Polymorphism In Regulatory Region Research Articles

Association between tridimensional personality questionnaire (TPQ) traits and three functional polymorphisms: dopamine receptor D4 (DRD4), serotonin transporter promoter region (5-HTTLPR) and catechol O-methyltransferase (COMT).

Dopamine D4 receptor (DRD4), serotonin transporter promoter regulatory region (5-HTTLPR) and catechol O-methyltransferase (COMT) polymorphisms were examined for association with TPQ personality factors in 455 subjects. Significant interactions were observed by multivariate analysis, (COMT x 5-HTTLPR: Hotelling's Trace = 2.3, P = 0.02) and by subsequent univariate 3-way ANOVA when Novelty Seeking (NS) was the dependent variable: 5-HTTLPR x D4DR (F = 6.18, P = 0.03) and COMT x 5-HTTLPR (F = 4.42, P = 0.03). In the absence of the short 5-HTTLPR allele and in the presence of the high enzyme activity COMT val/val genotype, NS scores are higher in the presence of the DRD4 seven-repeat allele. The effect of these three polymorphisms on NS was also examined using a within-families design. Siblings who shared identical genotype groups for all three polymorphisms (COMT, DRD4 and 5-HTTLPR) had significantly correlated NS scores (intraclass coefficient = 0.39, F = 2.26, P = 0.008, n = 49) whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for NS scores (intraclass coefficient = 0.177, F = 1.43, P = 0.09, n = 110). Similar interactions were also observed between these three polymorphisms and Novelty Seeking when the 150 independently recruited and non-related subjects were analyzed. The current results are consistent with two earlier reports in which we demonstrated an interaction between the 5-HTTLPR and DRD4 polymorphisms in 2-week-old neonates, in the same children assessed again at 2 months of age and in adults. Molecular Psychiatry (2000) 5, 96-100.

Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region.

To analyze the genotypes of the promoter region of the serotonin transporter gene (5-HTT) in patients with fibromyalgia (FM). Genomic DNA from 62 patients meeting the American College of Rheumatology 1990 criteria for FM and 110 healthy controls was analyzed by polymerase chain reaction. Additionally, the psychopathologic state of 52 of the FM patients was evaluated using the Beck Depression Inventory (BDI) and the Symptom Checklist-90-Revised (SCL-90-R). The 5-HTTLPR genotypes in FM patients versus controls were distributed as follows: L/L 27% versus 34%, L/S 42% versus 50%, and S/S 31% versus 16%. FM patients with the S/S genotype had higher mean scores on the BDI and the SCL-90-R compared with those in the L/L and L/S groups. A higher frequency of the S/S genotype of 5-HTT was found in FM patients compared with healthy controls. The S/S subgroup exhibited higher mean levels of depression and psychological distress. These results support the notion of altered serotonin metabolism in at least a subgroup of patients with FM.

APOE-491 promoter polymorphism is a risk factor for late-onset Alzheimer's disease.

The APOE e4 allele influences the occurrence of AD by lowering the age at disease onset.1 A case–control study of two (Spanish and North American) populations suggested an e4-independent association between an A/T polymorphism in the APOE regulatory region ( APOE −491) and sporadic AD,2 stronger in Spanish than in North American patients, thus suggesting genetic heterogeneity. Subsequent observations in different populations have been conflicting,3-6 ranging from a much weaker e4-independent association of APOE −491 and AD (alone3 or in association with other APOE polymorphisms4) to no5 or even a protective effect6 on the development of AD. So far, no association has been reported between this polymorphism and the age at AD onset. To explore this issue, we examined APOE −491 and e polymorphisms in Italian patients with AD and control subjects. A total of 358 white patients (age at disease onset 67.3 ± 9.3 [mean ± SD] years) affected by clinically probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria7 were enrolled. Patients were divided into those with an early onset (EO …

No interaction between serotonin transporter gene and dopamine receptorD4 gene in symptomatology of major psychoses

Previously, we reported an association of the dopamine receptor D4 (DRD4) gene with delusional symptomatology of major psychoses. However, DRD4 variants accounted for only 2% of the phenotypic variance, indicating that contributions from other genes were probable. The serotonin transporter gene is a primary candidate in major psychoses, and a functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has recently been reported to be associated with a number of psychopathological conditions. In the present study we investigated the original cohort of subjects to evaluate the 5-HTTLPR possible influence on the psychopathology of major psychoses in interaction with DRD4. Four hundred and sixty-one inpatients affected by major psychoses were assessed by the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and were also typed for the 5-HTTLPR and DRD4 variants using polymerase chain reaction techniques. Mania, depression, delusion, and disorganization were the four symptomatologic factors used as phenotype definition. 5-HTTLPR variants did not significantly influence the previously reported association of DRD4 with delusional symptoms. No interaction was observed on the other symptom factors. The serotonin transporter gene does not, therefore, interact with DRD4 in determining the symptomatology of major psychoses.

Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder.

Although modulation of symptoms of obsessive-compulsive disorder (OCD) by serotonergic agents is well established, it is unclear whether an abnormality in the central serotonergic system is involved in its etiology. The serotonin (5-HT) transporter (5-HTT), which is the key modulator of serotonergic neurotransmission, is the target for serotonin reuptake inhibiting drugs (SRIs) that are uniquely effective in the treatment of OCD. In this preliminary study we report an association of a functional polymorphism in the 5-HTT 5' regulatory-region and OCD. Seventy-five OCD Caucasian patients and 397 ethnically-matched individuals from a non-patient control group were genotyped for the 5-HTTLPR. Population-based association analysis revealed that patients with OCD were more likely to carry two copies of the long allele (l) as compared to controls (46.7% vs 32.3%: chi2 = 5.19, P = 0.023). This finding replicates a recent family-based study of this polymorphism in OCD, and thus indicates that the 5-HTTLPR may be associated with susceptibility to OCD.

No association between serotonin transporter gene polymorphisms and personality traits

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:430–436, 1999. © 1999 Wiley-Liss, Inc.

No association between serotonin transporter gene polymorphisms and personality traits

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study.

A Novel Polymorphism in the MCP-1 Gene Regulatory Region That Influences MCP-1 Expression

Two novel polymorphisms in the distal regulatory region of the MCP-1 gene were identified by directly sequencing PCR amplified genomic DNA. These polymorphisms are located at positions –2518 (G or A) and –2076 (A or T) relative to the major transcriptional start site of the gene. To examine the effect of these polymorphisms on MCP-1 transcription, polymorphic variants of the MCP-1 distal regulatory region were placed upstream of a luciferase reporter gene and transfected into A172 cells. IL-1β-induced luciferase activity was significantly greater from cells transfected with constructs containing G at position –2518. The polymorphism at –2076 did not affect MCP-1 transcription. IL-1β-treated peripheral blood mononuclear cells from individuals heterozygous or homozygous for G at –2518 produced more MCP-1 than cells from individuals homozygous for A at –2518. These data identify a polymorphism in the MCP-1 distal regulatory region that affects the level of MCP-1 expression in response to an inflammatory stimulus.

Serotonin transporter gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders.

Disturbances of the serotoninergic neutrotransmitter system have been implicated in the pathogenesis of mood disorders. A functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has been recently reported to be associated with both unipolar and bipolar disorder. In this study, we investigated the possibility that the 5-HTTLPR might be associated with depressive symptomatology in a sample of mood disorder subjects. One hundred and thirty-two psychiatric inpatients affected by major depressive (n = 67) and bipolar (n = 65) disorder (DSM-IV) were assessed at admission by the Hamilton Depression Rating Scale (HAMD-21, divided into Core, Sleep, Activity, Psychic anxiety, Somatic anxiety and Delusion clusters) and were typed using PCR techniques. The only prior treatment permitted was low dose benzodiazepines (<5 mg diazepam or equivalent); no prior (<2 weeks) antidepressant or neuroleptic treatment was allowed. 5-HTTLPR variants were not associated with total depressive symptomatology as measured by HAMD. The short 5-HTTLPR variant was marginally associated with higher psychic anxiety scores (F = 7.11, d.f. = 1,262, P = 0.008). The association was stronger among bipolars and early onset subjects. 5-HTTLPR variants were not associated with the remaining symptom clusters. The upstream regulatory region of the serotonin transporter gene has not, therefore, a major influence on the depressive symptomatology in mood disorder subjects.

