Additive effect of three noradrenergic genes (ADRA2A, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects

Halperin et al. (Halperin JM. Newcorn JH, Koda VH, Pick L, McKay KE, Knott P. Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension. J Am Acad Child Adolesc Psychiatry 1997: 36: 1688 1696) reported a significant increase in plasma norepinephrine (NE) in attention-deficit hyperactivity disorder (ADHD) children with reading and other cognitive disabilities compared to ADHD children without learning disabilities (LD). We examined the hypothesis that ADHD + LD was associated with NE dysfunction at a molecular genetic level by testing for associations and additive effects between polymorphisms at three noradrenergic genes the adrenergic alpha2A receptor (ADRA2A), adrenergic alpha2C receptor (ADRA2C), and dopamine beta-hydroxylase (DBH) genes. A total of 336 subjects consisting of 274 individuals with Tourette syndrome (TS) and 62 normal controls were genotyped. Regression analysis showed a significant correlation between scores for ADHD, a history of LD, and poor grade-school academic performance that was greatest for the additive effect of all three genes. Combined, these three genes accounted for 3.5% of the variance of the ADHD score (p = 0.0005). There was a significant increase in the number of variant NE genes progressing from subjects without ADHD (A-) or learning disorders (LD-) to A + LD - to A - LD + to A + LD + (p = 0.0017), but no comparable effect for dopamine genes. These data support an association between NE genes and ADHD, especially in ADHD + LD subjects.     

No association between ADRA2A polymorphisms and schizophrenia.

There is evidence to suggest that the alpha(2A)-adrenergic receptor may be involved in schizophrenia. With attention directed at the upstream regulatory region of the gene which codes for this receptor (ADRA2A), we proposed that single nucleotide polymorphisms (SNPs) within this region influences susceptibility to schizophrenia by altering the expression of this receptor. We opted to test for an influence on susceptibility by association study using 112 schizophrenic/schizoaffective disorder patients and 159 controls. The region of interest was screened for SNPs using a combination of bioinformatic searches and sequencing. A total of nine SNPs were discovered, of which four (-5972-G/A, -2211-A/T, -1291-C/G and -261-G/A) were genotyped in the entire clinical sample. No associations were evident, suggesting no influence for these SNPs in susceptibility to schizophrenia.     

Association between the adrenergic alpha 2A receptor gene (ADRA2A) and measures of irritability, hostility, impulsivity and memory in normal subjects

The noradrenergic system has been implicated in arousal, vigilance, irritability hostility, and memory. This suggests the hypothesis that genetic variants at noradrenergic receptors may be risk factors of these behaviors. To test this hypothesis, the potential association between measures of these traits and genetic variation at the adrenergic2A receptor gene (ADRA2A), using a common single nucleotide polymorphism (SNP) polymorphism of the promoter region, were examined in two independent sets of subjects: university students (student group), and parents of twins in the Minnesota Twin Study (twin group). In the student group, there was a significant linear association by genotype (11 > 12 > 22) for the total Brown ADD score (BADD), and BADD subscores of memory and irritability, and with the total Buss-Durkee Hostility Inventory (BDHI) score and BDHI subscores of indirect hostility, irritability, negativity, and verbal aggression. A multiple analysis of variance (MANOVA) of all the BADD and BDHI subscores was significant at P < or = 0.009. For the twin group, the same genotype associations were significant for the Multidimensional Personality Questionnaire (MPQ) impulsivity scores but not for the MPQ aggression or harm avoidance scores. The ADRA2A gene accounted for 1.8-8.3% of the variance of these scores.     

神经丛蛋白A2(PLXNA2)基因多态性与精神分裂症的关联研究

目的:探讨神经丛蛋白(PLXNA2)基因与汉族人群精神分裂症的关联。方法:采用DNA测序检测方法,依据ICD-10诊断标准,在735例汉族精神分裂症住院患者和1316例年龄、性别匹配的正常对照者中,探索PLXNA2基因5个单核苷酸多态性(SNP)位点与精神分裂症的关联。结果:PLXNA2基因的4个SNPs位点与精神分裂症关联(均P<0.05);由rs3811383-rs841865-rs2785622组成的单体型ATT及由rs841865-rs752016组成的单体型AC与精神分裂症关联(均P<0.05)。结论:本研究结果提示PLXNA2基因多态性在中国汉族人群中与精神分裂症关联。     

Association between cytochrome P450 (CYP) 2C19 polymorphisms and harm avoidance in Japanese.

