COMT基因多态性与ADHD患儿青春期预后的关联分析

目的: 探讨儿茶酚-O-甲基转移酶(COMT)基因Val108/158Met(rs4680)多态性对中国汉族男性注意缺陷多动障碍(Attention deficit hyperactivity disorder,ADHD)患儿青春期预后的影响.方法: 对77名基线时符合美国<精神障碍诊断与统计手册(第4版)>(DSM-IV)诊断标准的中国汉族ADHD男性患儿进行青春期的随访,以定式访谈方法按同样诊断标准对随访组确定诊断,并检测COMT基因Val158Met多态性.采用卡方检验对ADHD不同预后结局进行COMT基因Vall58Met多态性等位基因频率的比较.结果: 77名患者中,41人(53.25)ADHD无缓解,36人(46.8%)达到不同程度的缓解,缓解组中16人(20.8%)满足功能缓解,7人(9.1%)症状缓解,13人(16.9%)综合征缓解.各种缓解表型与无缓解型的COMT基因Val158Met等位基因频率差异无统计学意义.结论: COMT基因Val158Met多态性对ADHD男性患儿青春期预后无关联,但尚需进一步扩大样本量进行验证.     

Meta-analysis of Association Between a Catechol-O-Methyltransferase Gene Polymorphism and Attention Deficit Hyperactivity Disorder

There have been conflicting reports on the association between the Val158/108Met polymorphism of the catechol-O-methyltransferase (COMT) gene and attention deficit hyperactivity disorder (ADHD). Therefore we would like to perform a meta-analysis of previous studies to assess the overall magnitude and significance of the association. Family-based and case–control studies of the association between the COMT gene polymorphism and ADHD were searched systematically and comprehensively. Odds ratios (OR) of association were pooled by the fixed effects model if no significant heterogeneity was present among different studies. Subgroup analysis by gender and ADHD subtypes were also performed. Eleven family-based and two case–control studies were identified. After pooling the results, no significant association between the COMT Val158/108Met polymorphism and ADHD was found (OR 0.99 (95% CI: 0.88–1.12), P = 0.87). There was also no significant association when the results were stratified by gender or ADHD subtype. There was no significant statistical heterogeneity (χ² = 12.27, P = 0.2) although clinical heterogeneity was present in the studies, especially the ethnicity of subjects. Sensitivity analysis demonstrated absence of undue influence of any single study. Standard regression analysis showed no significant publication bias. We concluded that no significant association was present between the most common COMT gene polymorphism and ADHD. Further studies should employ larger sample size in more homogeneous subjects. Further investigations in moderator variables and gene–gene and gene–environment interactions are also warranted.     

多动儿童焦虑抑郁自评与父母他评一致性研究

目的探讨注意缺陷多动障碍(ADHD)伴情绪问题儿童自我情绪评价与父母他评在临床诊断中的一致性。方法41例ADHD伴情绪问题儿童及父母分别完成儿童焦虑性情绪障碍筛查诊断量表(SCARD)、儿童抑郁障碍自评量表(DSRSC)。结果儿童焦虑性情绪障碍筛查诊断量表(SCARD)、儿童抑郁障碍自评量表(DSRSC),儿童自评与父母他评之间差异有显著性(P0.01),两者诊断一致性程度不高,存在差异性(Kappa0.4,P0.05)。结论重视ADHD儿童对自身情绪问题的表达,对早期发现ADHD儿童共病情绪障碍有一定价值。     

Replication of an association of a promoter polymorphism of the dopamine transporter gene and Attention Deficit Hyperactivity Disorder

Genetic associations for Attention Deficit Hyperactivity Disorder (ADHD), a common highly heritable childhood behavioural disorder, require replication in order to establish whether they are true positive findings. The current study aims to replicate recent association findings from the International Multi-centre ADHD Genetics (IMAGE) project in one of the most studied genes related to ADHD, the dopamine transporter (DAT1) gene. In a family-based sample of 450 ADHD probands, three Single Nucleotide Polymorphism (SNP) markers have been genotyped using TaqMan assays. Transmission Disequilibrium Test analysis demonstrates that one of three SNP markers (rs11564750) in the 5′ promoter region of the gene is significantly associated with ADHD (P = 0.02). This provides further evidence that in addition to the well-known and investigated 3′UTR polymorphism associated with ADHD, there is potentially a further association signal emanating from the 5′ promoter region of the gene. Further replication and functional studies are now required to fully understand the consequence of polymorphisms present at both the 5′ and 3′ ends of the DAT1 gene and their role in ADHD pathophysiology.     

