Modeling Human Muscular Dystrophies in Zebrafish: Mutant Lines, Transgenic Fluorescent Biosensors, and Phenotyping Assays.

Muscular dystrophies (MDs) are a heterogeneous group of myopathies characterized by progressive muscle weakness leading to death from heart or respiratory failure. MDs are caused by mutations in genes involved in both the development and organization of muscle fibers. Several animal models harboring mutations in MD-associated genes have been developed so far. Together with rodents, the zebrafish is one of the most popular animal models used to reproduce MDs because of the high level of sequence homology with the human genome and its genetic manipulability. This review describes the most important zebrafish mutant models of MD and the most advanced tools used to generate and characterize all these valuable transgenic lines. Zebrafish models of MDs have been generated by introducing mutations to muscle-specific genes with different genetic techniques, such as (i) N-ethyl-N-nitrosourea (ENU) treatment, (ii) the injection of specific morpholino, (iii) tol2-based transgenesis, (iv) TALEN, (v) and CRISPR/Cas9 technology. All these models are extensively used either to study muscle development and function or understand the pathogenetic mechanisms of MDs. Several tools have also been developed to characterize these zebrafish models by checking (i) motor behavior, (ii) muscle fiber structure, (iii) oxidative stress, and (iv) mitochondrial function and dynamics. Further, living biosensor models, based on the expression of fluorescent reporter proteins under the control of muscle-specific promoters or responsive elements, have been revealed to be powerful tools to follow molecular dynamics at the level of a single muscle fiber. Thus, zebrafish models of MDs can also be a powerful tool to search for new drugs or gene therapies able to block or slow down disease progression.

Early start of enzyme replacement therapy in pediatric male patients with classical Fabry disease is associated with attenuated disease progression.

BACKGROUND: Enzyme replacement therapy (ERT) slows disease progression of Fabry disease (FD), especially when initiated before the onset of irreversible organ damage. However, with the clinically asymptomatic progression of renal, cardiac and cerebral disease manifestations spanning decades, optimal timing of ERT initiation remains unclear. METHODS: In this cross-sectional retrospective study, seven male FD patients with a classical disease phenotype (cFD) who started treatment with agalsidase-beta in childhood were evaluated after 10 years of treatment (median age at evaluation 24 years, range 14-26). Cardiac imaging (echocardiography and MRI), electrophysiological and biochemical data of these patients were compared to those of untreated male cFD patients (n = 23, median age 22 years, range 13-27). RESULTS: Albuminuria was less common and less severe in treated patients (albumin to creatinine ratio, ACR 0-8.8 mg/mmol, median 0.4) compared to untreated patients (ACR 0-248 mg/mmol, median 3.7, p = 0.02). The treated group had a lower left ventricular mass, measured using echocardiography (median 80 g/m2 versus 94 g/m2, p = 0.02) and MRI (median 53 g/m2 versus 68 g/m2, p = 0.02). Myocardial fibrosis was absent in all included patients. eGFR was normal in all treated patients whereas 7/23 (30%) of untreated patients had abnormal eGFR. Cerebral manifestations did not differ. CONCLUSIONS: Start of treatment with ERT before age 16, in male cFD patients is associated with reduced occurrence of renal and cardiac manifestations of FD, as assessed by intermediate endpoints. Confirmation that this approach delays or even prevents renal failure and cardiac events requires another decade of follow-up.

Root joint involvement in spondyloarthritis: a post hoc analysis from the international ASAS-PerSpA study.

