ABSTRACT
BACKGROUND: Age represents a significant risk factor for the development of Alzheimer's disease (AD); however, recent research has documented an influencing role of sex in several features of AD. Understanding the impact of sex on specific molecular mechanisms associated with AD remains a critical challenge to creating tailored therapeutic interventions. METHODS: The exploration of the sex-based differential impact on disease (SDID) in AD used a systematic review to first select transcriptomic studies of AD with data regarding sex in the period covering 2002 to 2021 with a focus on the primary brain regions affected by AD - the cortex (CT) and the hippocampus (HP). A differential expression analysis for each study and two tissue-specific meta-analyses were then performed. Focusing on the CT due to the presence of significant SDID-related alterations, a comprehensive functional characterization was conducted: protein-protein network interaction and over-representation analyses to explore biological processes and pathways and a VIPER analysis to estimate transcription factor activity. RESULTS: We selected 8 CT and 5 HP studies from the Gene Expression Omnibus (GEO) repository for tissue-specific meta-analyses. We detected 389 significantly altered genes in the SDID comparison in the CT. Generally, female AD patients displayed more affected genes than males; we grouped said genes into six subsets according to their expression profile in female and male AD patients. Only subset I (repressed genes in female AD patients) displayed significant results during functional profiling. Female AD patients demonstrated more significant impairments in biological processes related to the regulation and organization of synapsis and pathways linked to neurotransmitters (glutamate and GABA) and protein folding, Aß aggregation, and accumulation compared to male AD patients. These findings could partly explain why we observe more pronounced cognitive decline in female AD patients. Finally, we detected 23 transcription factors with different activation patterns according to sex, with some associated with AD for the first time. All results generated during this study are readily available through an open web resource Metafun-AD (https://bioinfo.cipf.es/metafun-ad/). CONCLUSION: Our meta-analyses indicate the existence of differences in AD-related mechanisms in female and male patients. These sex-based differences will represent the basis for new hypotheses and could significantly impact precision medicine and improve diagnosis and clinical outcomes in AD patients.
Subject(s)
Alzheimer Disease , Sex Characteristics , Transcription Factors , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Humans , Transcription Factors/genetics , Transcription Factors/metabolism , Female , Male , Transcriptome , Hippocampus/metabolismABSTRACT
BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGTâA (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).
Subject(s)
B-Cell Activating Factor/genetics , INDEL Mutation , Lupus Erythematosus, Systemic/genetics , Multiple Sclerosis/genetics , Autoimmunity , B-Cell Activating Factor/metabolism , Case-Control Studies , Gene Expression , Genome-Wide Association Study , Humans , Italy , Lupus Erythematosus, Systemic/immunology , MicroRNAs , Multiple Sclerosis/immunology , Phenotype , Polymorphism, Single Nucleotide , Risk , Sequence Analysis, RNA , Transcription, GeneticABSTRACT
Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA-G*01:05N and ASD is present. Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population. One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (pcâ¯=â¯1â¯×â¯10-3; OR:3.5, 95%CI: 1.8-6.8). However, given the lack of data on HLA-G*01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect. These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations.
Subject(s)
Autism Spectrum Disorder/genetics , HLA-G Antigens/genetics , Adult , Alleles , Autism Spectrum Disorder/immunology , Child , Cohort Studies , Ethnicity/genetics , Exons/genetics , Female , Gene Frequency/genetics , Genes, MHC Class I/genetics , Genetic Predisposition to Disease , Genotype , HLA-G Antigens/immunology , Haplotypes , Humans , Italy , Male , Polymorphism, Genetic/geneticsABSTRACT
BACKGROUND: The etiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leukocyte antigen (HLA) alleles, in particular, are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS. METHODS: HLA alleles, EBV viral load (VL) and serum anti-EBV antibody titers were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89). RESULTS: Significantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titer (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02-/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07-/DRB1*15- individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution. CONCLUSIONS: Host HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.
