-141 C del/ins polymorphism of the dopamine receptor 2 gene is associated with schizophrenia in a British population.

Dopamine has long been hypothesised to be involved in the pathogenesis of schizophrenia. The dopamine D2 receptor is a major site of action of neuroleptic agents used in the treatment of schizophrenia. Arinami et al. [1997; Human Mol Genet 6:577-582] have recently sequenced the dopamine receptor 2 (DRD2) gene in Japanese individuals and identified a novel polymorphism: a single cytosine deletion at position -141 disrupting a BstN1 restriction site with a frequency of 0.22 in their control group. They then found a strong association with this polymorphism and schizophrenia (p < 0.001) with an odds ratio of 0.60 in a Japanese population. We have attempted to verify their results by repeating the RFLP analysis on a sample of Scottish schizophrenics and controls. We then combined our data with those from another British sample recruited using similar procedures. The total combined sample size was 439 schizophrenics and 437 controls. We obtained a significant association--p = 0.02 with an odds ratio of 1.41. Schizophrenia is associated with the C insertion in the Japanese, but that association is reversed in Caucasians. Linkage disequilibrium with a causative polymorphism nearby is the most likely explanation for this reverse association.     

Dopamine DRD2/Cys311 is not associated with chronic schizophrenia

A mutation in the DRD2 receptor gene has been reported in association with schizophrenia in Japanese and Caucasian populations. The variation, Ser to Cys at codon 311, occurs in the third intracellular loop of the receptor and is therefore putatively functional. We report the results of screening US Caucasian schizophrenic and nonschizophrenic populations. We detected the occurrence of the DRD2 Cys311 variant in both schizophrenics and controls. Our data demonstrates no significant difference between the frequency of Cys311 in Caucasian schizophrenic and non-schizophrenic populations, indicating no association with schizophrenia. © 1996 Wiley-Liss, Inc.     

The apolipoprotein B signal peptide insertion/deletion polymorphism is not associated with myocardial infarction in Norway

The three-amino acid insertion/deletion (I/D) polymorphism in the apoB signal peptide (27 amino acid versus 24 amino acid signal peptide) was evaluated as a possible risk factor for myocardial infarction (MI) in a case-control study population comprising 238 MI survivors and 547 controls. In controls, homozygotes for the deletion allele (DD) had the highest mean levels of both total cholesterol and low density lipoprotein (LDL) cholesterol (LDLC), the homozygotes for the insertion allele (II) had the lowest mean values, while the heterozygotes (ID) had intermediate mean levels (p < 0.05). In MI survivors, the trend was similar, but only differences in mean LDLC levels were statistically significant (p < 0.05). No differences in genotype frequencies were detected between cases and controls in univariate analysis or in multivariate logistic regression analysis. Despite the results from the lipid analyses, we conclude that the I/D polymorphism in the apoB signal peptide is unlikely to be of major importance for MI risk in relatively young Norwegians.     

多巴胺D2受体-141C Ins/Del多态与海洛因渴求的关系

目的：探讨多巴胺D2受体-141C Ins／Del基因多态与线索诱发海洛因渴求程度的关系。方法：对戒断期380名海洛因依赖者实施线索诱发渴求实验，采用PCR-RFLP技术检测其DRD2-141C Ins／Del基因多态，比较不同基因型与线索诱发海洛因渴求程度的关系。结果：DRD2-141C Ins／Del三种多态基因型中，线索暴露前后海洛因渴求程度的差异均无显著性（P〉0．05）。结论：DRD2-141C Ins／Del基因多态可能与线索诱发海洛因渴求的易感性无关。     

102T/C polymorphism of serotonin receptor type 2A gene is not associated with schizophrenia in either Chinese or British populations

