Gene Promoter Region Polymorphism Research Articles

Tumor necrosis factor-α promoter -308/238 polymorphism association with less severe disease in ankylosing spondylitis is unrelated to serum TNF-α and does not predict TNF inhibitor response.

Despite the clinical efficacy of tumor necrosis factor inhibitors (TNFi), the manner in which TNF-α contributes to disease in patients with ankylosing spondylitis (AS) remains unresolved. We investigated the relationship between TNF-α gene promoter region polymorphism, serum TNF-α levels, and clinical phenotype. We did a cross-sectional and longitudinal cohort study in TNFi-naive patients with AS (n = 335). Clinical data and biological samples were collected during a research visit with genotyping for TNF-α -238 A/G and -308 A/G performed by Taqman RT-PCR and TNF levels determined by sandwich ELISA. Longitudinal TNF levels were monitored in unselected patients (n = 61). TNF-α -308 GA/AA genotype was present in 14% and TNF-α -238 GA/AA genotype in 1% of patients. TNF-α -308 GA/AA genotype was associated with a reduced risk of uveitis and better spinal function, while TNF-α -238 GA/AA genotype was associated with later age of onset and lower erythrocyte sedimentation rate (ESR). Serum TNF-α level was lower in patients with AS (151 pg/ml) than in controls (263 pg/ml), because more patients with AS had undetectable serum TNF-α (66 vs 25%, p < 0.001). TNFi treatment did not influence serum TNF-α. There was no effect of TNF-α -308/-238 or HLA-B27 genotype on serum TNF-α or subsequent initiation of TNFi. TNF-α -238 or -308 GA/AA genotypes in patients with AS are associated with signs of less severe disease. Serum TNF-α is, however, undetectable in two-thirds of patients with AS and is not influenced by TNF-α promoter genotype or TNFi therapy. These data suggest a more significant role for TNF-α at local sites of inflammation in AS than through systemic effects.

An investigation into the MMP1 gene promoter region polymorphism--1607 2G with recessive dystrophic epidermolysis bullosa disease severity in northeastern Mexican patients.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe genetic skin blistering disorder caused by mutations in the gene COL7A1 encoding type VII collagen. Most of the patients' clinical severity depends in part on the nature and location of the mutations, ranging from the mild form described as RDEBother-generalized (RDEB-O) to the more aggressive phenotype described as RDEBsevere-generalized (RDEB-sev gen). However, interfamilial and interindividual differences in subjects with identical COL7A1 mutations suggest the presence of modifier elements, which may influence severity. There is a single nucleotide polymorphism (SNP) at the promoter of the MMP1 gene-encoding matrix metalloproteinase type 1, which has been studied as a genetic disease modifier in different patient cohorts with different findings. We tested the SNP in 30 patients with RDEB and 130 controls whose four grandparents were born in northeastern Mexico. Patients were clinically classified as RDEB-sev gen and RDEB-O by three dermatologists. The SNPStats, RXC, and SPSS software were used to perform statistical testing. The allele frequencies for 2G were 0.607, 0.562, and 0.642 for RDEB-O, RDEB-sev gen, and the control group, respectively. When the genotype frequencies were compared, there was no significant difference between RDEB-sev gen (OR=0.38, CI 95% 0.12-1.21), RDEB-O (OR=1.03, CI 95% 0.21-4.96), and the control group. We found no significant association in relation to the severity of the study subjects and the SNP at the promoter of the MMP1 gene.