Polymorphic enzyme cytochrome P450 (CYP) 2C19 is expressed not only in the liver but also in the brain and mediates the biotransformation of 5-hydroxytriptamine (5-HT). We investigated possible association between genetic polymorphism of CYP2C19 and individual personality traits, possibly influenced by neurotransmitters. Mentally and physically healthy Japanese subjects were enrolled in this study (n = 352). Temperament and Character Inventory (TCI) and CYP2C19 genotyping were performed in all subjects. We detected CYP2C19*2 and *3 (http://www.imm.ki.se/CYPalleles/) using Amplichip CYP450 DNA tip. The number of genotypes classified as homozygous extensive metabolizer (EM), heterozygous EM, and poor metabolizer were 113, 181, and 58, respectively. Significant difference was found in TCI score in harm avoidance (HA; F = 3.138, P < 0.05). Post hoc analysis showed that TCI score in harm avoidance in homozygous EM was significantly lower than that in heterozygous EM (P < 0.05) or PM (P < 0.05). In sub-item analyses, HA3 (shyness with strangers, P < 0.01) and HA1 (anticipatory worry, P < 0.05) of TCI scores were significantly different among CYP2C19 genotypes. Meanwhile, there were no differences in TCI scores of novelty seeking (NS; F = 0.350, n.s.), reward dependence (RD; F = 1.080, n.s.), or persistence (P; F = 0.786, n.s.) among CYP2C19 genotypes. This study demonstrated that a significant association between CYP2C19 activity and HA is present in Japanese.     

肾上腺素能α1A受体基因多态与注意缺陷多动障碍共患学习困难的关联分析

目的:探讨肾上腺素能α1A受体基因(ADRA1A)多态性与注意缺陷多动障碍(ADHD)共患学习困难(LD)的关联.方法:依据美国精神障碍诊断与统计手册第4版(DSM-Ⅳ)标准,诊断ADHD、划分临床亚型并评定共患病.采用中国韦氏儿童智力量表(Chinese Wechsler Intelligence Scale for Children,C-WISC)评估智商.入组678例ADHD共患LD的儿童(含457个核心家系),1137例ADHD未共患LD的儿童(含792个核心家系)及936名正常对照.进行ADRA1A基因3个单核苷酸多态性位点(SNPs)的基因型检测,采用传递不平衡检验、x2检验对单个SNP位点及单体型与ADHD及其表型进行关联分析,采用协方差分析探讨基因与ADHD儿童智商的关联.结果:家系研究显示,rs17426222位点的C等位基因(校正P=0.026)及由rs17426222、rs573514、rs3808585组成的CAC单体型(校正P=0.011),在ADHD共患LD家系中存在过度传递.在ADHD共患LD样本中,rs573514位点的A等位基因频率具有高于对照组的趋势(0.596 vs.0.557,校正P=0.071),控制性别、年龄后该关联仍存在(P＜0.05).在ADHD未共患LD中,家系与病例对照研究均未发现任何关联(P＞0.05);将ADHD共患/未共患LD合并后,关联均消失(P＞0.05).协方差分析显示,rs573514位点基因型与ADHD儿童的操作智商存在关联(P＜0.05),AA基因型携带者操作智商低于AG[(95±15) vs.(97±15),P＜0.05]、GG[(95±15)vs.(98±14),P=0.007]基因型携带者.结论:ADRA1A可能与ADHD共患LD存在关联,ADHD共患LD与否可能存在遗传学差异;ADRA1A可能与ADHD操作性智商存在关联.     

