Serotonin 1A receptor genetic variations, suicide, and life events in the Iranian population

Aim: The association of serotonin 1A receptor (5‐HTR1A) gene polymorphisms with suicidal behavior has been reported in several previous studies, but the results have been inconsistent, which might be due to ethnic differences. The aim of the present study was therefore to investigate the association between polymorphisms ?1019C>G, 47C>T (Pro16Leu) and 815G>A (Gly272Asp) and suicidal behavior, taking into account age, gender, and the presence of stressful life and loss events in 1 year prior to suicide. Methods: A total of 191 suicide victims and 218 healthy control subjects were included in the present study. 5‐HT1RA gene polymorphisms were determined on polymerase chain reaction–restriction fragment length polymorphism. Results: The distribution of ?1019C>G genotypes was significantly different in suicide victims and healthy controls (P = 0.002), and the GG genotype was associated with a significantly higher number of more stressful life and loss events in the suicide victims (P = 0.017, P = 0.037, respectively). The distribution of 47C>T (Pro16Leu) and 815G>A (Gly272Asp) genotypes was not significantly different in the suicide victims and control subjects (P > 0.05). Moreover, these genotypes were not associated with stressful life and loss events (P > 0.05). Conclusion: The frequency of the ?1019G allele in the 5‐HTR1A gene was higher in suicide victims (with stressful life events) as compared with the control group. In contrast, neither 47C>T (Pro16Leu) nor 815G>A (Gly272Asp) polymorphisms were related with suicide and stressful life events.     

Associations between the serotonin-1A receptor C(-1019)G polymorphism and disordered eating symptoms in female adolescents

The purpose of this study was to examine the relationship between the C(-1019)G polymorphism of the serotonin-1A receptor gene and eating behavior in female adolescents. A total of 204 post-menarche, adolescent women, aged 16–17 years, were recruited from two neighboring high schools in Seoul. Polymerase chain reaction (PCR) was used to isolate and examine the C(-1019)G polymorphism in the serotonin-1A receptor genes (rs6295) of all participants. The Bulimia Investigatory Test, Edinburgh (BITE) and the Eating Attitude Test-26 (EAT-26) were administered to all participants. The total score of the EAT-26 differed significantly among the three genotype groups [CC, CG, GG (F = 4.844, p = 0.009)]. Both the EAT-26 (F = 9.69, p = 0.002) and the BITE (F = 5.22, p = 0.023) scores were higher in the participants who were G allele carriers than in the non-carrier group. The dieting subscale of the EAT-26 was higher among the G allele carriers (F = 12.941, p < 0.001), and these results were maintained even after adjusting for depression and anxiety. These findings suggest that the C(-1019)G polymorphism in the 5-HT1A receptor gene is associated with disordered eating symptoms in Korean female adolescents.     

Association between polymorphism in the promoter region of <Emphasis Type="Italic">Interleukin 6</Emphasis> (-174 G/C) and risk of Alzheimer’s disease: a meta-analysis

Studies of the relationship between Alzheimer’s disease (AD) and polymorphism in the promoter region of Interleukin 6 (IL-6) -174 G/C have reported inconsistent results. To assess the association between IL-6 -174 G/C promoter polymorphism and AD risk, a meta-analysis containing 3,101 AD cases and 3,860 controls from 18 case–control studies was performed. There were 16 studies involving Europeans and 2 studies involving non-Europeans. The combined results showed significant differences in recessive model [CC versus GC + GG, odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.54–0.90] and heterozygote comparison (CC versus GC, OR = 0.76, 95% CI = 0.60–0.96) on the basis of all studies. On subgroup analysis by ethnicity, similarly significant differences in recessive model (CC versus GC + GG) were found in both Europeans and non-Europeans, but significant difference in heterozygote comparison (CC versus GC) was found only in non-Europeans. In conclusion, there were statistically significant differences in genotype distribution of IL-6 -174 G/C between AD cases and controls in recessive model (CC versus GC + GG). Genotype CC of IL-6 -174 G/C could decrease the risk of AD. Further studies with large sample size, especially in subgroup analysis, should be done.     

The serotonin 1A receptor C(-1019)G polymorphism in relation to suicide attempt

Background  

Serotonergic neurotransmission has been implicated in suicidal behavior. Association between suicidal completers and a regulatory C(-1019)G polymorphism (rs6295) in the serotonin 1A receptor (HTR1A) gene was previously reported, whereas a following study showed no association in a sample of suicide attempters.     

