A human leukocyte antigen imputation study uncovers possible genetic interplay between gut inflammatory processes and autism spectrum disorders

Autism spectrum disorders (ASD) are neurodevelopmental conditions that are for subsets of individuals, underpinned by dysregulated immune processes, including inflammation, autoimmunity, and dysbiosis. Consequently, the major histocompatibility complex (MHC)-hosted human leukocyte antigen (HLA) has been implicated in ASD risk, although seldom investigated. By utilizing a GWAS performed by the EU-AIMS consortium (LEAP cohort), we compared HLA and MHC genetic variants, single nucleotide polymorphisms (SNP), and haplotypes in ASD individuals, versus typically developing controls. We uncovered six SNPs, namely rs9268528, rs9268542, rs9268556, rs14004, rs9268557, and rs8084 that crossed the Bonferroni threshold, which form the underpinnings of 3 independent genetic pathways/blocks that differentially associate with ASD. Block 1 (rs9268528-G, rs9268542-G, rs9268556-C, and rs14004-A) afforded protection against ASD development, whilst the two remaining blocks, namely rs9268557-T, and rs8084-A, associated with heightened risk. rs8084 and rs14004 mapped to the HLA-DRA gene, whilst the four other SNPs located in the BTNL2 locus. Different combinations amongst BTNL2 SNPs and HLA amino acid variants or classical alleles were found either to afford protection from or contribute to ASD risk, indicating a genetic interplay between BTNL2 and HLA. Interestingly, the detected variants had transcriptional and/or quantitative traits loci implications. As BTNL2 modulates gastrointestinal homeostasis and the identified HLA alleles regulate the gastrointestinal tract in celiac disease, it is proposed that the data on ASD risk may be linked to genetically regulated gut inflammatory processes. These findings might have implications for the prevention and treatment of ASD, via the targeting of gut-related processes

Analyse de l'influence de la diversité des gènes et des molécules HLA non classiques sur la survenue de la maladie du greffon contre l'hôte après greffe de cellules souches hématopoïétiques

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Circulating levels of brain-derived neurotrophic factor (BDNF) in patients with bipolar disorders may be influenced by mitochondrial dysfunction, inflammation, and history of childhood trauma

Background: Bipolar disorders are underpinned by deregulated immune processes including chronic inflammation. The crosstalk between immune factors and homeostatic molecules remains scarcely studied. The brain-derived neurotrophic factor is a neurotrophic molecule essential for neuronal and synaptic homeostasis. We explored correlations between BDNF levels and factors known to contribute to sustained inflammation, namely mitochondrial dysfunction (mtDNAcn), inflammation, and history of childhood maltreatment (CM). Methods: 175 patients with BD assessed either during acute mood episode or when euthymic and 85 healthy controls were included. CM history was assessed by the Childhood Trauma Questionnaire. Circulating levels of inflammatory molecules, BDNF and mitochondrial DNA copy number were determined. Correlations between the studied parameters were analyzed. Results: Low levels of BDNF were observed during acute mood episodes (mania/mixed/depression). We observed that IL-12/23p40 levels and history of CM were negatively correlated with circulating BDNF levels in acutely ill patients. In euthymic patients we found that while TNFα levels correlate negatively with BDNF levels, that of IL16, VEGF and mtDNAcn were positively correlated. Linear regression showed that: (i) in the whole BD sample, low mtDNAcn levels were associated with low BDNF levels (ii) in acutely ill BD patients, high CTQ-AE scores, and high IL-12/23p40 levels were associated with low BDNF levels. (ⅲ) in euthymic BD patients, low mtDNAcn levels were associated with low BDNF levels. Limitations: We acknowledge the relatively low sample size. Conclusions: We identified some of the immune factors possibly influencing the levels of BDNF. Future studies involving larger cohorts are warranted

Dectin-1 Polymorphism: A Genetic Disease Specifier in Autism Spectrum Disorders?

INTRODUCTION:In autism spectrum disorders (ASD), complex gene-environment interactions contribute to disease onset and progress. Given that gastro-intestinal dysfunctions are common in ASD, we postulated involvement of microbial dysbiosis in ASD and investigated, under a case-control design, the influence of DNA polymorphisms in the CLEC7A gene that encodes a pivotal fungal sensor, Dectin-1. MATERIAL AND METHODS:DNAs from 478 ASD patients and 351 healthy controls (HC) were analyzed for the CLEC7A rs16910631G/A and rs2078178 A/G single nucleotide polymorphisms (SNPs). Differences in the distribution of allele, genotype and haplotype by Chi-square testing and nonparametric analysis by Kruskal-Wallis/Mann-Whitney tests, where appropriate, were performed. The free statistical package R.2.13 software was used for the statistical analysis. RESULTS:We found that the CLEC7A rs2078178 G allele and GG genotype were more prevalent in HC as compared to ASD but failed to reach statistical significance for the latter (pc = 0.01, 0.06 respectively). However, after phenotype-based stratification, the CLEC7A rs2078178 G allele and GG genotype were found to be significantly more frequent in the Asperger group as compared to other ASD subsets (pc = 0.02, 0.01), a finding reinforced by haplotype analysis (rs2078178/rs16910631 G-G/G-G) (pc = 0.002). Further, intellectual quotient (IQ)-based stratification of ASD patients revealed that IQ values increase linearly along the CLEC7A rs2078178 AA, AG and GG genotypes (p = 0.05) and in a recessive manner (GG vs. AA+AG p = 0.02), further confirmed by haplotype distribution (CLEC7A rs2078178-16910631; A-G/A-G, A-G/G-G and G-G/G-G, p = 0.02, G-G/G-G vs. others, p = 0.01). CONCLUSION:Our data suggest that the genetic diversity of CLEC7A gene influences the ASD phenotype by behaving as a disease specifier and imply that the genetic control of innate immune response could determine the ASD phenotype

