Association between variation in the vesicular monoamine transporter 1 gene on chromosome 8p and anxiety-related personality traits

Vesicular monoamine transporters are involved in the presynaptic packaging of norepinephrine, dopamine and serotonin into storage vesicles. The vesicles release their content upon arrival of an action potential into the synaptic cleft. Dysregulation of monoaminergic neurotransmission has been long postulated to play a relevant role in the etiology of neuropsychiatric disorders. The gene encoding the vesicular monoamine transporter 1 (VMAT1/SLC18A1) maps to chromosome 8p21, a region where several linkage peaks overlap between schizophrenia, bipolar disorder and anxiety-related personality traits. In this study, we tested the hypothesis that the missence variation Thr136Ile in the VMAT1/SLC18A1 gene is associated with anxiety-related personality traits. We tested a total of 337 unrelated subjects of German descent (167 male, 170 female). All participants were carefully screened for psychiatric disorders. The self-report State–Trait Anxiety Inventory (STAI) was completed by all subjects. Genotypes were obtained for the Thr136Ile (rs1390938) variation in the VMAT1 gene for all subjects. Genotype effects on personality variables were computed with MANOVA including age as a co-variant and gender as independent factor (MANCOVA). Results show that STAI scores were significantly affected by genotype (F = 3.108; d.f. = 4,331; p = 0.015) and age (F = 7.233; d.f. = 2,331; p = 0.001) but not by gender. A gender-by-genotype effect was observed for both the STAI state (p = 0.052) and trait score (p = 0.035). Dissection of the group by gender and subsequent contrast analysis of the genotype effects performed within the female group showed significant results (STAI state: Thr/Ile vs. Ile/Ile: T = 4.408, p = 0.0004; STAI trait: Thr/Ile vs. Ile/Ile: T = 3.074, p = 0.009) but not in the male group. Our findings support the hypothesis that anxiety-related personality traits are associated with variation in the VMAT1/SLC18A1 gene.     

The effect of a monoclonal antibody to calcitonin-gene related peptide (CGRP) on injury-induced ectopic discharge following lingual nerve injury

The development of ectopic neural discharge at a site of peripheral nerve injury is thought to contribute to the initiation of sensory disturbances and pain. We have previously shown that this discharge can be initiated or increased by the neuropeptide calcitonin gene-related peptide (CGRP). We have now studied a potential therapeutic approach to reducing the discharge by evaluating the effect of a systemically administered monoclonal antibody to CGRP on injury-induced activity in the lingual nerve. In 16 anaesthetised adult ferrets the left lingual nerve was sectioned. One day after the injury, the animals received a subcutaneous injection of either a monoclonal antibody to CGRP or a vehicle control. Three days after the injury, under a second anaesthetic, single-unit electrophysiological recordings were made from central to the injury site (469 and 391 units were analysed in antibody and vehicle groups, respectively), and the proportion of units that were spontaneously active was determined. In the vehicle-treated animals 6.4 ± 2.7 [SEM]% of the units were spontaneously active, with conduction velocities of 8.8-40.8 m/s and discharge frequencies of 0.03-2.7 Hz. In the monoclonal antibody-treated animals 5.7 ± 2.0% of the units were spontaneously active, with conduction velocities of 13.9-38.8 m/s and discharge frequencies of 0.07-1.8 Hz. There was no significant difference between these two groups (for spontaneous activity and conduction velocity: p > 0.05, Student's t-test; for discharge frequency: p > 0.05, Mann-Whitney test), suggesting that the spontaneous activity initiated by a nerve injury cannot be modulated by administration of a monoclonal antibody to CGRP.     

