Multimorbidity and the Etiology of Schizophrenia.

PURPOSE OF REVIEW: A global study of multimorbidity in schizophrenia, especially of the association with physical conditions, might offer much needed etiological insights. RECENT FINDINGS: Our review suggests that life-style factors and medication related to schizophrenia are only part of the explanation of the increase in risk for cardiovascular, metabolic, pulmonary disorders, and some cancers. Positive associations with autoimmune disorders (with the exception of rheumatoid arthritis) and epilepsy are promising avenues of research but to date have not been fully exploited. The same holds for the negative comorbidity seen for rheumatoid arthritis and some cancers (e.g., prostate). As a whole, our review suggests that most of the explored conditions have a different prevalence in schizophrenia than in the general population. Several hypotheses emerged from this review such as the role of immune and genetic factors, of sex hormones, and of more general variability factors.

High unrecognized SARS-CoV-2 exposure of newly admitted and hospitalized psychiatric patients.

BACKGROUND: Patients with pre-existing mental disorders are at higher risk for SARS-CoV-2 infection and adverse outcomes, and severe mental illness, including mood and psychosis spectrum disorders, is associated with increased mortality risk. Despite their increased risk profile, patients with severe mental illness have been understudied during the pandemic, with limited estimates of exposure in inpatient settings. OBJECTIVE: The aim of this study was to describe the SARS-CoV-2 seroprevalence and antibody titers, and pro-inflammatory cytokine concentrations of newly admitted or hospitalized psychiatric inpatients without known history of COVID-19 infection, using robust quantitative multi-antigen assessments, and compare patients' exposure to that of hospital staff. METHODS: This multi-centric, cross-sectional study compared SARS-CoV-2 seroprevalence and titers of 285 patients (University Psychiatric Centre Duffel [UPCD] N = 194; Assistance-Publique-Hopitaux de Paris [AP-HP] N = 91), and 192 hospital caregivers (UPCD N = 130; AP-HP N = 62) at two large psychiatric care facilities between January 1st and the May 30th 2021. Serum levels of SARS-CoV-2 antibodies against Spike proteins (full length), spike subunit 1 (S1), spike subunit 2 (S2), spike subunit 1 receptor binding domain (S1-RBD) and Nucleocapsid proteins were quantitatively determined using an advanced capillary Western Blot technique. To assess the robustness of the between-group seroprevalence differences, we performed sensitivity analyses with stringent cut-offs for seropositivity. We also assessed peripheral concentrations of IL-6, IL-8 and TNF-a using ELLA assays. Secondary analyses included comparisons of SARS-CoV-2 seroprevalence and titers between patient diagnostic subgroups, and between newly admitted (hospitalization ≤ 7 days) and hospitalized patients (hospitalization > 7 days) and correlations between serological and cytokines. RESULTS: Patients had a significantly higher SARS-CoV-2 seroprevalence (67.85 % [95% CI 62.20-73.02]) than hospital caregivers (27.08% [95% CI 21.29-33.77]), and had significantly higher global SARS-CoV-2 titers (F = 29.40, df = 2, p < 0.0001). Moreover, patients had a 2.51-fold (95% CI 1.95-3.20) higher SARS-CoV-2 exposure risk compared to hospital caregivers (Fisher's exact test, P < 0.0001). No difference was found in SARS-CoV-2 seroprevalence and titers between patient subgroups. Patients could be differentiated most accurately from hospital caregivers by their higher Spike protein titers (OR 136.54 [95% CI 43.08-481.98], P < 0.0001), lower S1 (OR 0.06 [95% CI 0.02-0.15], P < 0.0001) titers and higher IL-6 (OR 3.41 [95% CI 1.73-7.24], P < 0.0001) and TNF-α (OR 34.29 [95% CI 5.00-258.87], P < 0.0001) and lower titers of IL-8 (OR 0.13 [95% CI 0.05-0.30], P < 0.0001). Seropositive patients had significantly higher SARS-COV-2 antibody titers compared to seropositive hospital caregivers (F = 19.53, df = 2, P < 0.0001), while titers were not different in seronegative individuals. Pro-inflammatory cytokine concentrations were not associated with serological status. CONCLUSION: Our work demonstrated a very high unrecognized exposure to SARS-CoV-2 among newly admitted and hospitalized psychiatric inpatients, which is cause for concern in the context of highly robust evidence of adverse outcomes following COVID-19 in psychiatric patients. Attention should be directed toward monitoring and mitigating exposure to infectious agents within psychiatric hospitals.