A novel link between Tourette's syndrome and histaminergic signalling

l ‐Histidine decarboxylase and Tourette's syndrome Ercan‐Sencicek et al. (2010) The New England Journal of Medicine 362(20): 1901–1908     

单胺氧化酶A基因多态性与精神分裂症的关联研究

目的探讨河南地区汉族人群单胺氧化酶A（monoamine oxidase A，MAOA）基因多态性与精神分裂症的关系。方法参照CCMD-3诊断标准，选取212例精神分裂症患者与168名正常对照，应用聚合酶链反应及限制性片段长度多态性技术检测MAOA基因多态性，采用病例一对照的关联分析方法对精神分裂症患者及正常对照的基因型和等位基因频率进行分析。结果（1）MAOA基因的基因型在患者组和对照组中均符合Hardy-Weinberg平衡定律（X^2=0．618，dr：2，P〉0、05；X^2=3．173，df=2，P〉0．05）。（2）MAOA基因的基因型和等位基因频率在患者组与对照组间的分布差异无统计学意义（P〉0．05）。（3）按性别分组，男性患者组中CT基因型分布频率显著高于男性对照组（X^2=7．654，P=0．022）。（4）MAOA基因的基因型和等位基因频率在家族史阴、阳性间的分布差异无统计学意义（P〉0．05）。结论没有发现MAOA基因多态性与汉族精神分裂症的发病有关联，但对性别发病有影响，基因型CT可能是男性精神分裂症发病的易感因素。     

炎症因子基因多态性与冠状动脉粥样硬化性心脏病的相关性

目的 研究中国南方汉族人群炎症因子基因多态性与冠状动脉粥样硬化性心脏病(简称冠心病)的相关性.方法 采用基质辅助激光解吸电离飞行时间质谱技术对283例经冠状动脉造影确诊的冠心病患者和176名对照者的5个炎症因子的基因多态性进行检测,评估不同基因型和等位基因与冠心病患病风险的关联性.结果 在受检测的5个炎症因子[乳腺癌易感基因1相关蛋白( BRCA1-associated protein,BRAP)、去整合素-金属蛋白酶8、中间a胰蛋白酶抑制因子H3、白细胞介素-15和环氧化酶-2]中,BRAP基因的270T/C及90A/G多态性在冠心病组与对照组间的差异有统计学意义,其等位基因和基因型的分布频率符合Hardy-Weinberg平衡(分别为:x2=0.878,P＞0.05;x2=0.776,P＞0.05).冠心病组BRAP 270C等位基因和90G等位基因频率高于对照组(分别为:29.51％vs.21.31％,P=0.006;30.04％ vs.21.31％,P=0.004).Logistic回归分析提示,BRAP 270CC和90GG基因型携带者患冠心病的发病风险高于BRAP 270TT和90AA基因型携带者(分别为:OR=4.51,95％CI:1.41～14.45,P=0.011;OR=5.09,95％CI:1.60～16.26,P=0.006),且该关联独立于性别、年龄、吸烟、高血压、糖尿病及血清总胆固醇、低密度脂蛋白胆固醇水平等风险因素之外.没有证据表明其余单核苷酸多态性与冠心病易感性相关.结论 BRAP基因内含子270T/C和外显子90A/G多态性可能是中国南方汉族人群冠心病发病的风险因素之一.     

Association between C13ORF31, NOD2, RIPK2 and TLR10 polymorphisms and urothelial bladder cancer

Several evidences have been published linking polymorphism in genes involved in chronic or recurrent inflammation with increased tumor risk and progression. Nevertheless the influence of innate immune receptors in urothelial cancer risk and characteristics has not been sufficient explored. We studied the possible association of polymorphisms in genes encoding NOD2, RIPK2, TLR10 and C13ORF31 with the risk, clinical/pathological characteristics and outcomes of urothelial cancer. We have found association between RIPK2 (rs42490) and cancer risk (AA vs AT&TT, p=0042). In addition, we found statistical differences in TLR10 (rs4129009) gen between low and high tumor infiltration stage (p=0.033). NOD2 (rs9302752) and RIPK2 (rs42490) were found to be associated with development of lymph node metastasis (p=0.011 and p=0.015). Importantly we detect association of TLR10 (Log Rank=0.035) and RIPK2 (Log Rank=0040) with overall survival. Multivariate Cox analysis revealed that both SNPs were survival prognosis factor independent of tumor stage and grade. Our results indicate that innate immunity receptors play a role in modulating urothelial cancer risk and progression.     