Serotonin transporter gene not associated with psychotic symptomatology of mood disorders

A functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has been recently reported to be associated with mood disorders. In the present study we investigated the possible influence of 5-HTTLPR on the symptomatology of mood disorders. Two hundred and thirty inpatients affected by mood disorders (160 bipolar and 70 major depressive disorder) were assessed by the Operational Criteria checklist for psychotic illness (OPCRIT) and were also typed for the 5-HTTLPR variants using PCR techniques. Mania, Depression, Delusion and Disorganization were the four symptomatologic factors used as phenotype definition. 5-HTTLPR variants were not associated with these symptomatologic factors, and consideration of possible stratification effects, such as sex, age of onset and polarity, did not reveal any association either. The serotonin transporter gene does not, therefore, appear to be associated with the symptomatology of mood disorders.

Study of the association between the serotonin transporter gene regulatory region polymorphism and personality traits in a Japanese population

Recently a relationship between serotonin transporter transcriptional control region (5-HTTLPR) polymorphism and anxiety related personality traits in Caucasians was reported. We performed PCR of DNAs from the blood for determining the 5-HTTLPR genotypes of 191 Japanese subjects, which were medical staff and students, and obtained Revised NEO Personality Inventory (NEO-PI-R) and the Temperament and Character Inventory (TCI) in 144 subjects. The association was analyzed by one-way ANOVA. The present study demonstrated that allelic frequency of 5-HTTLPR (s allele frequency was 0.785) in our subjects was considerably different from that in Caucasians. No significant differences were found in the anxiety-related personality traits among genotypes, while cooperativeness in TCI showed a significant difference among genotypes. The property of 5-HTTLPR may not be reflected directory on the personality inventories.

Serotonin transporter gene is not associated with symptomatology of schizophrenia

The serotonin transporter gene is a primary candidate for involvement in major psychoses. A functional polymorphism in the upstream regulatory region of the serotonin transporter gene (5-HTTLPR) has recently been reported to be associated with a variety of psychopathological conditions. In the present study, we investigated the potential influence of the 5-HTTLPR on the psychopathology of schizophrenia. One hundred and sixty-one inpatients affected by schizophrenia (DSMIII-R) were assessed by the Operational Criteria checklist for psychotic illness (OPCRIT) and were typed for their 5-HTTLPR variants by PCR techniques. Mania, Depression, Delusion and Disorganization were the four symptomatologic factors used to define phenotype. 5-HTTLPR variants 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. The serotonin transporter gene is not a liability factor for the symptomatology of schizophrenia.

Apolipoprotein E regulatory region genotype in schizophrenia

Clinical observations indicate that a proportion of patients with schizophrenia experience cognitive impairment, which suggests that a neurodegenerative basis might be involved in the etiology of schizophrenia. Apolipoprotein E (ApoE), which has been confirmed to be genetically associated with Alzheimer's disease, is thus highlighted as a candidate gene for schizophrenia. Recently, novel functional polymorphisms in the ApoE transcriptional regulatory region have been found. To investigate whether these polymorphisms are associated with the risk of schizophrenia, we genotyped 144 patients with schizophrenia and 134 controls for two polymorphisms (−491A/T and −219G/T). No significant positive associations between both polymorphisms and schizophrenia were observed. Our findings exclude the regulatory region of the ApoE gene as a locus that might confer increased susceptibility to schizophrenia.

Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression.

Allelic variants for the HIV-1 co-receptors chemokine receptor 5 (CCR5) and CCR2, as well as the ligand for the co-receptor CXCR4, stromal-derived factor (SDF-1), have been associated with a delay in disease progression. We began this study to test whether polymorphisms in the CCR5 regulatory regions influence the course of HIV-1 disease, as well as to examine the role of the previously identified allelic variants in 1,090 HIV-1 infected individuals. Here we describe the evolutionary relationships between the phenotypically important CCR5 alleles, define precisely the CCR5 regulatory sequences that are linked to the CCR5-delta32 and CCR2-641 polymorphisms, and identify genotypes associated with altered rates of HIV-1 disease progression. The disease-retarding effects of the CCR2-641 allele were found in African Americans but not in Caucasians, and the SDF1-3'A/3'A genotype was associated with an accelerated progression to death. In contrast, the CCR5-delta32 allele and a CCR5 promoter mutation with which it is tightly linked were associated with limited disease-retarding effects. Collectively, these findings draw attention to a complex array of genetic determinants in the HIV-host interplay.