TRPA1 expression in human lingual nerve neuromas in patients with and without symptoms of dysaesthesia

The TRPA1 receptor is a member of the ankyrin family and is found in both spinal and trigeminal neurones. There is evidence to suggest that this receptor may be a sensor of noxious thermal stimuli in normal animals. After nerve injury, TRPA1 shows increased expression in uninjured axons, and has been implicated in the development and maintenance of hyperalgesia. We examined expression of TRPA1 in lingual nerve neuromas and investigated any potential correlation with the presence or absence of symptoms of dysaesthesia. Thirteen neuroma-in-continuity specimens were obtained from patients undergoing repair of a lingual nerve that had previously been damaged during lower third molar removal. Visual analogue scales (VAS) were used to record the degree of pain, tingling and discomfort. Tissue was processed for indirect immunofluorescence and the percentage area of PGP 9.5-immunoreactive neuronal tissue also labelled for TRPA1 was quantified. No significant difference between levels of TRPA1 in neuromas from patients with or without symptoms of dysaesthesia and no relationship between TRPA1 expression and VAS scores for pain, tingling or discomfort were observed. TRPA1 expression and the time after initial injury that the specimen was obtained also showed no correlation. These data show that TRPA1 is expressed in lingual nerve neuromas, but, it appears that, at this site, TRPA1 does not play a principal role in the development of neuropathic pain.     

Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample

The serotonin transporter (5-HTT) regulates serotonergic neurotransmission and is thought to influence emotion. A 5-HTT-linked polymorphic region (5-HTTLPR) has two common variants, short (s) and long (l). We previously found population and within-family associations between the lower-expressing s allele and neuroticism, a trait related to anxiety, hostility, and depression, on a standard measure (the NEO Personality Inventory, Revised [NEO-PI-R]) in a primarily male population (n=505), and that the s allele was dominant. We investigated this association in a new sample (n=397, 84% female, primarily sib-pairs). The results robustly replicated the 5-HTTLPR neuroticism association, and the dominance of the s allele. Combined data from the two studies (n=902) showed a highly significant association between the s allele and higher NEO Neuroticism both across individuals and within families. Association between genotype and a related measure, Anxiety on the 16PF inventory, was replicated in the new population and within families in the combined sample. Association to another trait, estimated TPQ Harm Avoidance, was not replicated in the new sample but found only within the combined sibship group. Another association found in our original study, between the s allele and lower scores on NEO-PI-R Agreeableness, was also replicated and was more robust in the current and the combined samples. Associations between the functional 5-HTTLPR polymorphism were similar in women and men. These results help to define specific personality features reproducibly associated with 5-HTTLPR genotype. Such associations were strongest for traits defined by the NEO, enhancing the attractiveness of the five-factor personality model in genetic research on complex behavioral dimensions. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:202-216, 2000. Published 2000 Wiley-Liss, Inc.     

Involvement of GluR2 and GluR3 subunit C-termini in the trigeminal spinal subnucleus caudalis and C1-C2 neurons in trigeminal neuropathic pain

To clarify the involvement of GluR2 and GluR3 subunits of AMPA receptor in orofacial neuropathic pain, we studied changes in nocifensive behavior and extracellular-signal regulated kinase (ERK) phosphorylation followed by infraorbital nerve (ION)-partial transection model applied to GluR2 or GluR3 delta7 knock-in (KI) mice. In these animals, last seven amino acids of GluR2 or GluR3 subunit, the binding sites of interacting protein, are deleted in vivo. Head-withdrawal threshold to mechanical stimulation of the whisker pad skin ipsilateral to ION-partial transection was significantly reduced at 1, 3, 5, 7, 11 and 14 days after transection compared with that before transection in wild-type mice. In the GluR2 and GluR3 delta7 KI mice, the head-withdrawal threshold did not change following ION-partial transection. The number of pERK-LI cells examined in Vc and C1-C2 in wild-type mice after the non-noxious stimulation was larger than that of GluR2 and GluR3 delta7 KI mice. The present findings suggest that GluR2 and GluR3 subunits of AMPA receptor play roles in the trigeminal nerve injury-mediated enhancement of Vc and C1-C2 neuronal excitability, and hyperalgesia.     