Subject(s)
Alleles , HLA Antigens/genetics , Herpesvirus 4, Human/physiology , Multiple Sclerosis/genetics , Multiple Sclerosis/virology , Viral Load , Adult , Case-Control Studies , Cytomegalovirus/physiology , Female , Genotype , Humans , Male , Middle Aged , Multiple Sclerosis/blood , Seroepidemiologic StudiesABSTRACT
Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a cohort of Italian children affected by ASD (N=111) their mothers (N=81), and their healthy siblings (N=39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian pc=1×10-4; Danish pc=1×10-3). Since HLA-G distribution was similar in the two control groups, their data were pooled. Results indicated that HLA-G*01:01 was significantly less frequent (pc=1×10-4; OR:0.5, 95%CI: 0.3-0.7) whereas HLA-G*01:05N was significantly more frequent (pc=2×10-3; OR:7.3, 95%CI: 2.4-26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (pc=6×10-4 df=12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune activating milieu during pregnancy is more likely observed in association with the development of ASD, similarly to what occurs in women with recurrent miscarriages.
Subject(s)
Autism Spectrum Disorder/genetics , HLA-G Antigens/genetics , Child , Female , Gene Frequency , Humans , Male , Polymorphism, GeneticABSTRACT
Language-based Learning Disabilities (LLDs) encompass a group of complex, comorbid, and developmentally associated deficits in communication. Language impairment and developmental dyslexia (DD) represent the most recognized forms of LLDs. Substantial genetic correlations exist between language and reading (dis)abilities. Common variants in the FOXP2 gene were consistently associated with language- and reading-related neuropsychological and neuroanatomical phenotypes. We tested the effect of a FOXP2 common variant, that is, rs6980093 (A/G), on quantitative measures of language and reading in two independent Italian samples: a population-based cohort of 699 subjects (3-11 years old) and a sample of 572 children with DD (6-18 years old). rs6980093 modulates expressive language in the general population sample, with an effect on fluency scores. In the DD sample, the variant showed an association with the accuracy in the single word reading task. rs6980093 shows distinct genetic models of association in the two cohorts, with a dominant effect of the G allele in the general population sample and heterozygote advantage in the DD cohort. We provide preliminary evidence that rs6980093 associates with language and reading (dis)abilities in two independent Italian cohorts. rs6980093 is an intronic SNP, suggesting that it (or a linked variant) modulates phenotypic association via regulation of FOXP2 expression. Because FOXP2 brain expression is finely regulated, both temporally and spatially, it is possible that the two alleles at rs6980093 differentially modulate expression levels in a developmental stage- or brain area-specific manner. This might help explaining the heterozygote advantage effect and the different genetic models in the two cohorts.
ABSTRACT
HLA-G expressed by the trophoblast ligates KIR molecules expressed by maternal NK cells at the uterine fetal/maternal interface: this interaction is involved in generating immune tolerance during pregnancy. A 14-bp insertion in the HLA-G 3'-UTR associates with significantly reduced levels of both HLA-G mRNA and soluble HLA-G, thus hampering the efficacy of HLA-G-mediated immune tolerance during pregnancy. Because prenatal immune activation is suggested to play an important role in the onset of autistic spectrum disorders (ASD) we performed an in-depth evaluation of HLA-G polymorphisms in a well-characterized cohort of Italian families of ASD children. Results showed that frequency of both homozygous 14bp+/14bp+ genotype and 14bp+ allele was significantly higher in ASD children and their mothers compared to controls (p<0.05 in all cases); analysis of the frequency of transmission of the 14bp+ allele from parents to ASD children and their non-ASD siblings showed that the 14bp+ allele was more frequently transmitted (T) to ASD children, whereas it was preferentially not transmitted (NT) to the non-ASD siblings (overall discrepancy: p=0.02; OR: 2.6, 95% CI: 1.1-6.4). Results herein suggest that HLA-G polymorphisms are associated with ASD development, possibly as a consequence of prenatal immune activation. These data infer that the immune alterations seen in ASD are associated with the maternal-fetal interaction alone, and reinforce the observation that different genetic backgrounds characterize ASD children and their non-ASD siblings.