[Immunopsychiatry and SARS-CoV-2 pandemic: Links and possible consequences]. / Immuno-psychiatrie et pandémie de SARS-CoV-2 : liens et possibles conséquences.

OBJECTIVE: The SARS-CoV-2 (or COVID-19) pandemic has been propagating since December 2019, inducing a drastic increase in the prevalence of anxious and depressive disorders in the general population. Psychological trauma can partly explain these disorders. However, since psychiatric disorders also have an immuno-inflammatory component, the direct effects of the virus on the host's immune system, with a marked inflammatory response, but also the secondary inflammation to these psychosocial stressors, may cause the apparition or the worsening of psychiatric disorders. We describe here the probable immunopsychiatric consequences of the SARS-CoV-2 pandemic, to delineate possible screening actions and care that could be planned. METHOD: Data from previous pandemics, and existing data on the psychopathological consequences of the SARS-CoV-2 pandemic, allowed us to review the possible immunopsychiatric consequences of the SARS-CoV-2 pandemic, on the gestational environment, with the risk of consecutive neurodevelopmental disorders for the fetus on one hand, on the children and adults directly infected being at increased risks of psychiatric disorders on the other hand. RESULTS: As in previous pandemics, the activation of the immune system due to psychological stress and/or to infection during pregnancy, might lead to an increased risk of neurodevelopmental disorders for the fetus (schizophrenia and autism spectrum disorders). Furthermore, in individuals exposed to psychological trauma and/or infected by the virus, the risk of psychiatric disorders, especially mood disorders, is probably increased. CONCLUSION: In this context, preventive measures and specialized care are necessary. Thus, it is important to propose a close follow-up to the individuals who have been infected by the virus, in order to set up the earliest care possible. Likewise, in pregnant women, screening of mood disorders during the pregnancy or the postpartum period must be facilitated. The follow-up of the babies born during the pandemic must be strengthened to screen and care for possible neurodevelopmental disorders.

Human endogenous retroviral protein triggers deficit in glutamate synapse maturation and behaviors associated with psychosis.

Mobile genetic elements, such as human endogenous retroviruses (HERVs), produce proteins that regulate brain cell functions and synaptic transmission and have been implicated in the etiology of neurological and neurodevelopmental psychiatric disorders. However, the mechanisms by which these proteins of retroviral origin alter brain cell communication remain poorly understood. Here, we combined single-molecule tracking, calcium imaging, and behavioral approaches to demonstrate that the envelope protein (Env) of HERV type W, which is normally silenced but expressed in patients with neuropsychiatric conditions, alters the N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic organization and plasticity through glia- and cytokine-dependent changes. Env expression in the developing hippocampus was sufficient to induce behavioral impairments at the adult stage that were prevented by Env neutralization or tuning of NMDAR trafficking. Thus, we show that a HERV gene product alters glutamate synapse maturation and generates behavioral deficits, further supporting the possible etiological interplay between genetic, immune, and synaptic factors in psychosis.

Immunological biomarkers in neuropsychiatric systemic lupus erythematosus: a comparative cross-sectional study from a tertiary care center in South India.