Interaction between a serotonin transporter gene promoter region polymorphism and stress predicts anxiety symptoms in adolescents: a multi-wave longitudinal study

Objective To explore the interaction between a serotonin transporter gene promoter region polymorphism(5-HTTPR) and stress in predicting anxiety symptoms. Methods Through random cluster sampling, a total of 252 healthy adolescents participated in this study.During the initial assessment, all participants completed the Adolescent Life Events Questionnaire (ALEQ) and Multidimensional Anxiety Scale for Children (MASC) to assess their levels of stress and anxiety and were genotyped for the 5-HTTLPR polymorphism. Participants subsequently completed MASC and ALEQ once every three months during the subsequent 24 months. A multilevel model was used to investigate the interaction between 5-HTTLPR and stress that predict anxiety symptoms. Results The results indicated no major effect of 5-HTTLPR in males (β=0.80, P>0.05)or females(β=-0.21, P>0.05). There were major effects of stress in males(β=0.30, P<0.01) and females (β=0.33, P<0.01)and a significant interaction between 5-HTTLPR and stress. Females with at least one 5-HTTLPR S allele(β=0.11, P<0.01)and males with at least one 5-HTTLPR L allele(β=-0.10, P<0.01)exhibited more anxiety symptoms under stressful situations. Conclusion The interaction between 5-HTTLPR and stress can predict anxiety symptoms in adolescents. There are gender differences on the 5-HTTLPR × stress interaction. Key words: Anxiety symptoms; Serotonin transporter gene promoter region polymorphism; Stress; Adolescent

Uridine diphosphate glucuronide transferase 1A1FNx0128 gene polymorphism and the toxicity of irinotecan in recurrent and refractory small cell lung cancer.

The aim was to investigate the association between uridine diphosphate glucuronide transferase 1A1 (UGT1A1) gene promoter region polymorphism and irinotecan-related adverse effects and efficacy on recurrent and refractory small cell lung cancer (SCLC). A total of 31 patients with recurrent and refractory SCLC were enrolled in this study from June 2012 to August 2013 and received at least two cycles of single-agent irinotecan chemotherapy. The efficacy and adverse effects of irinotecan were evaluated. DNA was extracted from peripheral blood and direct sequencing method was employed to test UGT1A1FNx0128 polymorphism, thus analyzing the correlation between UGT1A1FNx0128 polymorphism and irinotecan-related side-effects and efficacy. A total of 25 cases (80.6%) were UGT1A1FNx0128 wild-type (TA) 6 /(TA) 6 ; 6 cases (19.4%) were heterozygous mutant (TA) 6 /(TA) 7 , no homozygous mutant genotype (TA) 7 /(TA) 7 was found. The incidences of grade 3/4 neutropenia, diarrhea and thrombocytopenia were 35.5%, 25.8% and 22.6% in all the patients, respectively. The incidence of 3/4 adverse effects in patients with genotype (TA) 6 /(TA) 6 and heterozygous (TA) 6 /(TA) 7 had no statistical difference (P > 0.05 for all). The overall response rate (ORR) was 32.3%. Median progression free survival (PFS) and overall survival (OS) were 4 months and 7.5 months in all patients, respectively. There was no statistical difference in ORR, PFS and OS between genotype (TA) 6 /(TA) 6 patients and heterozygous (TA) 6 /(TA) 7 patients. Irinotecan showed efficacy in patients with recurrent and refractory SCLC; UGT1A1 FNx01 28 polymorphism failed to predict the incidence of serious adverse effects and efficacy of irinotecan.

An initial assessment of correlations between host- and virus-related factors affecting analogues antiviral therapy in HBV chronically infected patients

BackgroundSuccess in treating hepatitis B virus (HBV) infection with nucleoside analogues drugs is limited by the emergence of drug-resistant viral strains upon prolonged therapy. In addition to mutation patterns in the viral polymerase gene, host factors are assumed to contribute to failure of treatment in chronic HBV infections. The aim of this study was to analyze the correlation between efficacy of antiviral therapy and the prevalence of HBV pretreatment drug-resistant variants. We also analyzed the role of heterogeneity in the promoter region of the IL-10 on the HBV pol/s gene polymorphisms and efficacy of analogues-driven therapy.Material/MethodsHBV DNA was extracted from 54 serum samples from chronic hepatitis B (CHB) patients. Drug-resistance mutations were analyzed using MALDI-TOF mass spectrometry technology (MALDI-TOF MS) and Multi-temperature single-strand conformation polymorphism (MSSCP). IL-10 gene promoter region polymorphisms at positions −1082, −819, and −592 were determined in allele-specific PCR reactions (AS-PCR).ResultsDrug-resistance mutations were detected in 74% of naïve and 93% of experienced patients, but the effect of pre-existence of drug-resistant HBV variants on antiviral therapy was not statistically significant (p=0.86). The role of polymorphisms at positions −1082 (p=0.88), −819 (p=0.26), and −592 (p=0.26) of IL-10 promoter region polymorphisms was excluded from the response-predicting factors. The main host factors predicting successful response to antiviral therapy were female sex (p=0.007) and young age (p=0.013).ConclusionsThe presence of drug-resistant HBV variants in baseline is not a viral predictor of good response to nucleoside/nucleotide analogues therapy. Only low HBV viral load predicted positive response to antiviral therapy. The ideal candidate for antiviral therapy is an immunocompetent, young female with low HBV viral load and elevated ALT activity.