Absence of association between Alzheimer disease and the −491 regulatory region polymorphism of APOE

A novel polymorphism (−491 A/T) within the regulatory region on the apolipoprotein E gene has recently been reported to be associated with risk for Alzheimer disease (AD). To test this association in an independent data set, we have examined this polymorphism in a sample of 88 well-characterized AD cases and compared the allele frequency and genotype frequencies for this polymorphism with those observed in 112 cognitively normal subjects drawn from the same ethnic group. These results suggest that in the current data set at least, the −491 A/T polymorphism is not associated with risk for AD, but may be in partial linkage disequilibrium with the APOE ϵ2/ ϵ3/ ϵ4 polymorphism.

Polymorphism in the Iα1 Germ-Line Transcript Regulatory Region and IgA Productivity in Patients with IgA Nephropathy

Abstract Enhanced in vivo and in vitro production of IgA has been reported in patients with IgA nephropathy (IgAN) and their family members. It is generally considered that IgA1 is a prominent subclass of IgA in IgAN. Although genetic mechanisms of IgA class switch recombination in IgAN have been studied enthusiastically, the critical factors that induce IgA1-specific class switching in IgAN have yet to be elucidated. A large body of data indicates that the germ-line transcript of Ig constant region (CH) genes that precedes actual class switching has regulatory effects on class switch recombination. To analyze structural abnormalities in the Iα1 germ-line transcript regulatory gene, a region about 1000 bp long located upstream of Iα1 exons was surveyed by the PCR-single strand conformation polymorphism method, and the polymorphism detected was confirmed by subsequent DNA sequencing. Three hot spots for point mutation were detected upstream of the promoter region of the Iα1 germ-line transcript, and the mutations were observed more frequently in patients than in controls. Patients with the mutations showed higher levels of serum IgA and higher in vitro IgA synthesis. In the luciferase assay, the regulatory gene with the mutations showed a potent effect for induction of the Iα1 germ-line transcript. The polymorphism in the Iα1 regulatory region possibly causes enhanced IgA production in some patients with IgAN.

Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene

In this work, we explored the existence of genetic variants within the apolipoprotein E gene transcriptional regulatory region, using a denaturing gradient gel electrophoresis screening of a region comprising nucleotides −1017 to +406. Upon a population study, three new polymorphic sites (−491, −427 and −219) and two mutations were found. Functional effects of the polymorphisms, assayed by transient transfection and electrophoretic mobility shift assays in a human hepatoma cell line, showed that polymorphisms at sites −491 and −219 of the APOE promoter produce variations in the transcriptional activity of the gene, most probably through differential binding of nuclear proteins.

Serotonin transporter (5-HTT) gene variants associated with autism?

An association study was performed to elucidate the role of the serotonin transporter (5-HTT) gene as a susceptibility factor for autism as treatment of patients with antidepressant drugs which selectively target 5-HTT reduced autistic or concomitant symptoms, such as repetitive behavior and aggression, and ameliorate language use. Using the transmission/disequilibrium test (TDT) an analysis was done for a common polymorphism in the upstream regulatory region (5-HTTLPR), a VNTR in intron 2 of the gene and a haplotype of both loci in 52 trios fulfilling stringent criteria for autism and an extended group of 65 trios including patients showing no language delay in their first 3 years of life. A higher frequency and preferential transmission of the long allele of the 5-HTTLPR was observed, but the TDT gave a statistically significant value ( P = 0. 032) only for the extended patient group. This result is in contrast to a recent study by a US group presenting preliminary evidence for preferential transmission of the short allele of 5-HTTLPR in 86 trios. Both studies failed to reveal significant linkage disequilibrium between the VNTR in intron 2 of the gene and autism. In our study haplotype analysis of the 5-HTTLPR and the VNTR in intron 2 supplied evidence for an association of 5-HTT and autism in the stringent ( P = 0.069) and extended patient group ( P = 0.049). Overall, we were not able to replicate the findings of the first study on 5-HTT and autism and instead observed a tendency for association of the opposite genetic variant of the gene with the disorder. The implications for genetic variants of the serotonin transporter in the etiology of autism and possible subgroups of patients, therefore, needs clarification in further studies with other and larger patient samples.

Serotonin transporter gene regulatory region polymorphism and anxiety-related traits in the Japanese.