Several pieces of evidence implicate serotonin receptors in the aetiology of schizophrenia, and recently a number of studies have reported a genetic association between the 102T/C polymorphism of serotonin receptor type 2A gene and schizophrenia. Unfortunately a number of failures to replicate these positive associations in both Caucasian and Chinese populations have also been reported. We have examined the 102T/C polymorphism by PCR amplification and restriction analysis of DNA from: 202 schizophrenics and 202 controls from Shanghai; 112 schizophrenics and 224 parents from Chengdu, Cina; and 253 schizophrenics and 244 controls from the the UK. We find no evidence of association or transmission disequilibrium between the 102T/C polymorphism and schizophrenia in any of the groups we have examined. We conclude that either the original positive reports occurred by chance or any effect must be minimal, and urge caution in interpreting small positive results derived using data from different centres.     

Increased susceptibility of sepsis associated with CD143 deletion/insertion polymorphism in Caucasians: a meta analysis

Background: Several lines of evidence have reported that serum angiotensin-converting enzyme (CD143) levels are genetically regulated by insertion/deletion (ins/del) polymorphism in intron 16 of the CD143 gene. In addition, published data on the association of ins/del polymorphism and sepsis risk yielded contradictory conclusions. Therefore, we determined to perform a meta-analysis to validate the association of much debate. Methods and major findings: Relevant literature was identified through weekly searches in databases and references of systematic reviews and the single studies incorporated in this meta-analysis. We combined ORs and its 95% CIs for several genetic models to evaluate the risk of sepsis associated with ins/del polymorphism. A total of seven studies were considered eligible for this analysis. We found significantly increased risk of sepsis in relation to the homozygote ins/ins (OR: 1.32, 95% CI: 1.04-1.68, P: 0.4201, for ins/ins vs. del/del), heterozygote del/ins (OR: 1.33, 95% CI: 1.11-1.61, P: 0.7937, for del/ins vs. del/del) and the two genotypes combined (OR: 1.33, 95% CI: 1.11-1.59, P: 0.7018, for ins/ins + del/ins vs. del/del). Subgroup analysis by age group showed a significant association in pediatric sepsis, but not in adult sepsis. Conclusions: The statistical data suggest that the CD143 gene ins/del polymorphism may influence the risk of sepsis, especially pediatric sepsis.     

The HLA-G 14-bp insertion/deletion polymorphism is associated with chronic hepatitis B in Southern Brazil: A case-control study

There is growing evidence that the non-classical HLA-G has a role in the process of the immune response against pathogens, including HBV and HIV. Previous studies demonstrated that a 14-bp insertion/deletion (indel) polymorphism at 3′-untranslated region of HLA-G gene interferes in the mRNA stability and expression. The present study aimed to evaluate the association of the 14-bp indel polymorphism (rs371194629) with HBV infection in chronic hepatitis B (CHB) mono-infected and HBV/HIV co-infected patients from Southern Brazil. A total of 817 individuals were analyzed, including 357 CHB patients, 134 HBV/HIV co-infected patients and 326 healthy controls. The 14-bp indel polymorphism was analyzed by DNA amplification using PCR. Logistic regression models were performed to compute adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs). To control for multiple comparisons, the Bonferroni correction was applied to the p-values. The 14-bp Ins allele was observed in 47.6% of the CHB mono-infected patients and in 41.6% of the controls (aOR = 1.33; 95% CI: 1.05–1.60; p = 0.02; p _corrected = 0.08). The results also showed that the 14-bp Ins/Ins genotype was present in 21.8% of the CHB mono-infected patients and in 12.9% of the controls (aOR = 1.91; 95% CI: 1.21–3.01; p < 0.01; p _corrected = 0.02). There was significant association between the 14-bp indel and CHB monoinfection, but not in HBV/HIV co-infection. In conclusion, the 14-bp indel polymorphism was associated with CHB in this specific population.     

Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta-analysis

ABSTRACT: BACKGROUND: A previous meta-analysis reported a positive association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the risk of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality. METHODS: We searched electronic databases through October 2011 for the terms "angiotensin-converting enzyme gene", "acute lung injury", and "acute respiratory distress syndrome," and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models. RESULTS: The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects (Pallele < 0.0001, Pdominant = 0.001, P recessive = 0.002). This finding remained significant after correction for multiple comparisons. CONCLUSIONS: There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians. Akihisa Matsuda and Taro Kishi These authors participated equally in this work.     

Allelic variation of a BalI polymorphism in the DRD3 gene does not influence susceptibility to bipolar disorder: results of analysis and meta-analysis

Bipolar disorder is a major psychiatric illness that has evidence for a significant genetic contribution toward its development. In recent years, the BalI RFLP (restriction fragment length polymorphism) in the dopamine D3 receptor gene has been examined as a possible susceptibility factor for both schizophrenia and bipolar disorder. While analysis in schizophrenia has produced examples of increased homozygosity in patients, less encouraging results have been found for bipolar disorder. Recently, however, a family-based association study has found a significant excess of allele 1 and allele 1-containing genotypes in transmitted alleles to bipolar probands over nontransmitted controls. In a large bipolar case control sample (n = 454), we have been unable to replicate the family-based association study (chi-square = 0.137, P = 0.71, 1 df) or detect an effect similar to the positive homozygosity findings in schizophrenia (chi-square = 0.463, P = 0.50, 1 df). A meta-analysis of previous association studies also revealed no difference in allele distributions between bipolar patients and controls for this polymorphism in ethnically homogeneous samples (odds ratio, OR, = 1.04; P = 0.60; 95% confidence interval, CI, = 0.89-1.20). In view of this evidence, we conclude that variation at the BalI RFLP is not an important factor influencing the susceptibility to bipolar disorder. It remains possible, however, that other sequence variations within the DRD3 gene could play a role.     

Association between DRD2/ANKK1 TaqIA polymorphism and common illicit drug dependence: Evidence from a meta-analysis

BackgroundGrowing evidence indicated conflicting results about the dopamine receptor D2 (DRD2)/kinase domain containing 1 gene (ANKK1) TaqIA single nucleotide polymorphism (rs1800497) and common illicit drug dependence risk including stimulants, opioid and marijuana. We conducted a meta-analysis to evaluate the association between the polymorphism and common illicit drug dependence risk.MethodA total of 25 available studies (26 subgroups) testing the association between the polymorphism and common illicit drug dependence were examined through Oct 2013. Pooled odds ratios (ORs) and 95% confidence intervals (CI) were estimated using fixed- and random-effects models when appropriate. Heterogeneity and publication bias were evaluated.ResultsWe found the DRD2/ANKK1 TaqIA polymorphism was significantly associated with increased risk of opioid dependence under homozygote, dominant, and recessive genetic model, respectively (homozygote: OR = 1.546, 95%CI = 1.279–1.87; dominant: OR = 1.265, 95%CI = 1.055–1.516; recessive: OR = 1.409, 95%CI = 1.182–1.680). Subgroup analyses were similar to the results of the total population by ethnicity and quality score. Besides, we also found that Caucasian and low-quality studies were major sources of heterogeneity for opioid dependence. We failed to find any significant association between the polymorphism and stimulants or marijuana neither in total population nor subgroup analyses under any genetic model.ConclusionsThe current meta-analysis suggested that DRD2/ANKK1 TaqIA polymorphism might be associated with opioid dependence risk, but not associated with stimulants or marijuana dependence.     

Clozapine-induced weight gain associated with the 5HT2C receptor -759C/T polymorphism.