Effects of 17β-estradiol on glucose transporter 1 expression and endothelial cell survival following focal ischemia in the rats

To characterize various animal models of neuropathic pain, we compared three previously developed rat models using the same behavioral testing methods. These models involve: (1) chronic constriction injury by loose ligation of the sciatic nerve (CCI); (2) tight ligation of the partial sciatic nerve (PSL); and (3) tight ligation of spinal nerves (SNL). Comparisons were made for the time course of behavioral signs representing various components of neuropathic pain as well as for the effects of surgical sympathectomy. In general, all three methods of peripheral nerve injury produced behavioral signs of both ongoing and evoked pain with similar time courses. However, there was a considerable difference in the magnitude of each pain component between models. Signs of mechanical allodynia were largest in the SNL injury and smallest in the CCI model. On the other hand, behavioral signs representing ongoing pain were much more prominent in the CCI model than in the other two. Although the behavioral signs of neuropathic pain tended to decrease after sympathectomy in all three models, the change was most evident in the SNL model. The results of the present study suggest that the three rat models tested have contrasting features, yet all are useful neuropathic pain models, possibly representing different populations of human neuropathic pain patients.     

Loose ligation of the sciatic nerve in rats elicits transient up-regulation of Homer1a gene expression in the spinal dorsal horn

Changes in the expression of many genes underlie injury-elicited plasticity in the spinal dorsal horn. Homer1 is a recently identified gene that appears to play a critical role in the expression of synaptic plasticity in several brain regions, including the hippocampus. In this study we investigated the early consequences of chronic constriction injury of the sciatic nerve on Homer1 gene expression in the spinal dorsal horn. Significant increases in Homer1a mRNA levels in the ipsilateral dorsal horn were detected at 4h post-ligation, and these levels remained elevated at 8h before returning to baseline values by 24h after the ligation. In contrast, the levels of Homer1b/c mRNA did not change at any of these selected post-ligation times. The ligation-associated induction of Homer1a was dependent on activation of NMDA receptors and the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway. The non-competitive NMDA-receptor antagonist, MK-801, and a specific inhibitor of the ERK1/2 pathway, U0126, significantly attenuated the injury-elicited increases in Homer1a mRNA when compared to saline-treated animals. These data provide the first evidence for a potential role of Homer1a in peripheral nerve injury-elicited plasticity in the spinal dorsal horn. These data also imply that the early and transient up-regulation of Homer1a gene expression may be an important contributor to the eventual development of neuropathic pain.     

No association between the -3081A/T polymorphism in the norepinephrine transporter gene promoter and personality traits in healthy subjects

There have been several data suggesting that norepinephrine neurotransmission is involved in the characterization of personality traits. Recently, the -3081A/T polymorphism in the promoter region of the norepinephrine transporter (NET) gene affecting promoter activity has been reported. In the present study, we studied the association between this NET polymorphism and personality traits in 553 Japanese healthy subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the NET genotypes were identified by a PCR-RFLP method. Multivariate two-factor analysis of covariance with genotype and gender as factors and with age as a covariate showed no association between the NET genotypes and the TCI dimension scores. The present study thus suggests that the -3081A/T polymorphism in the NET gene promoter is not involved in the characterization of personality traits in healthy subjects.     

Association between the SPRY1 gene polymorphism and obesity-related traits and osteoporosis in Korean women

BackgroundEmerging evidence has revealed a close relationship between obesity and osteoporosis. It was reported recently that conditional knockout of the Spry1 gene in mice adipocytes causes an increase in body fat and a decrease in bone mass, and that these phenotypes are rescued by Spry1 overexpression in adipose tissue. In this study, we investigated whether genetic variation in the human SPRY1 gene is associated with obesity-related phenotypes and/or osteoporosis in humans.MethodsWe performed a candidate gene association analysis between the four single nucleotide polymorphisms (SNPs) and 14 imputed SNPs in the SPRY1 gene and obesity-related traits and osteoporosis in a Korean women cohort (3013 subjects).ResultsAll four SPRY1 gene SNPs were significantly associated with either obesity-related traits or osteoporosis. The TGCC haplotype in the SRPY1 gene showed simultaneous association with an increased risk for obesity-related traits, percentage body fat (p = 0.0087) and percentage abdominal fat (p = 0.047), and osteoporosis (odds ratio = 1.50; p = 0.025) in the recessive genetic model.ConclusionsOur results support a previous finding in conditional Spry1 gene knockout mice and suggest that the SPRY1 gene is an important genetic factor for determining the risk of both obesity and osteoporosis in humans.     