OBJECTIVES: The primary objective was to compare the clinical characteristics of SpA patients with and without root joint disease (RJD+ and RJD-). The secondary objectives were to compare the prevalence of RJD across various SpA subtypes and in different world regions, and to compare the SpA axial severity and SpA burden between RJD+ and RJD-. METHODS: This is a post hoc analysis of the Assessment of Spondyloarthritis International Society PerSpA study (PERipheral involvement in SpondyloArthritis), which included 4465 patients with SpA [axial (axSpA), peripheral (pSpA), PsA, IBD, reactive and juvenile] according to the rheumatologist's diagnosis. RJD was defined as the 'ever' presence of hip or shoulder involvement related to SpA, according to the rheumatologist. Patient characteristics were compared between RJD+ and RJD-. Multivariable stepwise binary logistic regression analyses were conducted to identify factors associated with 'RJD', 'hip' and 'shoulder' involvement. RESULTS: RJD was significantly associated with the SpA main diagnosis (highest in pSpA), a higher prevalence of HLA-B27 positivity, enthesitis, tender and swollen joints, CRP, conventional synthetic DMARDs, loss of lumbar lordosis and occiput-wall distance >0. RJD was more prevalent in Asia, and occurred in 1503 patients (33.7%), with more hip (24.2%) than shoulder (13.2%) involvement. Hip involvement had a distinct phenotype, similar to axSpA (including younger age at onset, HLA-B27 positivity), whereas shoulder involvement was associated with features of pSpA (including older age at onset). CONCLUSION: RJD+ SpA patients had a distinctive clinical phenotype compared with RJD-. Hip involvement, based on the rheumatologist's diagnosis, was more prevalent than shoulder involvement and was clinically distinct.

Anti-mitochondrial Antibody-Negative Primary Biliary Cholangitis Is Part of the Same Spectrum of Classical Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease in which anti-mitochondrial antibodies (AMA) are the diagnostic hallmark. Whether AMA-negative PBC patients represent a different phenotype of disease is highly debated. AIMS: The purpose of our study was to compare AMA-positive and AMA-negative PBC patients in a large non-white admixed Brazilian cohort. METHODS: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian PBC patients, stratifying data according to AMA status. RESULTS: A total of 464 subjects (95.4% females, mean age 56 ± 5 years) with PBC were included. Three hundred and eighty-four (83%) subjects were AMA-positive, whereas 80 (17%) had AMA-negative PBC. Subjects with AMA-negative PBC were significantly younger (52.2 ± 14 vs. 59.6 ± 11 years, p = 0.001) and had their first symptom at an earlier age (43.2 ± 13 vs. 49.5 ± 12 years, p = 0.005). Frequency of type 2 diabetes was significantly increased in subjects with AMA-negative PBC (22.5% vs. 12.2%, p = 0.03). Lower IgM (272.2 ± 183 vs. 383.2 ± 378 mg/dL, p = 0.01) and triglycerides (107.6 ± 59.8 vs.129.3 ± 75.7 mg/dL, p = 0.025) and higher bilirubin (3.8 ± 13.5 vs. 1.8 ± 3.4 mg/dL, p = 0.02) levels were also observed in this subgroup. Response to ursodeoxycholic acid varied from 40.5 to 63.3% in AMA-positive and 34 to 62.3% in AMA-negative individuals, according to different response criteria. Outcomes such as development of liver-related complications, death and requirement for liver transplantation were similar in both groups. CONCLUSIONS: AMA-negative PBC patients are similar to their AMA-positive counterparts with subtle differences observed in clinical and laboratory features.

Animal models for studying COVID-19, prevention, and therapy: Pathology and disease phenotypes.

Translational models have played an important role in the rapid development of safe and effective vaccines and therapeutic agents for the ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Animal models recapitulating the clinical and underlying pathological manifestations of COVID-19 have been vital for identification and rational design of safe and effective vaccines and therapies. This manuscript provides an overview of commonly used COVID-19 animal models and the pathologic features of SARS-CoV-2 infection in these models in relation to their clinical presentation in humans. Also discussed are considerations for selecting appropriate animal models for infectious diseases such as COVID-19, the host determinants that can influence species-specific susceptibility to SARS-CoV-2, and the pathogenesis of COVID-19. Finally, the limitations of currently available COVID-19 animal models are highlighted.

Systemic sclerosis patients with negative antinuclear antibodies have distinctive clinical manifestations: a multicenter CRDC cohort in China.