Association of serotonin transporter gene promoter region polymorphisms with major depressive disorder

Objective To explore the association of serotonin transporter gene promoter region polymorphisms with the onset of major depressive disorder. Methods A case-control association study was taken, 350 patients which met the diagnostic and statistical manual of mental disorders in the fourth edition (DSM-IV) criteria for major depressive disorder (MDD), and 370 age- and gender-matched controls were recruited. HAMD-17 was used to evaluate the severity of depression. Peripheral blood of all the objects was collected, and genomic DNA was extracted. Polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) was used to detect 5-HTTLPR/rs25531 genotypes. SPSS19.0 statistical software was used for statistical analysis. Results The 5-HTTLPR genotypes and alleles frequency distribution between MDD patients (LL, LS, SS genotypes: 10.9%, 38.0%, 51.1%; L, S alleles: 29.9%, 70.1%) and controls (LL, LS, SS genotypes: 12.4%, 40.5%, 47.1%; L, S alleles: 32.7%, 67.3%) had no significant difference (P=0.522; P=0.245). However, the frequency of 5-HTTLPR/rs25531 genotypes and alleles distribution between MDD patients(L’L’, L’S’, S’S’ genotypes: 6.6%, 34.5%, 58.9%; L’, S’ alleles: 21.7%, 78.3%)and controls(L’L’, L’S’, S’S’ genotypes: 8.1%, 42.4%, 49.5%; L’, S’ alleles: 29.3%, 70.7%) had statistically significance(P=0.041; P=0.019). Logistic regression analysis showed that S’S’ (SS, LGS, LGLG) was the risk genotype for MDD (P=0.016, OR=1.461, OR95%CI=1.072-1.991). Conclusion No significant association was found between 5-HTTLPR polymorphism and the onset of major depressive disorder, 5-HTTLPR/rs25531 S’S’ genotype and S’ maybe the risk genes. Key words: Major depressive disorder; Serotonin transporter; Gene polymorphism

Interaction between a serotonin transporter gene promoter region polymorphism and stress predicts depressive symptoms in Chinese adolescents: a multi-wave longitudinal study

BackgroundThe serotonin transporter (5-HTT) gene may play an important role in the onset and development of mental disorders. Past studies have tested whether a functional polymorphism in the 5-HTT gene linked promoter region (5-HTTLPR) moderated the association between stress and depressive symptoms, but the results of these studies were inconsistent. Thus, the aim of the current study was to examine the interaction between 5-HTTLPR and stress that predict depressive symptoms in Chinese adolescents.MethodsA total of 252 healthy adolescents (131 females and 121 males, aged from 14 to 18, mean = 16.00, standard deviation = 0.60) participated in this study. During the initial assessment, all participants completed the Center for Epidemiological Studies Depression Scale (CES-D) and Adolescent Life Events Questionnaire (ALEQ) and were genotyped for the 5-HTTLPR polymorphism. Participants subsequently completed CES-D and ALEQ once every three months during the subsequent 24 months. A multilevel model was used to investigate the 5-HTTLPR × stress interaction in predicting depressive symptoms.ResultsThe results indicated no main effect of 5-HTTLPR and a significant 5-HTTLPR × stress interaction in females only. Females with at least one 5-HTTLPR S allele exhibited more depressive symptoms under stressful situations. No significant 5-HTTLPR × stress interaction was found in males.ConclusionsIn Chinese adolescents, there are gender differences on the interaction between 5-HTTLPR and stress that predict depressive symptoms. The association between stress and depressive symptoms is moderated by 5-HTTLPR in Chinese female adolescents.