Association between interleukin-1 receptor antagonist gene and asthma-related traits in a German adult population

Background:  A recent study in German and Italian families associated variants in the interleukin-1 receptor antagonist (IL1RA) gene with asthma. The aim of the present study was to further investigate the role of single nucleotide polymorphisms (SNPs) in the IL1RA gene in the development of atopy and lifelong asthma in a population-based study.
Methods:  DNA samples from the German centres of the European Community Respiratory Health Survey were analysed for genetic variants in the IL1RA gene and the development of asthma, atopy and bronchial hyperreactivity.
Results:  Carriers of the rare G allele of SNP rs447713 had a significantly increased risk of developing asthma ( P  = 0.0013) and allergic sensitization ( P  = 0.0119). Carriers of the rare C allele of SNP rs3087271 had an increased risk of asthma ( P  = 0.0227) and high immunoglobulin E (IgE) levels ( P  = 0.0232). A haplotype built from eight SNPs in the IL1RA gene (A-C-A-G-A-C-G-A) was associated with a higher prevalence of asthma ( P  = 0.007) and high total IgE ( P  = 0.02). Bronchial hyperreactivity was positively associated with the haplotype A-C-G-G-A-C-G-C ( P  = 0.02) and negatively with the A-C-G-G-A-C-T-C ( P  = 0.03).
Conclusion:  A previously described association between IL1RA and asthma in families could be reproduced in a population-based sample. The genetic variants of IL1RA gene do not to seem to affect asthma alone, but to act as modulators of asthma-related traits as well, where different haplotypes drive the development of different phenotypes.     

SLC22A12基因第8外显子和第8内含子多态与中国汉族人原发性高尿酸血症关联研究

目的 研究原发性高尿酸血症患者SLC22AI2基因第8内含子和第8外显子单核苷酸多态(single nucleotide polymorphism,SNP)位点与原发性高尿酸血症遗传易感性的关系.方法 选择山东沿海地区原发性高尿酸血症患者215例,正常对照人群323名.提取基因组DNA,PCR扩增SLC22A12基因第8内含子和第8外显子,对PCR扩增产物进行测序.结果 序列分析发现:(1)SLC22AI2基因第8外显子存在T1309C单核苷酸多态,第8内含子存在-103A＞G单核苷酸多态,这2个多态位点完全连锁.(2)高尿酸血症组-103A＞G G等位基因频率和T1309C C等位基因频率明显高于正常对照组(均为51.9%vs.42.4%,P＜0.01);(3)高尿酸血症组GG+GA基因型频率和CC+CT基因型频率显著高于正常对照组(均为80.0%vs.69.0%,P＜0.01).(4)-103 A＞G和T1309C基因多态中,含有等位基因G的基因型GG+GA及含有等位基因C的基因型CC+CT均使高尿酸血症的发病危险性上升了1.79倍(OR=1.79,95%CI:1.19～2.70).结论 SLC22A12基因第8外显子T130gC及第8内含子-103A＞G SNP与原发性高尿酸血症密切相关.     

Association between genes on chromosome 4p16 and non-syndromic oral clefts in four populations

Isolated cleft lip with or without cleft palate and cleft palate are among the most common human birth defects. Several candidate gene studies on MSX1 have shown significant association between markers in MSX1 and risk of oral clefts, and re-sequencing studies have identified multiple mutations in MSX1 in a small minority of cases, which may account for 1–2% of all isolated oral clefts cases. We explored the 2-Mb region around MSX1, using a marker map of 393 single nucleotide polymorphisms (SNPs) in 297 cleft lip, with or without cleft palate, case–parent trios and 84 cleft palate trios from Maryland, Taiwan, Singapore, and Korea. Both individual markers and haplotypes of two to five SNPs showed several regions yielding statistical evidence for linkage and disequilibrium. Two genes (STK32B and EVC) yielded consistent evidence from cleft lip, with or without cleft palate, trios in all four populations. These two genes plus EVC2 also yielded suggestive evidence for linkage and disequilibrium among cleft palate trios. This analysis suggests that several genes, not just MSX1, in this region may influence risk of oral clefts.     