Subject(s)
Child Development Disorders, Pervasive/genetics , HLA-G Antigens/genetics , INDEL Mutation , 3' Untranslated Regions , Adolescent , Adult , Child , Cohort Studies , Female , Genotype , Humans , Italy , Male , Middle Aged , Polymorphism, GeneticABSTRACT
BACKGROUND: Recent studies identified > 100 non-HLA (human leukocyte antigen) multiple sclerosis (MS) susceptibility variants in Northern European populations, but their role in Southern Europeans is largely unexplored. OBJECTIVE: We aimed to investigate the cumulative impact of those variants in two Mediterranean populations: Continental Italians and Sardinians. METHODS: We calculated four weighted Genetic Risk Scores (wGRS), using up to 102 non-HLA MS risk variants and 5 HLA MS susceptibility markers in 1691 patients and 2194 controls from continental Italy; and 2861 patients and 3034 controls from Sardinia. We then assessed the differences between populations using Nagelkerke's R(2) and the area under the Receiver Operating Characteristic (ROC) curves. RESULTS: As expected, the genetic burden (mean wGRS value) was significantly higher in MS patients than in controls, in both populations. Of note, the burden was significantly higher in Sardinians. Conversely, the proportion of variability explained and the predictive power were significantly higher in continental Italians. Notably, within the Sardinian patients, we also observed a significantly higher burden of non-HLA variants in individuals who do not carry HLA risk alleles. CONCLUSIONS: The observed differences in MS genetic burden between the two Mediterranean populations highlight the need for more genetic studies in South Europeans, to further expand the knowledge of MS genetics.
Subject(s)
Genetic Predisposition to Disease , HLA Antigens/genetics , Multiple Sclerosis/ethnology , Multiple Sclerosis/genetics , Biomarkers , Genotype , Humans , Italy/ethnology , Polymorphism, Single Nucleotide , RiskABSTRACT
The activity of natural killer (NK) cells is modulated by the interaction between killer-cell immune globulin-like receptor (KIR) proteins and their cognate HLA ligands; activated NK cells produce inflammatory cytokines and mediate innate immune responses. Activating KIR/HLA complexes (aKIR/HLA) were recently suggested to prevail in children with autism spectrum disorders (ASD), a neurodevelopmental syndrome characterized by brain and behavioral abnormalities and associated with a degree of inflammation. We verified whether such findings could be confirmed by analyzing two sample cohorts of Sardinian and continental Italian ASD children and their mothers. Results showed that aKIR/HLA are increased whereas inhibitory KIR/HLA complexes are reduced in ASD children; notably this skewing was even more significant in their mothers. KIR and HLA molecules are expressed by placental cells and by the trophoblast and their interactions result in immune activation and influence fetal, as well as central nervous system development and plasticity. Data herein suggest that in utero KIR/HLA immune interactions favor immune activation in ASD; this may play a role in the pathogenesis of the disease.
Subject(s)
Child Development Disorders, Pervasive/genetics , HLA Antigens/genetics , Receptors, KIR/genetics , Child , Child Development Disorders, Pervasive/diagnosis , Female , Humans , Ligands , Male , MothersABSTRACT
BACKGROUND: The contribution of genetic variants underlying the susceptibility to different clinical courses of multiple sclerosis (MS) is still unclear. OBJECTIVE: The aim of the study is to evaluate and compare the proportion of liability explained by common SNPs and the genetic burden of MS-associated SNPs in progressive onset (PrMS) and bout-onset (BOMS) cases. METHODS: We estimated the proportion of variance in disease liability explained by 296,391 autosomal SNPs in cohorts of Italian PrMS and BOMS patients using the genome-wide complex trait analysis (GCTA) tool, and we calculated a weighted genetic risk score (wGRS) based on the known MS-associated loci. RESULTS: Our results identified that common SNPs explain a greater proportion of phenotypic variance in BOMS (36.5%±10.1%) than PrMS (20.8%±6.0%) cases, and a trend of decrease was observed when testing primary progressive (PPMS) without brain MRI inflammatory activity (p = 7.9 × 10(-3)). Similarly, the wGRS and the variance explained by MS-associated SNPs were higher in BOMS than PPMS in males (wGRS: 6.63 vs 6.51, p = 0.04; explained variance: 4.8%±1.5% vs 1.7%±0.6%; p = 0.05). CONCLUSIONS: Our results suggest that the liability of disease is better captured by common genetic variants in BOMS than PrMS cases. The absence of inflammatory activity and male gender further raise the difference between clinical courses.