Tumor Necrosis Factor-Alpha Gene Promoter Region Polymorphism and the Risk of Coronary Heart Disease

Background. Tumor necrosis factor-alpha (TNF-α) gene polymorphisms have been implicated in the manifestation of atherosclerosis. Controversy exists regarding the link between the cytokine's variant genotype and CHD among different ethnic groups. There have been fewer studies on the TNF-α gene −1031T>C and −863C>A polymorphisms in relation to CHD. Therefore, the current study was designed to investigate the association of the TNF-α gene −1031T>C and −863C>A polymorphisms with CHD in a Pakistani population. Methods. Patients with CHD (n = 310) and healthy individuals (n = 310) were enrolled in this study. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results. A significant difference was observed in the −863C>A polymorphism between patients with CHD and control subjects (P < 0.0001). CHD risk was positively associated with the variant allele −863A (P < 0.0001) in the study subjects. There was no significant link between the −1031T>C polymorphism and CHD risk in the study population. Haplotypes A-T and A-C of the TNF-alpha gene loci at −863 and −1031 showed higher frequency in the patient group compared with controls (P < 0.05). Conclusion. The TNF-α −863C>A gene polymorphism was associated with the pathogenesis of CHD while the −1031T>C polymorphism did not show any link with the disease in a Pakistani population.

Mutational Screening of theSOCS3Gene Promoter in Metastatic Colorectal Cancer Patients

Cytokine-induced expression of suppressors of cytokine signalling (SOCS) molecules is important for the negative feedback control of STAT-dependent cytokine signalling. The aim of this study was to investigate possible association between the promoter region polymorphisms of the SOCS3 gene and metastatic colorectal carcinoma in a Turkish population. The DNA samples obtained from 103 patients and 109 healthy individuals were analyzed by polymerase chain reaction/single-strand conformation polymorphism (SSCP), and nucleotide sequence analysis. Five sets of primers designed for the SOCS3 gene were used, and we did not detect significant differences in genotype frequencies for any of these polymorphisms between the study groups. Only the S3P1 region showed polymorphism and displayed three (1,2,4, 2,3,4 and 2,4) genotypes. Interestingly, 2,3,4 genotype was observed in 3 patients, but not in controls. Moreover, the sequence analysis revealed that the nucleotides positioned at -914 and -1031 nt had the polymorphisms. Nucleotide sequence analysis of SSCP band 1 and band 3 revealed C-914A (rs12953258) and T-1031C (rs111033850) polymorphisms, respectively. The T-1031C polymorphism lies in the border of the STAT-binding site. The T-1031C polymorphism (rs111033850) is a newly identified single nucleotide polymorphism with this study, and we submitted this to the NCBI database. However, these results suggested that there is no marked association between SOCS3 gene promoter region polymorphisms and the risk of developing metastatic colorectal cancer.

Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients

The role of serotonin transporter (SERT) gene polymorphism in irritable bowel syndrome (IBS) has been demonstrated. However, the expression of SERT mRNA and proteins in the colonic mucosa with different 5-HTT gene-linked polymorphic region (5-HTTLPR) genotypes remains unknown. We examined SERT mRNA and protein levels in colon biopsies from patients with different 5-HTTLPR genotypes and evaluated the links between the polymorphism and the expression levels. Two hundred and fifty-four patients with IBS and 120 healthy subjects were studied. DNA samples were extracted from peripheral blood and genotyped by polymerase chain reaction (PCR). SERT mRNA and protein levels were evaluated by quantitative real time PCR and western blotting. The promoter efficiency of the serotonin transporter promoter (SERT-P) was evaluated with luciferase reporter system. The frequency of the L/L genotype in C-IBS group was significantly higher than that in the control and D-IBS. However, the S/S genotype in D-IBS was significantly higher than that in C-IBS. The transcriptional efficiency of the L/L genotype was significantly higher than that in the L/S and S/S genotype. Patients with the L/L genotype demonstrated increased production of the SERT protein when compared with L/S and S/S patients. The l variant increased SERT promoter activity by 2.43-fold when compared with the s variant. Polymorphism in the promoter region of the SERT gene can influence the expression of SERT mRNA and the levels of the SERT protein in the colonic mucosa, thereby playing a key role in motility-related symptoms of IBS patients.