Association study between a functional polymorphism of FK506-binding protein 51 (FKBP5) gene and personality traits in healthy subjects

Previous studies have shown that the function of hypothalamic-pituitary-adrenal (HPA) axis is involved in the characterization of personality traits. FK506-binding protein 51 (FKBP51 or FKBP5) is a co-chaperone of heat-shock protein 90, and plays an important role in the negative feedback regulation of HPA axis function. It has been reported that a C/T single nucleotide polymorphism in the intron 2 of FKBP5 gene (rs1360780) affects FKBP5 protein levels and cortisol response to dexamethasone and psychological stress tests. Therefore, it is hypothesized that the FKBP5 polymorphism affects personality traits. In the present study, we studied the association between this polymorphism and personality traits in 826 Japanese healthy subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the FKBP5 genotype was detected by a real-time PCR and cycling probe technology for SNP typing. In total subjects, the group with the T allele predictive of impaired negative feedback regulation of the HPA axis had higher scores of harm avoidance (HA) (p = 0.043) and lower scores of cooperativeness (CO) (p = 0.019) compared to that without the T allele. The T allele was associated with higher scores of HA in females (p = 0.020) and lower scores of CO in males (p = 0.015). The present study thus suggests that the FKBP5 polymorphism affects HA and CO in healthy subjects, with gender specificity.     

Lack of association between polymorphisms of the dopamine receptor D4 and dopamine transporter genes and personality traits in a Korean population

Human personality traits have a considerable genetic component. Cloninger et al. were the first to postulate that certain personality traits, such as novelty seeking, are related to the dopamine neurotransmitter system. In this study, we investigated the associations between dopamine receptor D4 (DRD4) exon III and dopamine transporter (DAT1) polymorphisms and personality traits. The DRD4 and DAT1 gene polymorphisms were genotyped in 214 healthy Korean subjects, whose personality traits were assessed with the Temperament and Character Inventory (TCI). There were no significant differences between scores of TCI temperament dimensions (novelty seeking, harm avoidance, reward dependence, and persistence) and DRD4 gene polymorphism. The DAT1 gene polymorphisms also showed no significant association with any of the temperament subscales of the TCI. These data suggest that DRD4 and DAT1 gene polymorphism may not associated with personality traits in a Korean population.     

Lack of association between the serotonin transporter promoter polymorphism (5-HTTLPR) and personality traits in asymptomatic patients with panic disorder

The serotonin transporter promoter polymorphism (5-HTTLPR) has been investigated regarding its association with neuroticism, which, in its turn, is a personality dimension often found in patients with panic disorder (PD). It has been recently evidenced that the long 5-HTTLPR polymorphism has a genetic variation (Lg), which is related to its lower expression. The objective of this study was to assess the association between the 5-HTTLPR polymorphism in the triallelic system and the neurotic personality traits in patients in PD remission. Sixty-seven Caucasian patients with PD diagnosis according to the DSM-IV-TR assessed with the MINI (mini international neuropsychiatric interview) were included. The MMPI (Minnesota multiphasic personality inventory) was used to assess the personality. The remission of PD symptoms was defined as CGI (clinical global impression) 相似文献   

Association between four SNPs on chromosome 9p21 and myocardial infarction is replicated in an Italian population

Genome-wide single nucleotide polymorphism (SNP) association studies recently identified four SNPs (rs10757274, rs2383206, rs2383207, and rs10757278) on chromosome 9p21 that were associated with coronary artery disease (CAD) and myocardial infarction (MI) in Caucasian populations from northern Europe and North America. Our aim was to determine whether these SNPs were associated with MI in a southern Europe/Mediterranean population. We employed a case–control association design involving 416 MI patients and 308 non-MI controls from Italy. Significant allelic association was identified between all four SNPs and MI. The association remained significant after adjusting for covariates for MI (P = 0.007–0.029). One risk haplotype (GGGG; P = 0.028) and one protective haplotype (AAAA; P = 0.047) were identified. Genotypic association analysis demonstrated that the SNPs conferred susceptibility to MI most likely in a dominant model (P = 0.0007–0.013). When the case cohort was divided into a group of MI patients with a family history (n = 248) and one group without it (n = 168), the positive, significant association was identified only in the group with the family history. These results indicate that chromosome 9p21 confers risk for development of MI in an Italian population. G.-Q. Shen, S. Rao, N. Martinelli, L. Li contributed equally to this work.     