Subject(s)
Multiple Sclerosis, Chronic Progressive/genetics , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Aged, 80 and over , Female , Genetic Markers , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Italy , Magnetic Resonance Imaging , Male , Middle Aged , Multiple Sclerosis, Chronic Progressive/diagnostic imaging , Multiple Sclerosis, Chronic Progressive/immunology , Phenotype , Risk Factors , Sex Factors , Young AdultABSTRACT
The vitamin D receptor (VDR) gene has been involved in the modulation of susceptibility to inflammatory and autoimmune conditions, and could play a role in the pathogenesis of type 2 diabetes mellitus (T2DM). Susceptibility to T2DM was recently also suggested to associate with HLA alleles. We evaluated possible correlations between VDR polymorphisms, HLA alleles, and risk for development of T2DM by analyzing 627 individuals (368 T2DM patients and 259 healthy control subjects) part of a well-characterized cohort followed in Riyadh, Kingdom of Saudi Arabia. Genomic DNA was genotyped for the VDR gene single nucleotide polymorphisms of Fok-1, Taq-1, ApaI, and Bsm-I. Analyses were run by allelic discrimination real-time PCR. HLA genotyping was performed as well by PCR using sequence-specific primers, whereas cytokine production was evaluated by FACS. Results showed T2DM to be significantly associated with the VDR Taq1 (rs731236-AG) and Bsm-I (rs1544410-CT) genotypes, and the VDR rs1544410-T allele. Cosegregations resulting in significant increases of T2DM odds ratio were detected between Taq1 and Bsm-I VDR polymorphisms and HLA DRB1*04. Notably, the VDR polymorphisms observed to be more frequent in T2DM patients correlated with increased VDR expression and IL-12 production, as well as with metabolic parameters of susceptibility to T2DM, including serum cholesterol and high-density lipoprotein levels. VDR polymorphisms are present in T2DM, and correlate with HLA DRB1*04 and with immunologic and metabolic parameters; results from this study add T2DM to the list of diseases that are likely modulated by an HLA/VDR interaction.
Subject(s)
Diabetes Mellitus, Type 2/genetics , HLA-DRB1 Chains/genetics , Polymorphism, Genetic , Receptors, Calcitriol/genetics , Case-Control Studies , Chromosome Segregation , Diabetes Mellitus, Type 2/epidemiology , Disease Susceptibility , Genetics, Population , Humans , Saudi Arabia/epidemiologyABSTRACT
BACKGROUND: The incidence of Alzheimer's disease (AD)-the most frequent cause of dementia-is expected to increase as life expectancies rise across the globe. While sex-based differences in AD have previously been described, there remain uncertainties regarding any association between sex and disease-associated molecular mechanisms. Studying sex-specific expression profiles of regulatory factors such as microRNAs (miRNAs) could contribute to more accurate disease diagnosis and treatment. METHODS: A systematic review identified six studies of microRNA expression in AD patients that incorporated information regarding the biological sex of samples in the Gene Expression Omnibus repository. A differential microRNA expression analysis was performed, considering disease status and patient sex. Subsequently, results were integrated within a meta-analysis methodology, with a functional enrichment of meta-analysis results establishing an association between altered miRNA expression and relevant Gene Ontology terms. RESULTS: Meta-analyses of miRNA expression profiles in blood samples revealed the alteration of sixteen miRNAs in female and 22 miRNAs in male AD patients. We discovered nine miRNAs commonly overexpressed in both sexes, suggesting a shared miRNA dysregulation profile. Functional enrichment results based on miRNA profiles revealed sex-based differences in biological processes; most affected processes related to ubiquitination, regulation of different kinase activities, and apoptotic processes in males, but RNA splicing and translation in females. Meta-analyses of miRNA expression profiles in brain samples revealed the alteration of six miRNAs in female and four miRNAs in male AD patients. We observed a single underexpressed miRNA in female and male AD patients (hsa-miR-767-5p); however, the functional enrichment analysis for brain samples did not reveal any specifically affected biological process. CONCLUSIONS: Sex-specific meta-analyses supported the detection of differentially expressed miRNAs in female and male AD patients, highlighting the relevance of sex-based information in biomedical data. Further studies on miRNA regulation in AD patients should meet the criteria for comparability and standardization of information.
Alzheimer's disease (AD)a neurodegenerative disease mainly affecting older patientsis characterized by cognitive deterioration, memory loss, and progressive incapacitation in daily activities. While AD affects almost twice as many females as males, and cognitive deterioration and brain atrophy develop more rapidly in females, the biological causes of these differences remain poorly understood. MicroRNAs (miRNAs) regulate gene expression and impact a wide variety of biological processes; therefore, studying the differential expression of miRNAs in female and male AD patients could contribute to a better understanding of the disease. We reviewed studies of miRNA expression in female and male AD patients and integrated results using a meta-analysis methodology and then identified those genes regulated by the altered miRNAs to establish an association with biological processes. We found 16 (females) and 22 (males) miRNAs altered in the blood of AD patients. Functional enrichment revealed sex-based differences in the affected altered biological processesprotein modification and degradation and cell death in male AD patients and RNA processing in female AD patients. A similar analysis in the brains of AD patients revealed six (females) and four (males) miRNAs with altered expression; however, our analysis failed to highlight any specifically altered biological processes. Overall, we highlight the sex-based differential expression of miRNAs (and biological processes affected) in the blood and brain of AD patients.