INTRODUCTION: The prevalence of various immunological biomarkers in neuropsychiatric systemic lupus erythematosus (NPSLE) differs among various patients with varied neuropsychiatric manifestations and different populations. We studied the prevalence of these biomarkers; especially the neuron specific autoantibodies in patients with systemic lupus erythematosus (SLE) and compared them among patients with and without neuropsychiatric involvement. METHODOLOGY: This is a comparative cross-sectional study conducted in a tertiary care hospital in South India. The prevalence of immunological biomarkers including complement levels, systemic and brain specific autoantibodies (anti-myelin antibody, anti-myelin oligodendrocyte glycoprotein and anti-myelin-associated glycoprotein antibody) were assessed and compared among those with and without NPSLE and with different NPSLE manifestations. RESULTS: A total of 522 SLE patients were enrolled in the study. The mean age of the study participants was 28.5 ± 8.8 years and 93.5% were women. Neuropsychiatric manifestations were seen in 167 (32%) patients. Seizure was the most common neuropsychiatric manifestation seen in 41.3%, followed by psychosis (18.6%), mood disorder (16.8%), stroke (10.8%), mononeuropathy (10.2%), headache (9.6%), acute confusional state (6.6%) and aseptic meningitis (5.4%). Patients with NPSLE had a higher SLE disease activity index score. Most of the autoantibodies, that is anticardiolipin antibody (aCL), anti-ß2 glycoprotein 1 antibody (ß2GP1), lupus anticoagulant (LA), anti-nucleosome, anti-ribosomal P, anti-Ro52, anti-Ro60 and anti-La, were seen in higher proportion in the NPSLE group, although the difference failed to reach statistical significance. On subgroup analysis, psychosis was significantly higher in patients with anti-ribosomal P positivity than without (11.8% versus 4.1%, p.0.007; odds ratio (OR) 3.1, confidence interval (CI) 1.4-6.8), while stroke had a higher proportion among those with positive b2GP1 IgG (6.3% versus 1.8%, p.0.03; OR 3.6, CI 1.2-11.0). A higher proportion of demyelination was seen among the LA positive than the negative (10.3% versus 0.2%, p.0.03; OR 5.39, CI 1.15-24.17) and anti-myelin oligodendrocyte glycoprotein in mood disorder (14.3% versus 3.4%, p = 0.03; OR 4.66, CI 1.13-19.13). CONCLUSION: No single biomarker correlated with NPSLE. Among different NPSLE manifestations, the prevalence of IgG ß2GP1 in stroke, LA in demyelination, anti-ribosomal P in psychosis and anti-myelin oligodendrocyte glycoprotein in mood disorder were higher. Further studies on the pathogenic mechanisms underlying NPSLE and its different manifestations may help us to identify better biomarkers.

Association of high-sensitivity C-reactive protein with susceptibility to Schizophrenia in Tunisian population.

The pathogenic mechanisms underlying Schizophrenia (SZ), one of the most frequent mental disorders, are complex and poorly understood. Several evidences suggest that inflammatory processes may underpin some of its neurobiological correlates. The aim of this study was: (i) to analyze the potential association between circulating levels of the C-reactive protein (CRP), a crucial inflammatory marker, and Schizophrenia in Tunisian patients and healthy controls (HC) cohorts; (ii) to investigate the genetic diversity of three CRP variants (rs1417938, rs1130864 and rs1205) and; (iii) to analyze a potential relationship between expression and genetic data and clinical and socio demographical characteristics. CRP polymorphisms were exanimated for 155 patients and 203 HC by taqMan5'-nuclease. High-sensitivity CRP (hs-CRP) serum level was measured in 128 clinically stable out-patient SZ patients and 63 HC subjects via an automated biochemical analyzer. We found that hs-CRP levels were significantly higher in SZ patients as compared to HC. No significant differences were found when the proportions of CRP variants were compared in patients and HC. Further analysis according to clinical and socio demographical characteristics revealed a positive association with age and hypertension. Our data on an original Tunisian sample confirm the previous finding in others population groups.

Oxidative and nitrosative stress markers in obsessive-compulsive disorder: a systematic review and meta-analysis.