Association analysis between Tourette's syndrome and dopamine D1 receptor gene in Taiwanese children

OBJECTIVE: Recent research suggests that Tourette's syndrome (TS) may result from a defect in the dopamine system. The dopamine 1 receptor (DRD1) gene is a candidate gene in the study of the etiology of neuropsychiatric diseases that may involve dopaminergic abnormalities. We sought to test the hypothesis that the DRD1 gene might play a role in TS. METHODS: By performing an association study, we collected an independent sample of patients from the midland region of Taiwan and investigated whether DRD1 gene polymorphisms can be used as markers of susceptibility to TS. A total of 148 children with TS and 83 normal control subjects were included in the study. A polymerase chain reaction was used to identify the A/G polymorphism of the DRD1 gene. Genotypes and allelic frequencies for the DRD1 gene polymorphisms in both groups were compared. RESULTS: The results showed that genotypes and allelic frequencies for the DRD1 gene polymorphisms in both groups were not significantly different. CONCLUSION: These data suggest that DRD1 gene may not be a useful marker for prediction of the susceptibility of TS.     

No associations between Parkinson's disease and polymorphisms of the quinone oxidoreductase (NQO1, NQO2) genes

Reactive oxygen species derived from dopamine metabolism can induce oxidative stress and thus may contribute to Parkinson's disease (PD) pathogenesis. The quinone oxidoreductases, nicotinamide adenine dinucleotide (phosphate) (NAD[P]H): quinone oxidoreductase 1 (NQO1) and dihydronicotinamide riboside (NRH): quinone oxidoreductase 2 (NQO2) detoxify quinones and quinonoid compounds. We investigated associations of genetic polymorphisms of NQO1 (C609T) and NQO2 (I/D, 29 base pairs) with PD in a population-based case-control study of 190 idiopathic PD cases and 305 unrelated controls matched on age and sex. No associations were detected for either gene variant or for any allele combinations.     

Association between cytokine genes polymorphisms and type 1 diabetes: a case-control study on Saudi population

Background: Association studies of genes encoding cytokines that play an important role in inflammatory response represent one approach to finding type 1 diabetes (T1D) disease genes. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) within cytokine genes with T1D in a cohort of Saudi subjects. Methods: A total of 300 well-characterized type 1 diabetic patients and 300 T1D-free control subjects were enrolled in this investigation. Cytokine SNPs were genotyped by using Polymerase chain reaction (PCR) with sequence-specific primers. Results: Our data revealed that IFN-γ +874T allele carriers [odds ratio (OR) = 1.87, p < 0.001] and TT homozygotes (OR = 1.28, p < 0.001) were significantly more susceptible to developing T1D than the A allele carriers. In addition, TNF-α ?308A allele carriers (OR = 1.73, p < 0.001) and AA homozygotes (OR = 1.74, p < 0.001) were also overrepresented among the diabetics than G allele carriers. IL-4 ?590C/T TT homozygotes (OR = 2.23, p < 0.001) were significantly more susceptible to develop T1D than CC genotypes, whereas CT heterozygotes were not significantly associated (OR = 1.43, p = 0.78) with T1D. Furthermore, IL-4 T allele was statistically associated with T1D patients compared to control group (OR = 2.24, p < 0.001). Similarly, IL-1β ?511C/T TT homozygotes (OR = 1.85, p = 0.012) and the T allele (OR = 1.85, p < 0.001) were significantly more susceptible to T1D than CC genotypes, whereas TC heterozygotes (OR = 1.04, p = 0.86) were not significantly associated with T1D. Conclusion: Our data concluded that IFN-γ +874T allele, TNF-α ?308A allele, IL-1β ?511T allele, and IL-4 ?590T allele could be considered risk factors for T1D development in Saudi subjects.     