Subject(s)
Alzheimer Disease , MicroRNAs , Humans , Male , Female , Alzheimer Disease/genetics , MicroRNAs/metabolism , Brain/metabolismABSTRACT
The THBS4 gene encodes a glycoprotein involved in inflammatory responses and synaptogenesis. THBS4 is expressed at higher levels in the brain of humans compared with nonhuman primates, and the protein accumulates in ß-amyloid plaques. We analyzed THBS4 genetic variability in humans and show that two haplotypes (hap1 and hap2) are maintained by balancing selection and modulate THBS4 expression in lymphocytes. Indeed, the balancing selection region covers a predicted transcriptional enhancer. In humans, but not in macaques and chimpanzees, THBS4 brain expression increases with age, and variants in the balancing selection region interact with sex in influencing THBS4 expression (pinteraction = 0.038), with hap1 homozygous females showing lowest expression. In Alzheimer disease (AD) patients, significant interactions between sex and THBS4 genotype were detected for peripheral gray matter (pinteraction = 0.014) and total gray matter (pinteraction = 0.012) volumes. Similarly to the gene expression results, the interaction is mainly mediated by hap1 homozygous AD females, who show reduced volumes. Thus, the balancing selection target in THBS4 is likely represented by one or more variants that regulate tissue-specific and sex-specific gene expression. The selection signature associated with THBS4 might not be related to AD pathogenesis, but rather to inflammatory responses.
Subject(s)
Alzheimer Disease/genetics , Brain/metabolism , Sex Factors , Thrombospondins/genetics , Alzheimer Disease/pathology , Animals , Base Sequence , Brain/pathology , Female , Genetics, Population , Haplotypes , Humans , Male , Sequence Homology, Nucleic AcidABSTRACT
BACKGROUND: Literature states that parents of individuals affected by autism spectrum disorder (ASD) can present social and cognitive deficits, restricted behavior patterns and psychiatric difficulties, without meeting standard diagnostic criteria for ASD ("broader autism phenotype"). We explored the relationship between parenting of children affected by ASD and levels of empathy and lack of emotion understanding (alexithymia). METHODS: We enlisted 58 families in which a child was affected by ASD. Parents' empathy and alexithymia were respectively assessed by means of Empathy Quotient (EQ) and Toronto Alexithymia Scale (TAS-20). Additionally, we included the assessment of the perception of children's behavior through the Child Behavior Checklist (CBCL). RESULTS: Our findings suggest that most parents have normal empathy and do not show significant alexithymia. We found lower EQ and higher TAS-20 scores being more frequent in fathers. Moreover, each parent's empathy degree negatively relates to his/her alexithymia and vice versa, showing that these two features are inversely correlated. Our study unveiled a strong correlation between maternal empathy and alexithymia and child's externalizing problems, as reported by mothers. CONCLUSIONS: Our data reveal differences in mothers and fathers' empathy and alexithymia profiles and confirm the importance of considering both parents' points of view either in the diagnostic and the therapeutic interventions. Parental empathy and alexithymia levels not only play a fundamental role in the evaluation of child's difficulties but can also influence the development of a good relationship with the child for what concerns affective resonance.
ABSTRACT
BACKGROUND: Many studies have already shown that individuals suffering from autism spectrum disorders (ASD) present low levels of empathy: in fact, reduced emotional reciprocity is considered a clinically significant indicator of autistic functioning. We decided to investigate the role of empathy in determining pathological behaviors in children affected by ASD considering parents' point of view; and to evaluate the presence of differences between mothers and fathers' perception of their child's empathy and behaviors. METHODS: We compared empathy levels in a sample of 58 patients with ASD as reported by a parent-filled questionnaire with the results of a global evaluation conducted by means of play observations, clinician-rated scales, a semistructured interview with both caregivers and parent-filled questionnaires. RESULTS: The majority of ASD patients have low levels of empathy according to both parents' points of view; noteworthy, mothers and fathers are highly concordant in this respect. Children's levels of empathy negatively correlate with many behavioral problems, both internalizing and externalizing. Furthermore, we found that mothers tend to perceive more internalizing problems, while fathers are more willing to notice externalizing ones. CONCLUSIONS: Involving both caregivers in children's diagnostic assessment could deepen patient's evaluation and finally the therapeutic results. Mothers and fathers seem to be highly consistent in describing the psychological characteristics of their child, but not in respect to symptoms.