Association of the Resistin Gene Promoter Region Polymorphism with Kawasaki Disease in Chinese Children

Objectives. The −420 C > G polymorphism located in the resistin gene (RETN) promoter has recently been suggested to play a potential role in proinflammatory conditions and cardiovascular disease. This study investigated the association of the RETN promoter polymorphism with Kawasaki disease (KD) and its clinical parameters in Chinese children. Methods. We compared patients with complete KD to incomplete KD children. Genotyping of the RETN promoter polymorphism was performed using MassARRAY system, and serum resistin levels were estimated using the sandwich enzyme immunoassay method. Results. There was no significant difference in RETN (−420 C > G) genotypes between KD and control groups. However, the frequency of the G allele was higher in iKD patients than in cKD children due to a significantly increased frequency of the GG genotypes. Serum levels of resistin were significantly higher in KD patients than in controls regardless of the presence of coronary artery lesions (CALs). Conclusion. The present findings suggest that while resistin may play a role in the pathogenesis of KD, there is no apparent association between CAL and the RETN (−420 C > G) gene polymorphism in KD children. However, the diagnosis of iKD is challenging but can be supported by the presence of the G allele and the GG genotypes.

The relationship between serotonin transporter gene promoter polymorphism and serum lipid levels at young age in a longitudinal population-representative study

The serotonin transporter gene promoter region polymorphism (5-HTTLPR) has been linked to psychiatric disorders, mostly anxiety and affective disorders. In elderly populations 5-HTTLPR polymorphism has also been reported to be associated with serum lipid levels. We have examined the interaction of the 5-HTTLPR polymorphism and the markers of lipid metabolism at young age in a longitudinal, population-representative cohort study. The sample of the Estonian Children Personality Behaviour and Health Study (initially cohorts of 9 and 15 year old children, complete lipid and genotype data for n=1176) was examined throughout 10 years. Subjects were genotyped and the levels of low-density lipoproteins, high-density lipoproteins, triglycerides, and total cholesterol were measured. Children and adolescents carrying the s allele of the 5-HTTLPR polymorphism had lower levels of low-density lipoprotein and total cholesterol. At the age of 25, the s allele carriers had higher levels of high-density lipoproteins. These associations were independent of gender. Thus the 5-HTTLPR can be associated with the serum lipid levels and in particular low-density lipoproteins already in a young age.

Promoter region polymorphism (−174 G/C) of interleukin-6 gene and SLE; are they associated?