惊恐障碍患者的父母育龄与胎次效应分析

目的探讨惊恐障碍患者的父母育龄与胎次效应。方法采用Haldane和Smith的方法,对75例惊恐障碍患者的家系进行了分析。结果惊恐障碍患者的父母育龄与胎次效应显著（X=2．56,P〈0．02）,结论父母育龄越大及胎次高者易患此病。     

No Association Between General Cognitive Ability and the A1 Allele of the D2 Dopamine Receptor Gene

Berman and Noble (1995) reported significantly reduced visuospatial performance in children with the TAQI A1 allele of the D2 dopamine receptor (DRD2) gene. Given that visuospatial performance loads highly on an unrotated principal component indexing general cognitive ability, we tested the association between DRJD2 and WISC-R IQ comparing 51 high-IQ, 51 average-IQ, and 35 low-IQ children in the IQ Quantitative Trait Loci (QTL) Project. No statistically significant association between the TAQI A DRD2 alleles and IQ was found. Given that a statistically significant portion of genetic variance for specific cognitive abilities is independent of general cognitive ability, it is possible that the TAQI DRD2 association is specific to visuospatial performance and independent of general cognitive ability.     

An Extension of the Regression of Offspring on Mid-Parent to Test for Association and Estimate Locus-Specific Heritability: The Revised ROMP Method

The Regression of Offspring on Mid-Parent (ROMP) method is a test of association between a quantitative trait and a candidate locus. ROMP estimates the trait heritability and the heritability attributable to a locus and requires genotyping the offspring only. In this study, the theory underlying ROMP was revised (ROMP_rev) and extended. Computer simulations were used to determine the type I error and power of the test of association, and the accuracy of the locus-specific heritability estimate. The ROMP_rev test had good power at the 5% significance level with properly controlled type I error. Locus-specific heritability estimates were, on average, close to simulated values. For non-zero locus-specific heritability, the proposed standard error was downwardly biased, yielding reduced coverage of 95% confidence intervals. A bootstrap approach with proper coverage is suggested as a second step for loci of interest.
ROMP_rev was applied to a study of cardiovascular-related traits to illustrate its use. An association between polymorphisms within the fibrinogen gene cluster and plasma fibrinogen was detected (p < 0.005) that accounted for 29% of the estimated fibrinogen heritability. The ROMP_rev method provides a computationally fast and simple way of testing for association and obtaining accurate estimates of locus-specific heritability while minimizing the genotyping required.     

Association of 5-HT3B Receptor Gene Polymorphisms with the Efficacy of Ondansetron for Postoperative Nausea and Vomiting

Purpose

Postoperative nausea and vomiting (PONV) is a common problem after general anesthesia. Although 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists have significantly reduced PONV, over 35% of patients treated with ondansetron can experience PONV. In this study, we investigated whether the Y129S and -100_-102AAG deletion polymorphisms of the 5-HT3B receptor gene affect the efficacy of ondansetron in preventing PONV.

Materials and Methods

Two hundred and forty-five adult patients who underwent laparoscopic cholecystectomy were enrolled. Ondansetron 0.1 mg/kg was intravenously administered 30 minutes before the end of surgery. Genomic DNA was prepared from blood samples using a nucleic acid isolation device. Both the Y129S variant and the -100_-102AAG deletion variant were screened for using a single base primer extension assay and a DNA direct sequencing method, respectively. The relationship between genetic polymorphisms and clinical outcomes of ondansetron treatment was investigated.

Results

Among the 5-HT3B AAG deletion genotypes, the incidence of PONV was higher in patients with the homomutant than with other genotypes during the first 2 hours after surgery (p=0.02). There were no significant differences in the incidence of PONV among genotypes at 2-24 hours after surgery. In the Y129S variants of the 5-HT3B receptor gene, there were no significant differences in the incidence of PONV among genotypes during the first 2 hours and at 2-24 hours after surgery.

Conclusion

The response to ondansetron for PONV was significantly influenced by the -100_-102AAG deletion polymorphisms of the 5-HT3B gene. Thus, the -100_-102AAG deletion variants may be a pharmacogenetic predictor for responsiveness to ondansetron for PONV.