Subject(s)
Autism Spectrum Disorder , Male , Female , Humans , Child , Autism Spectrum Disorder/diagnosis , Fathers/psychology , Empathy , Mothers/psychology , ParentsABSTRACT
Contrasting results have been reported concerning the association of a splice-site polymorphism (rs10774671) in OAS1 with multiple sclerosis (MS). We analysed two OAS1 regions encompassing alternatively spliced exons. While the region carrying the splice-site variant is neutrally evolving, a signature of long-standing balancing selection was observed across an alternative exon 7. Analysis of variants in this exon identified an insertion/deletion polymorphism (rs11352835, A/-) that originates predicted products with distinct C termini. This variant is located along the major branch of the haplotype genealogy, suggesting that it may represent the selection target. A case/control study for MS indicated that rs11352835 is associated with disease susceptibility (for an allelic model with the deleted allele predisposing to MS, OR 1.27, 95% CI 1.072-1.513, p = 0.010). No association was found between rs10774671 and MS. As the two SNPs are in linkage disequilibrium in Europeans, the previously reported association between rs10774671 and MS susceptibility might be driven by rs11352835, possibly explaining the contrasting results previously observed for the splice-site polymorphism. Thus, we describe a novel susceptibility variant for MS in OAS1 and show that population genetic analyses can be instrumental to the identification of selection targets and, consequently, of functional polymorphisms with an effect on phenotypic traits.
Subject(s)
2',5'-Oligoadenylate Synthetase/genetics , Genetic Predisposition to Disease , Genetics, Population , Haplotypes/genetics , Multiple Sclerosis/genetics , Polymorphism, Genetic/genetics , Adult , Case-Control Studies , DNA/analysis , DNA/genetics , Female , Genotype , Humans , Italy/epidemiology , Linkage Disequilibrium , Male , Multiple Sclerosis/epidemiology , Polymerase Chain ReactionABSTRACT
BACKGROUND: The T allele of rs9657904 within the CBLB gene was recently found to be significantly associated with multiple sclerosis (MS) in a genome-wide association study in Sardinia. OBJECTIVE: To replicate this association in an independent population with a different genetic background. METHODS: The rs9657904 variant was typed in a sample of 1435 cases and 1466 controls from the Italian mainland. RESULTS: It was found that in this sample also, the common allele T of rs9657904 is significantly positively associated (one-tailed p=7.35 × 10(-5)) and with a comparable effect size with MS (OR=1.31, 95% CI 1.14 to 1.52). CONCLUSION: These data provide further evidence of the association of MS disease with variation within CBLB.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Multiple Sclerosis/genetics , Proto-Oncogene Proteins c-cbl/genetics , White People/genetics , Adult , Alleles , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Italy , Male , Polymorphism, Single Nucleotide , Young AdultABSTRACT
BACKGROUND: The association of HLA A*02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw*05 significantly enhanced (threefold) the protective effect of HLA A*02. OBJECTIVES AND METHODS: Since A*02-Cw*05 is carried by two HLA extended haplotypes characterised by the B*4402 and B*1801 alleles, respectively, the association analysis was extended to HLA B*44 and B*18 in an Italian sample (1445 MS cases and 973 controls) and these associations were verified in a UK cohort (721 MS cases, 408 controls and 480 family trios). RESULTS: A strong protective effect, independent of DR15, of the A*02-Cw*05 combination carrying B*44 (OR 0.27, p=3.3×10(-5)) was seen in the Italian samples and confirmed in UK family trios (OR 0.33, p=5.5×10(-4)) and in a combined cohort of UK families and case-controls (OR 0.53, p=0.044). This protective effect was significantly stronger than that mediated by A*02 alone. Logistic regression showed that A*02-Cw*05 maintained a significant protection when adjusted for B alleles (Italy: OR 0.38, p=6.5×10(-7); UK: OR 0.60, p=0.0029), indicating that it was not secondary to linkage disequilibrium with B*44. Different from A*02, the other HLA class I tested markers individually showed no significant (Cw*05, B*18) or a modest (B*44) protection when adjusted for the remaining markers. CONCLUSIONS: This study identified at least two independent protective effects which are tagged by A*02-Cw*05 and A*02, respectively. Further studies are needed to elucidate whether this protective effect is due to the presence of an unanalysed factor characterising the HLA extended haplotype(s) carrying A*02 and Cw*05 or to a direct interaction between these alleles.