OBJECTIVE: Obsessive-compulsive disorder (OCD) is a chronic, prevalent, and highly impairing psychiatric illness. Although the pathophysiology of OCD remains unknown, pathways involved in oxidative and nitrosative stress (O&NS) have been implicated. The present study aims to systematically review the literature for quantitative evidence that patients with OCD have altered measures of blood O&NS markers. METHODS: Independent random-effects meta-analyses using standardized mean differences were conducted to assess each marker separately. Additionally, data from multiple markers were pooled together in a meta-analysis for measures of oxidant activity and another for measures of antioxidant activity. RESULTS: Thirteen studies met inclusion criteria, involving 433 OCD patients and 459 controls. Eleven blood O&NS markers were eligible for independent quantitative analyses. We found that, in OCD patients, the oxidant markers 8-hydroxydeoxyguanosine and malondialdehyde, and the antioxidants glutathione peroxidase and superoxide dismutase, were significantly increased while total antioxidant status, vitamin C, and vitamin E were significantly decreased, when comparing with controls. Regarding pooled meta-analyses, we found a statistically significant increase in oxidant markers, but non-significant results regarding antioxidant markers. CONCLUSIONS: Our meta-analysis suggests that OCD patients have a systemic oxidative imbalance that is not adequately buffered by the antioxidant system. Additional studies are needed in order to support this association.

HLA genetics in bipolar disorder.

OBJECTIVE: Bipolar Disorder (BD) is characterized by deregulated adaptive immune processes. Recent genome-wide association studies (GWAS) implicate the major histocompatibility complex (MHC) region in BD. The present study investigates the potential influence of variations in human leukocyte antigen (HLA) on BD risk and/or clinical presentations. This may have relevance to the dysregulated inflammatory processes commonly found in BD. METHOD: DNAs from 475 BD patients and 195 healthy controls (HC) were genotyped for classical HLA class I and II loci. RESULTS: We found that: (i) the HLA-A*02~B*44~DRB1*07 sub-haplotype is less prevalent in BD, vs. HC (pc = 2.4 × 10-2 ); (ii) the 57.1 and the 8.1-derived ancestral haplotypes i.e. HLA-A*02~B*57~Cw*06~DRB1*07~DQB1*09 and HLA-A*02~B*08~Cw*07 are associated with rapid cycling (pc = 1.9 × 10-3 and 1.05 × 10-2 , respectively); (iii) the 8.1AH-derived HLA class II-DRB*03~HLA-DQB1*02 sub-haplotype is more frequent in BD patients with a history of suicidal behaviors (pc = 2.1 × 10-2 ); and (iv) disease onset by an hypomanic episode or by psychotic symptoms are, respectively, more frequent in BD patients bearing the 7.1 AH-derived A*03~B*07~DRB1*15 sub-haplotype (pc = 8.5 × 10-3 ) and the HLA-A*02~B*07~DRB1*15 sub-haplotype (pc = 4.0 × 10-2 ). CONCLUSION: Corroborating the established link between these HLA haplotypes/sub haplotypes and common immune disorders, our findings suggest possible HLA-mediated proinflammatory processes operating in BD.

Infectious and immunogenetic factors in bipolar disorder.

OBJECTIVE: Despite the evidence supporting the association between infection and bipolar disorder (BD), the genetic vulnerability that mediates its effects has yet to be clarified. A genetic origin for the immune imbalance observed in BD, possibly involved in the mechanisms of pathogen escape, has, however, been suggested in recent studies. METHOD: Here, we present a critical review based on a systematic literature search of articles published until December 2016 on the association between BD and infectious/immunogenetic factors. RESULTS: We provide evidence suggesting that infectious insults could act as triggers of maladaptive immune responses in BD and that immunogenetic vulnerability may amplify the effects of such environmental risk factors, increasing susceptibility to subsequent environmental encounters. Quality of evidence was generally impaired by scarce attempt of replication, small sample sizes and lack of high-quality environmental measures. CONCLUSION: Infection has emerged as a potential preventable cause of morbidity in BD, urging the need to better investigate components of the host-pathogen interaction in patients and at-risk subjects, and thus opening the way to novel therapeutic opportunities.

Polymorphisms in the promoter region of iNOS predispose to rheumatoid arthritis in south Indian Tamils.