Weight gain has been documented as a significant adverse effect associated with many of the atypical antipsychotic medications. Several recent reports have linked a -759C/T polymorphism of the 5HT2C receptor gene and obesity as well as chlorpromazine, risperidone, and clozapine induced to weight gain. This aim was to determine the association between changes in body mass index (BMI) during clozapine treatment and the -759C/T polymorphism of the 5HT2C receptor gene. This study included 41 patients with treatment-refractory schizophrenia (DSM-IV) who were followed prospectively during treatment with clozapine. Weight and height measurements were obtained prior to starting clozapine and after 6-months of treatment. Genomic DNA was isolated from a whole blood sample and analyzed for the -759C/T polymorphism of the 5HT2C receptor gene. A chi(2) analysis comparing whether or not the subjects carried a -759T allele in subjects grouped as having an increase of more or less than 7% of their baseline BMI during treatment with clozapine found that the presence of the -759T allele was significantly higher in subjects with less than or equal to a 7% increase in baseline BMI compared to those with a greater than 7% increase in BMI. A multiple linear regression analysis showed that both baseline BMI and the presence or absence of the -759T allele had significant effects on 6-month BMI. The T allele may have a protective function in preventing significant weight gain from clozapine. Subjects without the -759T variant allele were at a greater risk for weight gain from clozapine over 6-months compared to those with the -759T allele.     

Interleukin-10 -1082 promoter polymorphism is associated with schizophrenia in a Han Chinese sib-pair study

The interleukin-10 (IL-10) gene has been identified as a susceptibility gene for schizophrenia in Caucasians. A previous case-control study conducted by our group revealed a weak association between polymorphism, -592C/A, of the IL-10 gene promoter and schizophrenia. Our present study was aimed at confirming the association of the IL-10 promoter with schizophrenia using 197 Han Chinese sib-pair families. A family-based association test (FBAT) and haplotype analysis was undertaken using the FBAT v1.5.5. The global TDT was significant for a different polymorphism, -1082G/A (chi2=13.16, P=0.000285) and that the allele -1082G was preferentially transmitted to schizophrenia-affected children. Furthermore, haplotype TDT analysis showed that haplotype "GCC" was significantly associated with the disease (chi2=8.1, P=0.00443). Our results also indicate that the IL-10 gene may play a significant role in the etiology of schizophrenia among Han Chinese.     

Serotonin-2A receptor gene is not associated with symptomatology of schizophrenia

The serotonin receptor type 2A (5-HT2A) is a primary candidate for involvement in major psychoses. Polymorphisms within the 5-HT2A gene have recently been reported to be associated with a variety of psychopathological conditions. In the present study, we investigated the potential influence of the T102C polymorphism on the psychopathology of schizophrenia. One hundred eighty-eight inpatients affected by schizophrenia (DSM-III-R) were assessed by the Operational Criteria checklist for psychotic illness (OPCRIT) and were typed for their 5-HT2A variants by PCR techniques. Mania, depression, delusion and disorganization were the four symptomatologic factors previously derived from our psychotic population that were used to define phenotype in our sample. Genetic variants of the polymorphism under study were not associated with these symptomatologic factors, and consideration of possible stratification effects such as sex and age of onset did not reveal any association either. Our results do not, therefore, support the hypothesis that the serotonin receptor 2A gene is a liability factor for the symptomatology of schizophrenia as defined by the OPCRIT checklist. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:84-87, 2000.     

Alpha-2-macroglobulin intronic polymorphism is not associated with autopsy-confirmed late-onset Alzheimer's disease.

Alpha-2-macroglobulin (A2M) intronic polymorphism has recently been reported to be associated with late-onset Alzheimer's disease (LOAD). To corroborate this association, we analysed the A2M and apolipoprotein E (APOE) polymorphisms in autopsy cases of the MRC Alzheimer's Disease Brain Bank, Institute of Psychiatry, London. The frequencies of the insertion and deletion alleles in AD were 0.81 and 0.19, respectively, and these were not significantly different from control frequencies. After pooling the AD cases in epsilon4 positive and negative subgroups, there was again no significant difference between the A2M allele frequency in the two subgroups. In our present study, we were unable to corroborate the association between A2M intronic polymorphism and LOAD in autopsy cases.