Polymorphism C776G in the transcobalamin II gene and homocysteine, folate and vitamin B12 concentrations. Association with MTHFR C677T and A1298C and MTRR A66G polymorphisms in healthy children

One of the etiologies of hyperhomocysteinemia is decreased vitamin B(12). Genetic variation in the transcobalamin II gene, the transporter of vitamin B(12) to the cells, may produce altered homocysteine levels. We determined transcobalamin II C776G polymorphism, homocysteine, folate and vitamin B(12) levels and analyzed the interactive effect with the methylenetetrahydrofolate reductase C677T and A1298C and methionine synthase reductase A66G polymorphisms in 207 healthy Brazilian children. The prevalence of GG genotype of transcobalamin II C776G polymorphism in this Brazilian population, a highly miscigeneous population was 12.5% and the statistical analysis showed that this population is in Hardy-Weinberg equilibrium, it could be considered representative of the general population. We observed a significant increase in homocysteine in the 776GG vs. 776CC genotype, corroborating the influence of age as a determinant of homocysteine in relation to this polymorphism. When we analyzed vitamin B(12) and its relationship with the C776G polymorphism, we found no significant differences. Only 776CG/66AA or 776GG/66AG genotypes presented a significant increase in homocysteine when compared with other groups. In the multivariate analysis, transcobalamin II C776G (CC/CG vs. GG), methylenetetrahydrofolate reductase C677T (CC/CT vs. TT), folate, gender and age presented statistical significance in relation to the homocysteine. These can be considered independent risk factors for hyperhomocysteinemia in this children group. Our results, if confirmed in other populations, highlight the necessity for investigation of the transcobalamin II C776G polymorphism in the research for hyperhomocysteinemia risk factors.     

Functional 5‐HT1a receptor polymorphism selectively modulates error‐specific subprocesses of performance monitoring

Our study investigates the dependence of response monitoring and error detection on genetic influences modulating the serotonergic system. This was done using the event‐related potentials (ERPs) after error (Ne/ERN) and correct trials (Nc/CRN). To induce a sufficient amount of errors, a standard flanker task was used. The subjects (N = 94) were genotyped for the functional 5‐HT1A C(−1019)G polymorphism. The results show that the 5‐HT1A C(−1019)G polymorphism specifically modulates error detection. Neurophysiological modulations on error detection were paralleled by a similar modulation of response slowing after an error, reflecting the behavioral adaptation. The 5‐HT1A −1019 CC genotype group showed a larger Ne and stronger posterror slowing than the CG and GG genotype groups. More general processes of performance monitoring, as reflected in the Nc/CRN, were not affected. The finding that error‐specific processes, but not general response monitoring processes, are modulated by the 5‐HT1A C(−1019)G polymorphism is underlined by a wavelet analysis. In summary, the results suggest a specific effect of the 5‐HT1A C(−1019)G polymorphism on error monitoring, as reflected in the Ne, and suggest a neurobiological dissociation between processes of error monitoring and general response monitoring at the level of the serotonin 1A receptor system. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

脑出血患者脂蛋白脂酶Ser447Ter基因多态性的研究

目的探讨脂蛋白脂酶(LPL)Ser447Ter基因多态性与脑出血关系。方法应用聚合酶链式反应-限制性片段长度多态性技术(PCR-RFLP)对313例脑出血患者和351例正常对照者脂蛋白脂酶(LPL)Ser447Ter基因多态性进行研究。结果在脑出血组中,LPLSer447Ter3种基因型频率分别为CC85.6%、CG14.1%和GG0.3%。LPLSer447Ter基因型和等位基因频率的分布在脑出血组与对照组之间无显著性差异(P>0.05);而LPLSer447TerCG+GG基因型携带者甘油三酯(TG)、载脂蛋白B(ApoB)和脂蛋白(a)[LP(a)]水平低于GG基因型携带者(P<0.05)。结论研究未发现LPLSer447Ter基因多态性与脑出血存在相关关系。     

Repeated suicidal behaviour: Stressful life events and 5-HTTLPR genetic polymorphism

Stressful life events and dysregulated mono-aminergic neurotransmission have been associated with suicidal behaviour. The aim of this investigation was to analyze suicidal behaviour in multiple attempters in relation to the stressful life events, and to the polymorphism of the serotonin transporter (SERT) gene. Multiple suicide attempters, admitted to the University Psychiatric Clinic, were interviewed for the number of previous suicide attempts and for the occurrence of stressful life events, recorded in a Life History Calendar. The patients were further genotyped for 5-HTTLPR polymorphism of SERT. The number of suicide attempts was found to be significantly correlated with the number of negative life events experienced during the 6 months preceding each suicide attempt. The L/L genotype was associated with a reduced number of multiple suicide attempts. These results should prompt future study with a larger number of subjects to further investigate the interaction of genetic and environmental factors in repeated suicidal behaviour.     