IntroductionSLE is a systemic autoimmune disease with polyclonal B cell hyperactivity, spontaneous lymphocyte proliferation, and the production of pathogenic antibodies to self-antigens. Interleukin-6 is a pleiotropic cytokine with diverse functions including B-cell growth and differentiation. IL-6 levels have been shown to be affected by single nucleotide change from G to C at position −174 in the promoter region of the IL-6 gene. Aim of the workTo find out whether single nucleotide polymorphisms in the promoter region of the IL-6 gene (−174 G/C) constitute a genetic susceptibility for SLE and its association with various disease clinical and immunological features. Patients and methodsForty-two female SLE patients and 40 healthy controls were genotyped for IL-6 gene promoter region (−174 G/C) polymorphism using PCR. SLE patients satisfied the 1982 revised criteria of the American Rheumatism Association for the classification of SLE, with a mean age of 32.4±5.5years and mean disease duration of 5.7±1.5years. The healthy controls were matched for age and sex, with a mean age of 31.7±4.9years. All subjects were recruited from the Rheumatology and Rehabilitation and Internal Medicine Departments, Kasr El Aini Hospitals. SLE clinical and laboratory features were recorded including constitutional, hematological, joint, renal, and neuropsychiatric manifestations, oral ulcers, serositis, malar rash, and photosensitivity and CBC, liver, kidney functions and serum C3 and C4 levels. Positivity for ANAs, Anti-dsDNA and Anti-Sm antibodies were determined. ResultsGenotypic and allelic distributions showed no significant differences between SLE patients and controls. The frequency of G allele was higher than C allele in both patients (83.3% vs. 16.7%) and controls (85% vs. 15%). SLE patients with GG genotype showed significantly higher frequencies and increased risk of; constitutional manifestations at disease onset (P=0.02), OR (95% CI)=6.55 (1.22–35.12), photosensitivity (P=0.03), OR (95% CI)=4.67 (1.11–19.54), hematological disorders (P=0.02), OR (95% CI)=5.5 (1.29–23.39) and positivity of ANAs and Anti-dsDNA [P=0.046, 0.03: OR (95% CI)=7 (1.1–45.44), 6.43 (1.23–33.65), respectively]. Furthermore, those patients had significantly lower mean WBCs counts when compared to SLE patients with (GC and CC) genotypes (4.54±1.31 vs. 5.98±1.04/dl, P=0.002). Twenty-five patients had lupus nephritis (LN) proved by renal biopsy but none of them had CC genotype. LN patients with GG genotype had nearly similar mean 24-h proteinuria to those with GC genotype (2.93±1.07 vs. 2.68±1.06g/24h and P=0.39). No significant difference was found in IL-6 genotype and allele distributions when patients with diffuse proliferative glomerulonephritis (class IV), which has the worst prognostic outcome, were compared to patients with non-class IV glomerulonephritis (classes II and III) [P=0.12, 0.15, respectively]. ConclusionIL-6 promoter region (−174 G/C) polymorphism does not confer susceptibility to SLE but it is related to the presence of distinct clinical and immunological features. Furthermore, the increased frequency of the high-response G allele suggests that a genetically determined high IL-6 response may have a pathogenic role.

Associations between serotonin transporter gene promoter region (5-HTTLPR) polymorphism and gaze bias for emotional information.

The serotonin transporter promoter region polymorphism (5-HTTLPR) is associated with neural response to negative images in brain regions involved in the experience of emotion. However, the behavioral implications of this sensitivity have been studied far less extensively. The current study used eye-tracking methodology to examine how individuals genotyped for the 5-HTTLPR, including the single nucleotide polymorphism (SNP) rs25531, allocated attention during prolonged (30-s) exposure to face stimuli depicting positive and negative emotion. Short 5-HTTLPR allele carriers and carriers of the long allele with guanine at the sixth nucleotide (S/LG) displayed a stronger gaze bias (total fixation time, number of fixations, mean fixation length) for positive than for sad, threat, or neutral stimuli. In contrast, those homozygous for the long 5-HTTLPR allele with adenine at the sixth nucleotide (LA) viewed the emotion stimuli in an unbiased fashion. Time course analyses indicated no initial 5-HTTLPR group differences; however, S/LG 5-HTTLPR allele carriers were more likely than LA 5-HTTLPR homozygotes to direct gaze toward happy than toward sad stimuli over time. This bias toward positive stimuli during the later stages of information processing likely reflects a strategic effort to downregulate heightened reactivity to negative stimuli among 5-HTTLPR S/LG allele carriers.