Subject(s)
Histocompatibility Antigens Class I/genetics , Multiple Sclerosis/genetics , Adult , Alleles , Case-Control Studies , Female , Gene Expression Regulation , Gene Order , Genetic Association Studies , Genetic Predisposition to Disease , HLA-DR Antigens/genetics , Haplotypes , Humans , Italy , Male , Middle Aged , United Kingdom , Young AdultABSTRACT
Multiple sclerosis (MS) is an autoimmune disease with a multifactorial etiology. The HLA-DRB1*15 allele, is the main genetic risk factor for MS in Caucasians; recent findings showed that the transcription of this molecule is regulated by the vitamin D/vitamin D receptor (VDR) complex. We analyzed SNPs within the VDR gene in association with the HLA-DRB1 locus in 641 MS patients diagnosed according to McDonald criteria and 558 age- and sex-matched healthy controls, to verify possible correlations between the vitamin D/VDR complex, HLA-DRB1, and susceptibility to MS. Results confirmed that HLA-DRB1*15 is a strong predisposing allele (p<1×10(-7); OR: 3.04; 95% CI: 2.02-4.60) for MS. Cosegregation analyses of VDR SNPs with HLA-DRB1*15 indicated a reduction of risk for MS given by the presence of the -DRB1*15-rs731236 T VDR haplotype (p=9.5×10(-5); OR: 2.52; 95% CI: 1.56-4.06) and, conversely, an augmented risk for disease associated with the -DRB1*15-rs731236 C VDR haplotype. Analyses performed on HLA-DRB1*15-positive MS patients and HC alone confirmed the protective role of rs731236 TT VDR genotype (p(y)=0.004; OR: 0.53; 95% CI: 0.33-0.83); notably, FACS, PCR, and confocal microscopy analyses showed that rs731236 TT genotype is associated with an augmented VDR expression in MBP-stimulated PBMC from patients. In conclusion, rs731236 TT VDR genotype modulates VDR expression and confers protection against MS in HLA-DRB1*15-positive individuals. Results herein offer a model justifying the interaction between the major genetic (HLA-DRB*15) and environmental (vitamin D) factors associated with MS onset.
Subject(s)
Genetic Predisposition to Disease , HLA-DRB1 Chains/genetics , Multiple Sclerosis/genetics , Polymorphism, Single Nucleotide , Receptors, Calcitriol/genetics , Adult , Alleles , Female , Gene Frequency , Genotype , HLA-DRB1 Chains/immunology , Haplotypes , Humans , Male , Middle Aged , Multiple Sclerosis/immunology , Risk Factors , White People/geneticsABSTRACT
Synaptosomal-associated protein of 25kD (SNAP-25), a protein participating in the regulation of synaptic vesicle exocytosis and in calcium homeostasis, was recently involved in neuropsychiatric conditions. Because alterations affecting the homeostasis of calcium are described in patients affected by autism spectrum disorders (ASD) we investigated a possible involvement of SNAP-25 in ASD by evaluating five SNAP-25 gene polymorphisms in a cohort of 67 ASD children. Data analyzed in relationship with clinical outcomes and compared to those of 205 healthy sex-matched children did not reveal significant differences. Further analyses nevertheless showed the presence of highly significant associations of the rs363043 (CT) genotype, localized in the intron 1 region that affects the transcription factor binding sites of the SNAP-25 gene, with both increasing CARS (p=0.001) and hyperactivity scores (p=0.006). The finding that polymorphisms of the SNAP-25 gene, a gene involved in neurotransmission and regulation of calcium homeostasis, are associated with the degree of hyperactivity in children with ASD, reinforces the hypothesis that alterations of these mechanisms play a pivotal role in the events leading to ASD-associated behavioral impairment. Modulation of these processes could result in novel therapeutic strategies.