The Effects of 5-HTR1A Polymorphism on Cingulum Connectivity in Patients with Panic Disorder

Objective

Serotonin-1A receptors (5-HTR1A) is suggested to be involved in the etiology of several psychiatric disorders including panic disorder (PD). A few imaging studies have suggested the alterations of the cingulum bundle in PD. The objective of this study is to examine the structural changes of cingulum related to the 5-HTR1A polymorphism rs6295 in the patients with PD.

Methods

Thirty-two right-handed patients with PD [11 men, 21 women; 40.34±13.17 (mean±SD) age] who met the diagnostic criteria in Structured Clinical Interview for DSM-IV were examined by means of MRI at 3 Tesla. We divided the patients with PD into CC genotype group and non CC genotype group (GG/CG genotype group) of the 5-HTR1A rs6295 polymorphism to compare the cingulum white matter connectivity.

Results

Tract-based spatial statistics showed significantly increased fractional anisotropy (FA) values in cingulate gyrus process of left cingulum in 5-HTR1A CC genotype compared to GG/CG genotype in PD. Significant positive correlations were shown between the Albany Panic and Phobia Questionnaire (APPQ) interoceptive fear subscale scores, the Anxiety Sensitivity Inventory-Revised fear of publicly observable anxiety reaction subscale scores and FA values of cingulate gyrus process of left cingulum in 5-HTR1A rs6295 GG/CG genotype group. In CC genotype group, APPQ total, APPQ agoraphobia subscale and APPQ social phobia subscale scores also showed significant positive correlations with FA values of hippocampal process of right cingulum.

Conclusion

This preliminary study suggests that 5-HTR1A polymorphism may be associated with the cingulum white matter connectivity in PD.     

Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood

Background: The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene–environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A −42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing. Methods: Fronto‐limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel‐based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database. Negative mood symptoms were also assessed. Results: The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippocampal structures, which extended to the frontal cortices for those CC genotype individuals also exposed to ELS. Elevations in depressed mood were also evident. Conclusions: These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

BDNF Val66Met,stress, and positive mothering: Differential susceptibility model of adolescent trait anxiety

Etiological research has indicated the gene–environment interaction (G × E) on adolescent anxiety. This study aimed to examine how the BDNF Val66Met polymorphism interacted with stressful life events and positive mothering to influence youth trait anxiety. The study sample included 780 community adolescents of Chinese Han ethnicity (M = 13.6, 51.3% females). Participants’ trait anxiety, exposure to stressful life events, and mother's warmth-reasoning were assessed by self-reported questionnaires. We found that BDNF Val66Met polymorphism significantly moderated the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. The influences were significantly greater in adolescents carrying one or two Val allele than those with Met/Met genotype. Moreover, the G × E interactions were more consistent with the differential susceptibility than the diathesis–stress model. Adolescents carrying Val allele who were more susceptible to adversity were also more likely to benefit from supportive experiences. These findings provide novel evidence for the role of BDNF Val66Met as a genetic susceptibility modulating the influences of stressful life events and mother's warmth-reasoning on adolescent anxiety. We speculate that BDNF Val66Met may moderate anxious youths’ responses to mindfulness-based stress reduction program and family-based treatment targeting the enhancement of positive parenting.     

Serotonin transporter gene × environment and risk of depression in community-treated epilepsy

ObjectivesThis study aimed to test whether a specific serotonin transporter (5HTT) gene polymorphism interacting with life stress increased the risk of depression in patients with epilepsy.MethodsThe Tasmanian Epilepsy Register Mood Study (TERMS) used a cross-sectional study design of a community sample of patients with epilepsy previously recruited into the Tasmanian Epilepsy Register. It employed a mailed self-complete questionnaire and saliva DNA collection. Depression was assessed using the Center for Epidemiologic Studies Depression Scale. Environmental measures were selected to cover recent stressful events, epilepsy-related stress, current social support, and early life stress.ResultsOf 820 eligible participants, 553 (67%) participants completed the study. Experience of at least one stressful life event was very common, with a significant association between depression and the stressful life events (F = 26.2, df = 3, p < 0.001). There was no association between serotonin transporter genotype and level of depressive symptoms reported (F = 0.421, df = 2, p = 0.7). There was no evidence of any adverse life experiences interacting with serotonin transporter genotype to moderate the risk of depression.SignificanceThe failure to demonstrate a main effect of genotype on depression or a gene × environment interaction differs from several studies of patients with other chronic diseases. However, it is consistent with larger general population studies.     