BACKGROUND: The presence of circulating antinuclear antibodies (ANAs) is a hallmark of immune dysregulation in patients with systemic sclerosis (SSc). OBJECTIVE: A variety of ANAs are associated with unique sets of disease manifestations and are widely used in clinical practice in SSc. This study aimed to investigate the clinical features of SSc patients negative for ANAs in a Chinese Rheumatism Data Center (CRDC) multicenter cohort in China. METHODS: Patients were prospectively recruited between April 2008 and June 2019 from 154 clinical centers nationwide, and all cases fulfilled the 2013 ACR/EULAR classification criteria for systemic sclerosis. Results for antinuclear antibodies were intensively collected. Demographic, clinical, and laboratory data were compared between ANA-positive SSc patients and those negative for ANAs. RESULTS: Antinuclear antibodies were detected in 2129 of 2809 patients enrolled in the study; 4.2% of patients were negative. There were more males among ANA-negative SSc patients (29/60 vs. 294/1746, p < 0.001). The incidence of certain critical organ involvement, including gastroesophageal reflux (5.6% vs. 18.5%, p = 0.002), interstitial lung disease (65.2% vs. 77.9%, p = 0.015), and pulmonary arterial hypertension (11.5% vs. 29.0%, p = 0.006) was significantly lower in ANA-negative patients than in ANA-positive patients. The proportion of abnormal erythrocyte sedimentation rate (32.4% vs. 47.6%, p = 0.013) and IgG elevation (14.3% vs. 37.0%, p = 0.003), an indicator of disease activity, was significantly lower in ANA-negative patients than in ANA-positive patients. CONCLUSION: Antinuclear antibodies are strongly associated with the clinical manifestations of systemic sclerosis, with ANA-negative SSc patients tending to exhibit relatively milder disease.

PubCaseFinder: A Case-Report-Based, Phenotype-Driven Differential-Diagnosis System for Rare Diseases.

Recently, to speed up the differential-diagnosis process based on symptoms and signs observed from an affected individual in the diagnosis of rare diseases, researchers have developed and implemented phenotype-driven differential-diagnosis systems. The performance of those systems relies on the quantity and quality of underlying databases of disease-phenotype associations (DPAs). Although such databases are often developed by manual curation, they inherently suffer from limited coverage. To address this problem, we propose a text-mining approach to increase the coverage of DPA databases and consequently improve the performance of differential-diagnosis systems. Our analysis showed that a text-mining approach using one million case reports obtained from PubMed could increase the coverage of manually curated DPAs in Orphanet by 125.6%. We also present PubCaseFinder (see Web Resources), a new phenotype-driven differential-diagnosis system in a freely available web application. By utilizing automatically extracted DPAs from case reports in addition to manually curated DPAs, PubCaseFinder improves the performance of automated differential diagnosis. Moreover, PubCaseFinder helps clinicians search for relevant case reports by using phenotype-based comparisons and confirm the results with detailed contextual information.

Ovine Herpesvirus 2 Encodes a Previously Unrecognized Protein, pOv8.25, That Targets Mitochondria and Triggers Apoptotic Cell Death.

Malignant catarrhal fever (MCF) is a rare but frequently lethal disease of certain cloven-hoofed animals. At least 10 different viruses, all members of the Macavirus genus in the subfamily Gammaherpesvirinae, are known as causative agents of MCF. Among these, ovine herpesvirus 2 (OvHV-2) is the most frequent and economically most important MCF agent. Phenotypically, MCF is characterized by severe lymphocytic arteritis-periarteritis, which leads to the accumulation of activated lymphocytes accompanied by apoptosis and necrosis in a broad range of tissues. However, a viral factor that might be responsible for tissue damage has not yet been identified. We have studied a seemingly intergenic locus on the OvHV-2 genome, which was previously shown to be transcriptionally highly active in MCF-affected tissue. We identified by 5' and 3' rapid amplification of cDNA ends (RACE) a conserved, double-spliced transcript that encoded a 9.9-kDa hydrophobic protein. The newly detected gene, Ov8.25, and its splicing pattern were conserved among OvHV-2 strains of different origins. Upon transient expression of synthetic variants of this gene in various cell types, including bovine lymphocytes, the protein (pOv8.25) was shown to target mitochondria, followed by caspase-dependent apoptosis and necrosis. Notably, a deletion mutant of the same protein lost these abilities. Finally, we detected pOv8.25 in brain-infiltrating lymphocytes of cattle with MCF. Thus, the cell death-causing properties of pOv8.25 in affected cells may be involved in the emergence of typical MCF-associated apoptosis and necrosis. Thus, we have identified a novel OvHV-2 protein, which might contribute to the phenotype of MCF-related lesions.IMPORTANCE Ovine herpesvirus 2 (OvHV-2) circulates among sheep without causing disease. However, upon transmission to cattle, the same virus instigates a frequently lethal disease, malignant catarrhal fever (MCF). While the cause of death and pathogenesis of tissue lesions are still poorly understood, MCF is characterized by the accumulation of lymphocytes in various tissues, associated with vasculitis and cell death. As infectious virus is hardly present in these lesions, the cause of cell death cannot be explained simply by viral replication. The significance of our research is in identifying and characterizing a previously overlooked gene of OvHV-2 (Ov8.25), which is highly expressed in animals with MCF. Its encoded protein targets mitochondria, causing apoptosis and necrosis, thus contributing to an understanding of the source and nature of cell death. As the corresponding genetic locus is also active in the context of MCF due to a different macavirus, we may have detected a common denominator of the disease phenotype.