Gene Expression and Promoter Region Polymorphisms of Interleukin-10 in Meningitis Patients

Meningitis is an inflammatory disease caused by bacteria, fungi, and viruses with various clinical symptoms. Interleukin-10 (IL-10) levels have been shown to be increased in blood or cerebrospinal fluid of patients with meningitis, but the association of IL-10 gene promoter polymorphisms or gene expression with meningitis has not been evaluated. IL-10 gene promoter polymorphisms A-592C, T-819C, and A-1082G in 61 patients with meningitis and 64 healthy controls were determined by real-time polymerase chain reaction analysis. mRNA from blood and cerebrospinal fluid samples was extracted, and real-time polymerase chain reaction was performed for IL-10 gene expression. No statistically significant differences were found in the allele and genotypic frequencies between patients and control subjects. Expression of IL-10 in meningitis at mRNA levels was detected in the infiltrating leukocytes. IL-10 gene expression in blood from patients was significantly higher than the control group. Our results suggest that there was no association between promoter polymorphisms of IL-10 and meningitis, but a significant increase of IL-10 gene expression was present in patients with meningitis.

Genes and Environment: Multiple Pathways to Psychopathology

In this issue of Biological Psychiatry, the work by van IJzendoorn et al. ( 1 van IJzendoorn M.H. Caspers K. Bakermans-Kranenburg M.J. Steven R.H. Beach R. Philibert Methylation matters: interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma. Biol Psychiatry. 2010; 68: 405-407 Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar ) describes how the report of a previous abusive event in children adopted shortly after birth can result in unresolved grief or loss, depending on the serotonin-transporter (5HTT) gene promoter region polymorphism and DNA methylation levels of an associated CpG island. This study attempts to determine whether genetic and epigenetic factors can contribute to increased vulnerability to loss and attachment-related trauma. Clinical studies have found that reported childhood adversity such as physical or sexual abuse or deprivation are risk factors for psychopathology in later childhood and adulthood. Examples of such psychopathology include mood disorders, anxiety disorders, and suicide. At the same time there is evidence that these disorders are heritable, although the identities of the genes involved in the etiology of such psychopathology have remained elusive. Not all those exposed to adversity during childhood manifest psychopathology later in life, indicating the existence of a diathesis in some but not all individuals. Studies have shown that the risk of psychopathology in those with a reported history of childhood adversity is affected by genotype ( 2 Caspi A. Sugden K. Moffitt T.E. Taylor A. Craig I.W. Harrington H. et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science. 2003; 301: 386-389 Crossref PubMed Scopus (6152) Google Scholar ). Such gene–environment interactions have been observed clinically for a number of genes, such as the 5HTT, monoamine oxidase A, catechol O-methyl transferase, and the glucocorticoid receptor. Understanding how genes and the environment interact in increasing the risk of psychopathology requires studying the influence of the environment on gene expression. Epigenetics might be a mediating factor, in that the environment might alter the epigenome, and these alterations in epigenetic marks might then influence gene expression and dynamics. Methylation Matters: Interaction Between Methylation Density and Serotonin Transporter Genotype Predicts Unresolved Loss or TraumaBiological PsychiatryVol. 68Issue 5PreviewDo genetic or epigenetic factors play a role in making some individuals more vulnerable than others to loss of attachment figures or other traumatic experiences? Full-Text PDF

Insulin VNTR and IGF-1 Promoter Region Polymorphisms Are Not Associated with Body Composition in Early Childhood: The Generation R Study

Objective: The objective of this study was to examine the associations between insulin gene variable number of tandem repeats (INS VNTR) and insulin-like growth factor 1 (IGF1) gene promoter region polymorphisms with body composition in early childhood. Methods: This study was embedded in an ongoing prospective cohort study. Growth in early childhood (body mass index, total subcutaneous fat mass and waist-hip ratio) was assessed at birth and at the ages of 6 weeks and 24 months. DNA for genotyping was available in 738 children. Results: The genotype distribution of the INS VNTR gene was I/I 50.4%, I/III 40.4%, and III/III 9.2%. IGF1 genotypes were categorized in the following categories based on their 192-bp allele: homozygous (wild-type) 43.1%, heterozygous 45.8%, and noncarrier 11.2%. No differences were found in body mass index, total subcutaneous fat mass and waist-hip ratio in early childhood between the three groups for both the INS VNTR and IGF1 genotypes. We also did not find interactions between these genotypes and gender or birth weight on the effects of body composition measures. Conclusions: Our results do not support previous studies showing associations between INS VNTR and IGF1 promoter region polymorphisms with body composition in early childhood.