Examination of PPP1R3B as a candidate gene for the type 2 diabetes and MODY loci on chromosome 8p23

The product of the PPP1R3B gene (G_L) is the regulatory subunit of PP1 ‐ a serine/threonine phosphatase involved in the modulation of glycogen synthesis in the liver and skeletal muscle. The PPP1R3B gene is located on chromosome 8p23 in a region that has been linked with type 2 diabetes and maturity‐onset diabetes of the young (MODY). We examined whether sequence variants at the PPP1R3B locus are responsible for the linkage with diabetes observed at this location. RT‐PCR analysis revealed the existence of two alternative promoters. These and the two exons of this gene were sequenced in the probands of 13 Joslin families showing the strongest evidence of linkage at 8p23. A total of 20 variants were observed: two in the 5′ flanking region, one in the intron (9 bp 5′ of exon 2), and 17 in the 3′ UTR. The intronic variant generated a new acceptor splice site, resulting in an alternative splice variant with a longer 5′ UTR. However, neither this nor other variants segregated with diabetes in the 13 ‘linked’ families. Furthermore, allele frequencies were similar in 90 family probands from the Joslin Study and 347 unrelated controls. Thus, genetic variability in the PPP1R3B gene does not appear to contribute to diabetes in our mostly Caucasian families. However, a role cannot be excluded in other populations such as the Japanese, among whom linkage to diabetes is also observed at 8p23 and a non‐synonymous mutation has been detected in the PPP1R3B gene.     

Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder

We describe the identification and clinical presentation of four individuals from three unrelated families with hemizygous deletions involving the DPYD gene at chromosome 1p21.3. DPYD encodes dihydropyrimidine dehydrogenase, which is the initial and rate-limiting enzyme in the catabolism of pyrimidine bases. All four individuals described met diagnostic criteria for autism spectrum disorder with severe speech delay. Patient 1's deletion was originally reported in 2008, and more detailed clinical information is provided. Subsequently, this male individual was found to have a missense mutation in the X-linked PTCHD1 autism susceptibility gene, which may also contribute to the phenotype. Patients 2 and 3 are siblings with a novel deletion encompassing the DPYD gene. In their mother, the genomic region deleted from chromosome 1p21.3 was inserted into chromosome 10. A fourth proband had a novel 10-kb intragenic deletion of exon 6 of the DPYD gene detected on a higher resolution microarray. Our study suggests that hemizygous deletions involving the DPYD locus present with variable phenotypes which can include speech delay and autistic features, and may also be influenced by additional mutations in other genes, issues which need to be considered in genetic counseling.     

屏氧酶1与ATP结合盒转运子A1基因多态性的相互作用对血脂的影响

目的探讨屏氧酶1(paranoxonase 1, PON1)基因多态性与ATP结合盒转运子A1基因(ATP-binding cassette transporter 1, ABCA1)多态性对血脂水平的相互作用.方法 1019例受试者,其中680例脑卒中患者及339名正常对照组人群.采用聚合酶链反应-限制性片段长度多态性方法测定 PON1 A/B192和 ABCA1 R219K基因多态性.结果 PON1 A/B192各基因型之间血脂水平差异无统计学意义(P>0.05).在 ABCA1的RR、RK和KK 3种基因型中,HDL-C水平依次明显上升(P<0.05);TG水平依次呈下降趋势,相互之间差异无统计学意义.PON1基因型影响 ABCA1基因型与血脂的关系,AA型/RR型和BB型/KK型的HDL-C[(1.41±0.40)mmol/L,(1.41±0.39)mmol/L]高于BB型/RR型[(1.28±0.36)mmol/L],差异有统计学意义(P<0.05).结论 PON1基因型与ABCA1基因型的相互作用影响血脂水平.