Computational resources associating diseases with genotypes, phenotypes and exposures.

The causes of a disease and its therapies are not only related to genotypes, but also associated with other factors, including phenotypes, environmental exposures, drugs and chemical molecules. Distinguishing disease-related factors from many neutral factors is critical as well as difficult. Over the past two decades, bioinformaticians have developed many computational resources to integrate the omics data and discover associations among these factors. However, researchers and clinicians are experiencing difficulties in choosing appropriate resources from hundreds of relevant databases and software tools. Here, in order to assist the researchers and clinicians, we systematically review the public computational resources of human diseases related to genotypes, phenotypes, environment factors, drugs and chemical exposures. We briefly describe the development history of these computational resources, followed by the details of the relevant databases and software tools. We finally conclude with a discussion of current challenges and future opportunities as well as prospects on this topic.

Endogenous activated small interfering RNAs in virus-infected Brassicaceae crops show a common host gene-silencing pattern affecting photosynthesis and stress response.

Viral infections are accompanied by a massive production of small interfering RNAs (siRNAs) of plant origin, such as virus-activated (va)siRNAs, which drive the widespread silencing of host gene expression, and whose effects in plant pathogen interactions remain unknown. By combining phenotyping and molecular analyses, we characterized vasiRNAs that are associated with typical mosaic symptoms of cauliflower mosaic virus infection in two crops, turnip (Brassica rapa) and oilseed rape (Brassica napus), and the reference plant Arabidopsis thaliana. We identified 15 loci in the three infected plant species, whose transcripts originate vasiRNAs. These loci appear to be generally affected by virus infections in Brassicaceae and encode factors that are centrally involved in photosynthesis and stress response, such as Rubisco activase (RCA), senescence-associated protein, heat shock protein HSP70, light harvesting complex, and membrane-related protein CP5. During infection, the expression of these factors is significantly downregulated, suggesting that their silencing is a central component of the plant's response to virus infections. Further findings indicate an important role for 22 nt long vasiRNAs in the plant's endogenous RNA silencing response. Our study considerably enhances knowledge about the new class of vasiRNAs that are triggered in virus-infected plants and will help to advance strategies for the engineering of gene clusters involved in the development of crop diseases.

Phenotype and treatment of elderly onset compared with younger onset rheumatoid arthritis patients in international daily practice.

OBJECTIVE: To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset. METHODS: Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis <45 years, 45-65 years, >65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders. RESULTS: The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of -0.02 and -0.05 DAS points and, -0.01 and 0.02 HAQ points per month in the <45 and 45-65 years age-groups as compared with the >65 year age group, a difference that did not seem clinically relevant. CONCLUSION: In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ.

Genetic diversity of Staphylococcus aureus influences disease phenotype of systemic lupus erythematosus.