Variantes del gen ABCB1 como factores de riesgo y factores moduladores de la edad de inicio en pacientes mexicanos con enfermedad desmielinizante

IntroductionThe C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases.This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes.MethodsPolymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease.ResultsThe TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI: 1.12-2.86; P = .015), as were the genotypes GG2677 (OR: 2.72; 95% CI: 1.11-6.68; P = .025) and CC3435 (OR: 1.82; 95% CI: 1.15-2.90; P = .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P = .010), and the CAT haplotype (OR: 0.21; 95% CI: 0.05-0.66; P = .001).TTTTTT carriers presented the earliest age of onset (23.0 ± 7.7 years, vs. 31.6 ± 10.7; P = .0001).ConclusionsThe GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates.In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.     

囊泡相关膜蛋白8基因多态性与动脉粥样硬化性脑梗死相关性研究

目的探讨囊泡相关膜蛋白8(VAMP8)基因rs13426038和rs10666612多态性与动脉粥样硬化性脑梗死(ACI)的相关性。方法采用聚合酶链反应-限制性片段长度多态性技术,对动脉粥样硬化性脑梗死组和正常对照组VAMP8基因rs13426038和rs10666612位点进行基因分型。结果两位点基因型分布均符合Hardy-Weinberg遗传平衡检验。VAMP8基因rs13426038位点CC/GG基因型频率在ACI组和对照组分别为20.5%/35.9%和15.0%/36.0%,C/G等位基因频率为42.3%/57.7%和39.5%/60.5%;两组间基因型及等位基因频率差异比较无统计学意义(P=0.08,P=0.25)。VAMP8基因rs10166612位点AA/GG基因型频率在ACI组和对照组分别为92.7%/0.5%和91.8%/0%,A/G等位基因频率为96.1%/3.9%和95.9%/4.1%;两组间基因型及等位基因频率分布比较亦无统计学差异(P=0.16,P=0.46)。结论 VAMP8基因rs13426038 C/G和rs10166612 A/G多态性可能与ACI发生无关。     

Influence of the interaction between the serotonin 1A receptor C-1019G polymorphism and negative life stressors on the development of depression

The current study aimed to investigate the interaction between the serotonin 1A receptor gene (HTR1A) C-1019G polymorphism and recent negative life stressors on depression in a Korean community sample. The HTR1A C-1019G polymorphism was genotyped in 416 community-dwelling Koreans (156 males, 260 females; 44.37 ± 14.67 years old). Lifetime and current major depressive episodes were diagnosed using the Structured Clinical Interview for DSM-IV. The Center for Epidemiological Studies for Depression Scale (CES-D) was self-applied and face-to-face interviews investigating negative life stressors within the last 6 months were also performed. The results indicated that there were significant interactions between the C-1019G polymorphism and negative life stressors on CES-D scores (p = 0.02) as well as on current major depressive episodes (p = 0.002), but not on past major depressive episodes. G carriers alone had higher CES-D scores and more frequently experienced major depressive episodes after stressors. The interaction between the C-1019G polymorphism in HTR1A and recent negative life stressors accounted for current major depressive episodes and depressive symptoms. Our findings suggest that people with this gene variant may be more susceptible to developing depression especially after negative life stressors.     

Risk factors of stroke and −717A > G (rs2794521) CRP gene polymorphism among stroke patients in West Pomerania province of Poland

Background and purposeSome of the risk factors of ischaemic stroke influence the development of atherosclerosis, which is a significant cause of vascular incidents. An inflammatory component plays a role in pathogenesis of both atherosclerosis and atrial fibrillation, the most important risk factor of embolic strokes. C-reactive protein (CRP) concentration in blood reflects the inflammatory process. Concentration of this protein depends on the CRP gene polymorphism. The aim of the study was to assess the relationship between selected risk factors of stroke and variant of −717A > G (rs2794521) CRP gene polymorphism in population of West Pomerania Province of Poland.Materials and methodsThere were 125 consecutive patients with ischaemic stroke analysed, who met the inclusion and exclusion criteria. In all patients, −717A > G CRP gene polymorphism was genotyped and analysed in relation to selected stroke risk factors.ResultsPrevalence of type 2 diabetes was lower in patients with AA genotype of −717A > G CRP gene polymorphism than in patients with other alleles (p = 0.017). Subjects with GG genotype had significantly higher concentration of CRP comparing to AG genotype (p = 0.023). No correlation was found between −717A > G CRP gene polymorphism and the lipid profile and other selected risk factors of stroke.ConclusionsIn patients with ischaemic stroke in West Pomerania Province, the GG genotype of −717A > G CRP gene polymorphism is associated with significantly higher CRP concentration in relation to AG genotype. Patients with AA genotype may be characterised by lower prevalence of type 2 diabetes.     