Nitric oxide synthase (NOS) catalyses the production of nitric oxide (NO) from L-Arginine, which participates in diverse biological processes including inflammation and apoptosis. Macrophages, chondrocytes, osteoblasts and osteoclasts express inducible NOS (iNOS) at the site of synovial inflammation. NO produced at the inflamed joint may contribute to peri-articular bone loss, mediate apoptosis and regulate Th1/Th2 balance in rheumatoid arthritis (RA). Variations in the promoter region of NOS gene regulate the nitric oxide synthase expression and iNOS (NOS2) polymorphisms have been associated with susceptibility to autoimmune disorders. Hence, this study was conducted to identify the possible contributions of NOS2 -1659G/A, -1026C/A, -277A/G promoter polymorphisms towards development of RA in South Indian Tamils. A total of 242 (219 females, 23 males) patients with RA (mean age 41.2 ± 10.9 years, disease duration 8.5 ± 4.3 years) and 279 age- and sex-matched healthy individuals of South Indian Tamil ethnicity were genotyped for NOS2 -1659C/T, -1026G/T and -277A/G promoter polymorphisms by TaqMan chemistry. Nature of disease (erosive or nonerosive), the presence of extra-articular manifestations, seropositivity for rheumatoid factor and anticyclic citrullinated peptide, serum C-reactive protein (CRP) level and response to therapy were assessed for all patients. The three single nucleotide polymorphisms (SNPs) were in Hardy-Weinberg equilibrium. The frequency of GG genotype and G allele of NOS2-277 was higher in patients (pc = 5.7 × 10-9 , OR = 6.09, 95% CI = 3.09-12.8 and pc = 4 × 10-13 , OR = 2.37, 95% CI = 2.06-3.62, respectively) compared to controls. Similarly, the frequency of NOS2-1026 (rs2779249) GT genotype and the T allele was higher in patients with RA (pc = .01, OR = 1.61, 95% CI = 1.09-2.36, and pc = .04, OR = 1.40, 95% CI = 1.02-1.91, respectively). However, no significant difference in frequency of NOS2-1659C/T polymorphism was observed between patients and controls. None of the studied SNPs were associated with erosive disease, seropositivity or extra-articular manifestations. The -277A/G and -1026 G/T promoter polymorphisms in iNOS may confer susceptibility to RA in South Indian Tamils.

Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis.

NKG2D (KLRK1) is a C-type lectin receptor present on natural killer (NK) cells, γδ, CD8+ and CD4+ T cells. Upon ligand binding, NKG2D mediates activatory and co-stimulatory signals to NK cells and activated CD4+ T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0·03, odds ratio (OR) = 2·44, 95% confidence interval (CI) = 1·09-5·98 and 10 versus 4%, Pc = 0·04, OR = 2·45, 95% CI = 1·05-6·39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0·03, OR = 0·41, 95% CI = 0·17-0·91 and Pc = 0·04, OR = 0·41, 95% CI = 0·16-0·96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G-C-A-G-A-T-C-C was higher in patients than in controls (12 versus 8%, P = 0·04, OR = 1·61, 95% CI = 1·01-2·55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA.

HLA class II alleles influence rheumatoid arthritis susceptibility and autoantibody status in South Indian Tamil population.