American Journal of Medical GeneticsVolume 74, Issue 5 p. 544-545 Brief Clinical Report Serotonin transporter gene regulatory region polymorphism and anxiety-related traits in the Japanese Toshiaki Nakamura, Toshiaki Nakamura Department of Psychiatry, Kurihama National Hospital, Kanagawa, JapanSearch for more papers by this authorTaro Muramatsu, Corresponding Author Taro Muramatsu Department of Psychiatry, Kurihama National Hospital, Kanagawa, JapanDepartment of Psychiatry, Kurihama National Hospital, 5-3-1 Nobi Yokosuka, Kanagawa 239, JapanSearch for more papers by this authorYutaka Ono, Yutaka Ono Department of Neuropsychiatry, Keio University School of Medicine, Keio, JapanSearch for more papers by this authorSachio Matsushita, Sachio Matsushita Department of Psychiatry, Kurihama National Hospital, Kanagawa, JapanSearch for more papers by this authorSusumu Higuchi, Susumu Higuchi Department of Psychiatry, Kurihama National Hospital, Kanagawa, JapanSearch for more papers by this authorHiroko Mizushima, Hiroko Mizushima Department of Neuropsychiatry, Keio University School of Medicine, Keio, JapanSearch for more papers by this authorKimio Yoshimura, Kimio Yoshimura Department of Neuropsychiatry, Keio University School of Medicine, Keio, JapanSearch for more papers by this authorShigenobu Kanba, Shigenobu Kanba Department of Neuropsychiatry, Yamanashi Medical University, Yamanashi, JapanSearch for more papers by this authorMasahiro Asai, Masahiro Asai Department of Neuropsychiatry, Keio University School of Medicine, Keio, JapanSearch for more papers by this author Toshiaki Nakamura, Toshiaki Nakamura Department of Psychiatry, Kurihama National Hospital, Kanagawa, JapanSearch for more papers by this authorTaro Muramatsu, Corresponding Author Taro Muramatsu Department of Psychiatry, Kurihama National Hospital, Kanagawa, JapanDepartment of Psychiatry, Kurihama National Hospital, 5-3-1 Nobi Yokosuka, Kanagawa 239, JapanSearch for more papers by this authorYutaka Ono, Yutaka Ono Department of Neuropsychiatry, Keio University School of Medicine, Keio, JapanSearch for more papers by this authorSachio Matsushita, Sachio Matsushita Department of Psychiatry, Kurihama National Hospital, Kanagawa, JapanSearch for more papers by this authorSusumu Higuchi, Susumu Higuchi Department of Psychiatry, Kurihama National Hospital, Kanagawa, JapanSearch for more papers by this authorHiroko Mizushima, Hiroko Mizushima Department of Neuropsychiatry, Keio University School of Medicine, Keio, JapanSearch for more papers by this authorKimio Yoshimura, Kimio Yoshimura Department of Neuropsychiatry, Keio University School of Medicine, Keio, JapanSearch for more papers by this authorShigenobu Kanba, Shigenobu Kanba Department of Neuropsychiatry, Yamanashi Medical University, Yamanashi, JapanSearch for more papers by this authorMasahiro Asai, Masahiro Asai Department of Neuropsychiatry, Keio University School of Medicine, Keio, JapanSearch for more papers by this author First published: 24 October 2002 https://doi.org/10.1002/(SICI)1096-8628(19970919)74:5<544::AID-AJMG18>3.0.CO;2-CCitations: 71AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume74, Issue519 September 1997Pages 544-545 RelatedInformation

No association between the serotonin transporter gene regulatory region polymorphism and the Tridimensional Personality Questionnaire (TPQ) temperament of harm avoidance.

A functional polymorphism in the upstream regulatory region of the serotonin transporter gene has been recently reported to be associated with anxiety-related traits assessed by the NEO-PI-R. Individuals both hetero- and homozygous for the short form of a highly repetitive regulatory element in this gene have significantly higher neuroticism scores. We have attempted to replicate these findings in a normal cohort of 120 individuals, whom we have previously examined for association between personality dimensions and other serotonergic and dopaminergic receptor polymorphisms. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality dimensions in this cohort. No association was observed in the present study between individuals grouped by the long and short form of the transporter gene and any of the personality dimensions measured by the TPQ including Harm Avoidance, which incorporates many aspects of anxiety and is correlated with NEO-PI-R Neuroticism.