The -11377 C>G promoter variant of the adiponectin gene, prevalence of coronary atherosclerosis, and incidence of vascular events in men

No prospective data demonstrating an association between the -11377 C > G adiponectin gene promoter variant and cardiovascular risk are available. We therefore prospectively evaluated the cardiovascular risk associated with adiponectin gene single nucleotide polymorphisms (SNPs) including SNP -11377 in a consecutive series of men undergoing coronary angiography. We recorded vascular events over four years in 402 men undergoing coronary angiography for the evaluation of coronary artery disease. No significant associations of SNPs +276 G > T and +45 T > G with serum adiponectin, with significant coronary stenoses >50%, or with vascular events were observed. However, for SNP -11377 C > G, serum adiponectin levels significantly decreased (p(trend) = 0.003), and the prevalence of significant coronary stenoses significantly increased from the CC over the GC to the GG genotype (p(trend) = 0.004). Prospectively, the risk of vascular events significantly increased from the CC over the CG to the GG genotype of this SNP (adjusted hazard ratios 1.555 [0.957 - 2.525] and 2.309 [1.067 - 4.998], respectively; p(trend) = 0.014). The -11377 C > G adiponectin gene promoter variant is i) associated with decreased serum adiponectin levels, ii) correlated with the presence of coronary atherosclerosis and iii) significantly predictive of vascular events among men undergoing coronary angiography.     

Association between CRP gene polymorphism 717A/G,C-reactive protein and neurological deficit in ischemic stroke

Inflammatory components play an important role in the pathogenesis of arteriosclerosis, one of the main causes of stroke. Blood C-reactive protein (CRP) level is connected with the severity of neurological deficit and disability after stroke. Production of CRP depends on CRP gene polymorphism. This study enrolled 125 patients with ischemic stroke. CRP 717A/G polymorphism was tested in all patients along with an assay of CRP levels measured on the first and tenth day after stroke onset. Neurological deficit on admission and before discharge from hospital was evaluated according to National Institutes of Health Stroke Scale (NIHSS), and then associated with CRP levels and the CRP polymorphism. The CRP 717AA genotype was the most frequent, observed in 53.6% of patients; AG genotype in 40%, and GG genotype in 6.4%. Carriers of the 717GG genotype had a significantly higher CRP level on the first day after stroke versus heterozygotes (p = 0.023). The improvement in neurological state evaluated with the NIHSS was significantly better in CRP 717AA patients in comparison with other CRP 717 genotypes (p = 0.035). A higher level of CRP on the first day after ischemic stroke was slightly associated with the CRP 717AG genotype. The CRP 717AA genotype promotes improvement of neurological state in patients with ischemic stroke.     

Association of MIF and MBL2 gene polymorphisms with attempted suicide in patients diagnosed with schizophrenia or bipolar disorder

The aim of this study to investigate the genetic polymorphisms in macrophage inhibitory factor (MIF) and mannose-binding lectin 2 (MBL2) gene in schizophrenia (SCZ) or bipolar disorder (BD) patients with attempted suicide by comparing with a non-attempted SCZ or BD patients and healthy controls. A sample of 108 patients with SCZ, 100 patients with BD and 100 healthy volunteers were included in the study. SCID-I was used to confirm the diagnosis according to DSM-IV-TR criteria. The patients were evaluated by data forms that included sociodemographic, suicidal behavior and symptom severity information. PCR-RFLP was used to determine MIF and MBL2 gene polymorphisms from DNA material. Our results demonstrated that the distributions of MBL2 genotype (AA, AB, BB), combined genotype (AA, AB/BB) and the allele frequencies (A, B) of attempted suicide patients in SCZ were significantly different from the non-attempted SCZ patients. The distributions of the MBL2 genotype of attempted suicide patients in SCZ were significantly different from the control group. The distributions of MIF genotype (GG, GC, CC), combined genotype (GG, GC/CC) and the allele frequencies (G, C) of attempted suicide patients in BD were significantly different from the non-attempted BD patients or control group. In summary MBL2 gene polymorphism may be associated with attempted suicide in SCZ and MIF gene polymorphism might be associated with attempted suicide in BD. However, further studies with other gene variants in different ethnic populations are needed to address the exact role of these polymorphisms in SCZ or BD.