Polymorphisms in MMP-2 and MMP-9 promoter regions are associated with endometriosis

In this case-control study, we investigated the potential associations of MMP-2 and MMP-9 gene promoter region polymorphisms as well as MMP-2 promoter haplotypes with susceptibility to endometriosis in women of caucasian origin. The results demonstrated that polymorphisms in MMP-2 (-735 C/T) and MMP-9 (-1562 C/T) were associated with elevated risk of endometriosis and that certain MMP-2 promoter haplotypes were more common in control group.

Resistin gene promoter region polymorphism and the risk of hypertrophic cardiomyopathy in patients

Resistin, a novel cytokine, is associated with an inflammatory process and is suggested to induce hypertrophy in rat cardiomyocytes. Resistin gene expression has not been investigated in patients with hypertrophic cardiomyopathy (HCM). This study investigates resistin levels in HCM patients and healthy controls and the molecular basis for the regulation of the resistin gene (RETN) in a Pakistani population. Patients with HCM (n = 105) and healthy individuals (n = 110) were enrolled in this investigation. Serum resistin levels were determined by enzyme-linked immunosorbent assay (ELISA). RETN genotyping was performed by polymerase chain reaction (PCR) and DNA sequencing. Our data showed a statistically significant increase in resistin levels from HCM patients compared with healthy subjects (6.3 +/- 2.7 ng/mL in patients vs 3.4 +/- 2.1 ng/mL in controls, P < 0.0001). The RETN -420 C > G polymorphism was significantly high in patients with HCM compared with the control group (P < 0.001). There was a significant difference between the C and G alleles from HCM cases and controls (odds ratio [OR] = 3.54, 95% confidence interval [CI] = 2.36-5.30, P < 0.0001). Logistic-regression analysis showed that the increased resistin levels, and the RETN-420 C > G polymorphism were significantly associated with HCM. Our data suggest that the elevated resistin levels and the RETN -420 C > G polymorphism may be associated with cardiac hypertrophy in the study population.

Healthy young women with serotonin transporter SS polymorphism show a pro-inflammatory bias under resting and stress conditions

The study of functionally relevant biological effects of serotonin transporter gene promoter region (5-HTTLPR) polymorphisms is especially important given the current controversy about the clinical relevance of these polymorphisms. Here we report an intrinsic immunobiological difference between individuals carrying two short (SS) versus long (LL) 5-HTTLPR alleles, that is observed in healthy subjects reporting low exposure to life stress. Given that 5-HTTLPR polymorphisms are thought to influence susceptibility to depression and are associated with robust neurobiological effects, that depression is associated with higher pro-inflammatory and lower anti-inflammatory cytokines, and that acute stressors increase circulating concentrations of pro-inflammatory cytokines, we hypothesized that compared to LL individuals, SS individuals may show a pro-inflammatory bias under resting conditions and/or during stress. 15 LL and 11 SS individuals participated in the Trier Social Stress Test (TSST). Serum IL-6 and IL-10 were quantified at baseline and 30, 60, 90, and 120min after beginning the 20-min stress test. Compared to LL individuals, SS individuals showed a higher IL-6/IL-10 ratio at baseline and during stress. Importantly, this pro-inflammatory bias was observed despite both groups being healthy, reporting similar intensities of stress and negative emotionality during the TSST, and reporting similar low exposures to early and recent life stress. To our knowledge, this is the first report of a pro-inflammatory bias/phenotype in individuals carrying the SS genotype of 5-HTTLPR. Thus, healthy SS individuals may be chronically exposed to a pro-inflammatory physiological burden under resting and stress conditions, which could increase their vulnerability to disorders like depression and other diseases that can be facilitated/exacerbated by a chronic pro-inflammatory state.