Association of markers of inflammation and intestinal permeability in suicidal patients with major mood disorders /

Background: Patients with major mood disorders are at high risk of suicidal behavior compared to the general population. Suicide is a public health concern, accounting for around 1.2% of deaths worldwide. Understanding its underlying mechanisms may help identify predictive biomarkers and design novel targeted treatments. Immune dysfunctions, in particular affecting the gut-brain axis, are of interest given their dual involvement in mood disorders and suicidal behavior. We thus explored the possible relationships between suicide attempt (SA) and circulating biomarkers of intestinal permeability and systemic inflammation in patients with major depressive disorder (MDD) or bipolar disorder (BD) with and without a history of SA. Method: 137 patients with BD and 168 with MDD were included, and among them, 133 had a history of SA and 172 did not. Among them, 104 were males (34%) and 201 females (66%). Depressive symptoms were evaluated using the Inventory of Depressive Symptomatology clinical scale (IDS-C30). Circulating levels of intestinal fatty acid binding protein (IFABP), calprotectin, apolipoprotein E (ApoE), lipopolysaccharides binding protein (LBP), lipopolysaccharides (LPS), soluble beta-2-microglobulin (B2m), and C-reactive protein (CRP), were determined. Multivariate linear regressions were performed according to the gender status given the proportion of the herein studied male and female individuals and the higher propensity of females to experience SA as compared to males. Results: After adjusting for confounding variables, patients in the SA group had significantly higher CRP, and lower IFABP levels in comparison to the NSA group. Limitations: The unavailability of confounding variables such as dietary habits, should be noted. In addition, the cross-sectional nature of the study hampers the identification of causative effects. Conclusion: Although preliminary, our observations revealed associations between markers of inflammation and intestinal permeability in patients with suicidal behavior warranting further confirmation in larger cohorts

The HLA-G low expressor genotype is associated with protection against bipolar disorder.

International audienceImplication of immune processes in bipolar disorder (BD) has recently gained increasing attention. Tolerogenic molecules, among which HLA-G plays a prominent role, mediate the modulation of such processes. The HLA-G locus is characterized by a high number of polymorphisms including a functionally relevant 14 base pair (bp) insertion/deletion (Ins/Del) allele affecting the HLA-G expression. Here, we analyzed the distribution of this polymorphism in 561 BD patients and 161 healthy and found that the HLA-G 14bp Ins/Ins genotype was significantly more prevalent in healthy controls than in patients (corrected p; pc=0.032) and that the prevalence of such protective genotype is lower among patients born during the winter season as compared to those born in other periods (pc=0.006). Possible mechanisms between low HLA G expression and resistance to infections as well as potential relationships between infections in early life and susceptibility to BD are discussed

<i>CLEC7A</i> alleles and genotypes distribution in patients with Asperger and other ASD types.

<p>Other ASD: Classical autism and PDD-NOS</p><p>n: number</p><p>pc: corrected p-value</p><p>OR: odds ratio; 95%</p><p>CI: confidence interval 95%.</p><p><i>CLEC7A</i> alleles and genotypes distribution in patients with Asperger and other ASD types.</p

Haplotypes distribution in patients with classical autism and Asperger and controls.

<p>CA: Classical autism</p><p>Other ASD: Classical autism and pervasive developmental disorders not otherwise specified (PDD-NOS)</p><p>HC: healthy controls</p><p>n: number</p><p>pc: corrected p-value</p><p>OR: odds ratio; 95%</p><p>CI: confidence interval 95%.</p><p>Haplotypes distribution in patients with classical autism and Asperger and controls.</p

Demographic and clinical data of ASD patients and healthy controls.

<p>ASD: autism spectrum disorders</p><p>SD: standard deviation</p><p>CA: Classical autism</p><p>PDD-NOS: pervasive developmental disorders not otherwise specified.</p><p>Demographic and clinical data of ASD patients and healthy controls.</p

<i>CLEC7A</i> genotype and allele frequencies among patients and controls.

<p>ASD: autism spectrum disorders</p><p>HC: healthy controls</p><p>n: number</p><p>pc: corrected p-value</p><p>OR: odds ratio; 95%</p><p>CI: confidence interval 95%.</p><p><i>CLEC7A</i> genotype and allele frequencies among patients and controls.</p