Association study between CYP24A1 gene polymorphisms and cancer risk

CYP24A1, an essential gene in regulation of vitamin D, has been reported to play an important role in enhancing immune activity and inhibiting tumorigenesis. Previous studies proposed that rs2585428, rs4809960, rs6022999 and rs6068816 in CYP24A1 gene might be greatly associated with cancer risk. To validate the findings, we here investigated the associations of these four polymorphisms and colorectal cancer (CRC) risk in a central Chinese population (426 colon cancer patients, 361 rectal cancer patients and 800 healthy controls). The genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by sequencing. Our results revealed that the rs4809960 and rs6022999 were strongly associated with the CRC risk, especially with the colon cancer risk. Moreover, the analysis of haplotypes consisting of rs2585428(G > A), rs4809960(T > C), rs6022999(A > G) and rs6068816(C > T) indicated that haplotype ATGC significantly decreased the CRC risk, especially the colon cancer risk. Haplotype GCAT significantly increased the CRC risk, especially the rectal cancer risk. However, haplotype ACAC was only found to be associated with increased risk of CRC. To improve the statistical strength, an updated meta-analysis was further performed. The results showed that rs2585428 was associated with cancer risk in Caucasian population, rs4809960 was associated with breast cancer risk in Caucasian population, and rs6022999 was associated with cancer risk in Asian population. Collectively, the rs4809960 and rs6022999 may be the genetic biomarkers for prediction of colon cancer risk in Chinese population, the rs2585428 and rs6022999 may link to cancer susceptibility in Caucasian population and in Asian population respectly.     

Association between Parkinson's disease and polymorphisms in the nNOS and iNOS genes in a community-based case-control study

Excess of nitric oxide (NO) has been shown to exert neurotoxic impacts in the brain. Moreover, inhibition of two NO-synthesizing enzymes, neuronal NOS (nNOS) and inducible NOS (iNOS), displays neuroprotective effects in the MPTP model of Parkinson's disease (PD). These data suggest a possible involvement of NOS as factors controlling the resistance of the nigral dopaminergic neurons to environmental insults. Therefore, we investigated whether polymorphisms present in these genes could contribute to the risk of developing PD. We carried out a community-based case-control study among subjects enrolled in the Mutualité Sociale Agricole, the French health insurance organization for workers connected to agriculture. Two-hundred and nine PD patients and 488 controls of European (mostly French) ancestry and matched for age, sex and region of residency were included in this study. Associations were observed with polymorphisms present in exon 22 of iNOS (OR for AA carriers=0.50, 95% CI=0.29-0.86, P=0.01) and in exon 29 of nNOS (OR for carriers of the T allele=1.53, 95% CI=1.08-2.16, P=0.02); no association was observed with a polymorphism in exon 18 of nNOS (OR for carriers of the T allele=1.20, 95% CI=0.85-1.69, P=0.30). Moreover, a significant interaction of the nNOS polymorphisms with current and ever cigarette smoking was found (nNOS 18, P=0.05; nNOS 29, P=0.04). All together, these data favour an involvement of these two genes as new modifier genes in PD.     

CACNB2基因多态性与原发性高血压的关联性研究

目的 探讨钙离子通道β2亚基基因(calcium channel β2 gene,CACNB2)多态性与温州汉族人群原发性高血压的相关性及应用荧光素酶报告基因技术检测rs7069292不同等位基因对基因表达的影响.方法 收集原发性高血压患者637例,以血压正常者600名作对照,采用飞行时间质谱分型技术对CACNB2基因rs2228645、rs2357928、rs7069292、rs7099380、rs10764319和rs11014166共6个SNP位点进行分型.构建CACNB2基因5’上游-2831 bp到-2460 bp的rs7069292的侧翼序列的荧光素酶报告基因载体.结果 高血压组rs7069292 CT基因型频率及C等位基因频率高于正常对照组(5.20％ vs.2.17％,2.59％ vs.1.08％,均P＜0.05),分型未发现rs7069292 CC基因型;含rs7069292 C等位基因的启动子活性与T等位基因相比明显增高,差异有统计学意义(P＜0.05);其余5个SNP位点各基因型频率及等位基因频率与对照组比较差异均无统计学意义(均P＞0.05).结论 CA CNB2基因rs7069292多态性与温州汉族人群原发性高血压病有关联,T＞C变异可能是CACNB2基因功能表达的一个影响因子.