SORBS1 T228A polymorphism and ischaemic stroke.
Methods:  Genotyping was achieved by a rapid-cycle PCR and melting curve analysis using fluorescent probes in 1049 incident cases of ischaemic stroke and 1049 age- and sex-matched control subjects recruited from the Hisayama study.
Results:  The allele distributions of the SORBS1 T228A polymorphism were similar amongst cases and controls. The multivariate-adjusted odds ratio (OR) of the AA genotype for ischaemic stroke was 2.897 (95% CI, 0.907–8.018) compared with the TT genotype. In terms of stroke subtype, there was a trend toward a difference in the AA genotypes for lacunar infarction, compared with the TT genotype (OR = 8.740, P  = 0.0510), and combined TT and TA genotypes (OR = 8.768, P  = 0.0505). The other polymorphisms genotyped were not associated with any subtypes of ischaemic stroke. T228A polymorphism of SORBS1 was not associated with the prevalence of diabetes.
Conclusions:  The AA genotype of SORBS1 T228A polymorphism may play a role in lacunar infarction in the Japanese population.     

Fyn Polymorphisms are Associated with Distinct Personality Traits in Healthy Chinese-Han Subjects

The Src family tyrosine kinase Fyn regulates a myriad of neurophysiological processes, including learning and memory. To date, the role of Fyn in the neurological mechanisms that determine personality traits has not been addressed. To this end, we determined the association between the rs706895C/T polymorphism of the Fyn gene (FYN) and personality traits measured by the Tridimensional Personality Questionnaire in 502 healthy Chinese-Han subjects. There were no significant differences in the total scores for novelty seeking (χ ² = 5.12, P = 0.077), harm avoidance (HA; χ ² = 2.63, P = 0.269), or reward dependence (RD; χ ² = 3.94, P = 0.139) among the rs706895C/T genotypes. In sub-item analyses, however, both fear of uncertainty (HA2; χ ² = 7.84, P = 0.020) and sentimentality (RD1; χ ² = 8.27; P = 0.016) scores were significantly different among rs706895C/T genotypes. Our results suggest that FYN alleles can contribute to the variance in human personality traits.     

MTHFR C677T mutation increased the risk of Ischemic Stroke,especially in large-artery atherosclerosis in adults: an updated meta-analysis from 38 researches

Background: To date, many publications have evaluated the correlation between the Ethylenetetrahydrofolate reductase gene (MTHFR) C677T and Ischemic Stroke susceptibility in adults. However, the results remain inconclusive. The meta-analysis was performed to resolve the problem. Methods: Based on 38 studies, dichotomous data were presented as the odds ratio (OR) with a 95% confidence interval (CI). Results: This study found, the carriers of the MTHFR 677C→T variation were more likely to increase the risk of Ischemic Stroke susceptibility in all over pooled population, including Asian and European, but not in African population (Europe: TT vs. CC+TC: OR = 1.364 95% CI = 1.010–1.841 p = 0.043; Asia subgroup: T vs. C: OR = 1.245, 95% CI = 1.141–1.358, p < 0.001; Africa: T vs. C: OR = 1.202, 95% CI = 0.990–1.459, p = 0.062). Among etiology stratified analysis, only large-artery atherosclerosis subgroups had a significant different, and the p value was less than 0.01 in all genetic models (T vs. C: OR = 1.29, 95% CI = 1.09-1.52, p = 0.002; TT+TC vs. CC: OR = 1.27, 95% CI = 1.06-1.51, p = 0.009; TT vs. CC+TC: OR = 1.62, 95% CI = 1.19–2.19, p = 0.002). Conclusions: This meta-analysis suggests that MTHFR C677T mutation increased the risk of Ischemic Stroke in adults, especially in large-artery atherosclerosis.     

醛固酮合成酶基因多态性与急性脑梗死相关性研究

目的研究醛固酮合成酶(CYP11B2)基因-344T／C多态性与急性脑梗死(ACI)的关系。方法应用多聚酶链-限制性片段长度多态性(PCR-RFLP)技术,对341例ACI患者和329例正常人的CYP11B2基因-344位点基因多态性进行检测,并用放射免疫方法测定其血浆醛固酮的浓度。结果病例组CYP11B2基因TC和CC基因型的频率显著高于对照组,分别为38．12％和9．97％,相对于TT基因型,暴露于TC和CC基因型人群的OR值分别为 1．72和1．88;病例组C等位基因的频率也显著高于对照组,为29．03％,相对于T等位基因,C等位基因的OR值为 1．57。携带CC基因型的个体,ALD浓度病例组显著高于对照组(P<0．05);病例组中CC基因型的血浆醛固酮 (ALD)浓度显著高于TT基因型(P<0．05)。结论醛固酮合成酶(CYP11B2)基因-344T／C多态性与ACI相关;C 等位基因可能是中国人ACI的一个遗传标志。