Rheumatoid arthritis (RA) is a complex multifactorial autoimmune disease characterized by inflammatory arthritis. The precise etiology and pathogenesis of RA remains elusive but evidence points towards stochastic interactions between genetic and environmental factors. This study investigated the distribution of human leucocyte antigen (HLA)-DRB1/DQB1 alleles in South Indian patients with rheumatoid arthritis (RA) and their influence on RA susceptibility and clinical phenotype. Low resolution HLA-DRB1 and -DQB1 typing was performed in 271 RA patients and 233 healthy controls by polymerase chain reaction (PCR) using sequence-specific primers (SSP). HLA-DRB1*10 was found to be more frequent in patients (Pc = 0.004, OR = 2.23, 95% CI = 1.5-3.34) than controls. This difference persisted in RF positive (Pc = 9 × 10-6 , OR = 2.45, 95% CI = 1.62-3.74), ACPA positive (Pc = 0.007, OR = 2.10, 95% CI = 1.35-3.29), ACPA negative (Pc = 0.001, OR = 2.45, 95% CI = 1.50-3.97) and both RF and ACPA positive subgroup of patients (Pc = 0.003, OR = 2.22, 95% CI = 1.41-3.51). On the contrary, the HLA-DRB1*13 (Pc = 0.01, OR = 0.43, 95% CI = 0.25-0.73) and HLA-DRB1*14 (Pc = 0.003, OR = 0.43, 95% CI = 0.26-0.69) alleles were over-represented in controls than patients. Further, distribution of the prominent Caucasian RA risk allele DRB1*04 did not differ between patients and controls in our study population. We did not find any association between DQB1 alleles and RA susceptibility or autoantibody status. The haplotypes DQB1*05-DRB1*10 (P = 6.8 × 10-6 , OR = 2.46, 95% CI = 1.63-3.79) and DQB1*06-DRB1*15 (P = 0.03, OR = 1.41, 95% CI = 1.02-1.96) were more frequent in patients while DQB1*05-DRB1*14 (P = 8.4 × 10-4 , OR = 0.44, 95% CI = 0.26-0.74) and DQB1*06-DRB1*13 (P = 9.5 × 10-4 , OR = 0.40, 95% CI = 0.21-0.72) were higher in controls. To conclude, HLA-DRB1*10 is associated with RA while HLA-DRB1*13 and HLA-DRB1*14 alleles confer protection in south Indian Tamils.

A double amino-acid change in the HLA-A peptide-binding groove is associated with response to psychotropic treatment in patients with schizophrenia.

The choice of an efficient psychotropic treatment for patients with schizophrenia is a key issue to improve prognosis and quality of life and to decrease the related burden and costs. As for other complex disorders, response to drugs in schizophrenia is highly heterogeneous and the underlying molecular mechanisms of this diversity are still poorly understood. In a carefully followed-up cohort of schizophrenic patients prospectively treated with risperidone or olanzapine, we used a specially designed single-nucleotide polymorphism (SNP) array to perform a large-scale genomic analysis and identify genetic variants associated with response to psychotropic drugs. We found significant associations between response to treatment defined by the reduction in psychotic symptomatology 42 days after the beginning of treatment and SNPs located in the chromosome 6, which houses the human leukocyte antigen (HLA). After imputation of the conventional HLA class I and class II alleles, as well as the amino-acid variants, we observed a striking association between a better response to treatment and a double amino-acid variant at positions 62 and 66 of the peptide-binding groove of the HLA-A molecule. These results support the current notion that schizophrenia may have immune-inflammatory underpinnings and may contribute to pave the way for personalized treatments in schizophrenia.

Violent suicidal behaviour in bipolar disorder is associated with nitric oxide synthase 3 gene polymorphism.

OBJECTIVE: Given the importance of nitric oxide system in oxidative stress, inflammation, neurotransmission and cerebrovascular tone regulation, we postulated its potential dysfunction in bipolar disorder (BD) and suicide. By simultaneously analysing variants of three isoforms of nitric oxide synthase (NOS) genes, we explored interindividual genetic liability to suicidal behaviour in BD. METHOD: A total of 536 patients with BD (DSM-IV) and 160 healthy controls were genotyped for functionally relevant NOS1, NOS2 and NOS3 polymorphisms. History of suicidal behaviour and violent suicide attempt was documented for 511 patients with BD. Chi-squared test was used to perform genetic association analyses and logistic regression to test for gene-gene interactions. RESULTS: NOS3 rs1799983 T homozygous state was associated with violent suicide attempts (26.4% vs. 10.8%, in patients and controls, P = 0.002, corrected P (Pc) = 0.004, OR: 2.96, 95% CI = 1.33-6.34), and this association was restricted to the early-onset BD subgroup (37.9% vs. 10.8%, in early-onset BD and controls, P = 0.0003, Pc = 0.0006 OR: 5.05, 95% CI: 1.95-12.45), while we found no association with BD per se and no gene-gene interactions. CONCLUSION: Our results bring further evidence for the potential involvement of endothelial NOS gene variants in susceptibility to suicidal behaviour. Future exploration of this pathway on larger cohort of suicidal behaviour is warranted.

Human leukocyte antigen-G polymorphism influences the age of onset and autoantibody status in rheumatoid arthritis.

The study was conducted to investigate the frequency of three gene polymorphisms in the 3'-untranslated region (3'-UTR) of human leucocyte antigen-G (HLA-G) gene in south Indian patients with rheumatoid arthritis (RA) and analyze their influence on disease susceptibility, phenotype and treatment response. HLA-G 14 bp insertion (Ins)/deletion (del) (rs66554220), HLA-G +3142G>C (rs1063320) and +3187A>G (rs9380142) polymorphism was analyzed in 221 RA patients and 200 healthy controls. Frequency of HLA-G genotypes or alleles did not differ between patients and controls. Analysis based on rheumatoid factor (RF) status revealed that the frequency of allele 'A' (rs9380142) was significantly higher in RF-positive than in RF-negative patients [84% vs 74%, Yates-corrected P value (Pc) = 0.04, odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.0-3.2]. A similar difference was maintained in RF-positive female patients than their RF-negative counterparts (83% vs 71%, Pc = 0.02, OR = 1.9, 95% CI = 1.0 to 3.4) and between RF-positive and RF-negative young onset RA (YORA) patients (84% vs 73%, Pc = 0.03, OR = 1.9, 95% CI = 1.0-3.2), suggesting that rs9380142 polymorphism influenced RF status. The 14 bp Ins allele of rs66554220 was significantly more prevalent in RF-positive YORA than in RF-positive late onset RA (LORA) patients (51% vs 25%, P = 0.03, OR = 3.1, 95% CI = 1.1-9.8). Frequency of the four major haplotypes [InsGA (48%), DelGA (22%), DelCG (18%), DelCA (9.7%)] observed did not differ between cases and controls. HLA-G does not appear to be a risk factor for development of RA in south Indian Tamils but may act as a genetic modifier of clinical phenotype in terms of autoantibody production, gender preference and age at disease onset.

The "psychomicrobiotic": Targeting microbiota in major psychiatric disorders: A systematic review.

The gut microbiota is increasingly considered as a symbiotic partner in the maintenance of good health. Metagenomic approaches could help to discover how the complex gut microbial ecosystem participates in the control of the host's brain development and function, and could be relevant for future therapeutic developments, such as probiotics, prebiotics and nutritional approaches for psychiatric disorders. Previous reviews focused on the effects of microbiota on the central nervous system in in vitro and animal studies. The aim of the present review is to synthetize the current data on the association between microbiota dysbiosis and onset and/or maintenance of major psychiatric disorders, and to explore potential therapeutic opportunities targeting microbiota dysbiosis in psychiatric patients.

IRF5rs2004640 single nucleotide polymorphism is associated with susceptibility to rheumatoid arthritis in South Indian Tamils.

Polymorphism of interferon regulatory factor 5 (IRF5), a latent transcription factor gene has been associated with various auto-immune diseases. Our aim was to study the IRF5rs2004640 gene polymorphism and its association with disease susceptibility, disease phenotype and treatment response in South Indian Tamil patients with rheumatoid arthritis (RA).The study was conducted on 217 RA patients fulfilling the American College of Rheumatology (ACR) 2010 criteria and 482 healthy controls (HCs) without family history of autoimmune disease. The IRF5rs2004640 genotyping was performed using a TaqMan 5' allelic discrimination assay. We found that the IRF5rs2004640T allele [P < 0.0001, odds ratio (OR) 3.25, 95% confidence interval (CI) 2.55-4.12] and TT genotype (P < 0.0001, OR 4.60, 95% CI 3.23-6.57) were significantly more frequent in RA patients as compared with HCs. No association was found between IRF5rs2004640 polymorphism, clinical manifestations, autoantibody profile and treatment response. IRF5rs2004640 T (mutant) allele may be a susceptibility factor conferring risk for RA in South Indian Tamils, whereas G allele (wild type) may be protective.