OBJECTIVE: We investigated the genetic diversity, molecular epidemiology and evolutionary dynamics of Staphylococcus aureus (SA) isolated from SLE patients by means of phylogenetic analysis. METHODS: Consecutive SLE patients (ACR 1997 criteria) were enrolled: clinical/laboratory data were collected and nasal swab for SA identification was performed. On the basis of the translation elongation factor (tuf) gene, a phylogenetic analysis was performed to investigate relationships and to assess significant clades. Selective pressure analysis was used to investigate the evolution of the SA tuf gene. The gene sequences from non-SLE individuals, downloaded from the GenBank database, were compared through phylogenetic analysis with the tuf gene from SLE patients. RESULTS: We enrolled 118 patients [M/F 10/108; median (interquartile range (IQR)) age 45.5 (13.2) years; median (IQR) disease duration 120 (144) months]. Twenty-four patients (20.3%) were SA carriers (SA+), three of them MRSA. SA+ SLE showed significantly higher SLEDAI-2k values [SA+: median (IQR) 2 (3.75); SA-: 0 (2); P = 0.04]. The phylogenetic analysis, restricted to 21 non-MRSA SA+, revealed a statistically supported larger clade (A, n = 17) and a smaller one (B, n = 4). Patients located in clade A showed a significantly higher prevalence of joint involvement (88.2%) in comparison with clade B (50.0%, P < 0.0001) and SA- (62.7%, P < 0.0001). Haematological manifestations were significantly more frequent in clade A (64.7%) compared with B (50.0%, P = 0.004). CONCLUSION: We suggest a possible role of SA nasal carriage status in SLE disease activity. Moreover, our findings support the hypothesis that bacterial genetic variants may be associated with specific disease features.

Neuronal degeneration and cognitive impairment can be prevented via the normalization of mitochondrial dynamics.

Neuronal cells possess a certain degree of plasticity to recover from cell damage. When the stress levels are higher than their plasticity capabilities, neuronal degeneration is triggered. However, the factors correlated to the plasticity capabilities need to be investigated. In this study, we generated a novel mouse model that able to express in an inducible manner a dominant-negative form of MFN2, a mitochondrial fusion factor. We then compared the phenotype of the mice continuously expressing the mutated MFN2 with that of the mice only transiently expressing it. Remarkably, the phenotypes of the group transiently expressing mutant MFN2 could be divided into 3 types: equivalent to what was observed in the continuous expression group, intermediate between the continuous expression group and the control group, and equivalent to the control group. In particular, in the continuous expression group, we observed remarkable hyperactivity and marked cognitive impairments, which were not seen, or were very mild in the transient expression group. These results indicate that abnormal mitochondrial dynamics lead to stress, triggering neuron degeneration; therefore, the neurodegeneration progression can be prevented via the normalization of the mitochondrial dynamics. Since the availability of mouse models suitable for the reproduction of both neurodegeneration and recovery at least partially is very limited, our mouse model can be a useful tool to investigate neuronal plasticity mechanisms and neurodegeneration.

CD36 polymorphisms and the age of disease onset in patients with pathogenic variants within the mutation cluster region of APC.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5' and 3' ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36. We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort. METHODS: In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression. RESULTS: Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression. CONCLUSIONS: This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

ncRPheno: a comprehensive database platform for identification and validation of disease related noncoding RNAs.

Noncoding RNAs (ncRNAs) play critical roles in many critical biological processes and have become a novel class of potential targets and bio-markers for disease diagnosis, therapy, and prognosis. Annotating and analysing ncRNA-disease association data are essential but challenging. Current computational resources lack comprehensive database platforms to consistently interpret and prioritize ncRNA-disease association data for biomedical investigation and application. Here, we present the ncRPheno database platform (http://lilab2.sysu.edu.cn/ncrpheno), which comprehensively integrates and annotates ncRNA-disease association data and provides novel searches, visualizations, and utilities for association identification and validation. ncRPheno contains 482,751 non-redundant associations between 14,494 ncRNAs and 3,210 disease phenotypes across 11 species with supporting evidence in the literature. A scoring model was refined to prioritize the associations based on evidential metrics. Moreover, ncRPheno provides user-friendly web interfaces, novel visualizations, and programmatic access to enable easy exploration, analysis, and utilization of the association data. A case study through ncRPheno demonstrated a comprehensive landscape of ncRNAs dysregulation associated with 22 cancers and uncovered 821 cancer-associated common ncRNAs. As a unique database platform, ncRPheno outperforms the existing similar databases in terms of data coverage and utilities, and it will assist studies in encoding ncRNAs associated with phenotypes ranging from genetic disorders to complex diseases. ABBREVIATIONS: APIs: application programming interfaces; circRNA: circular RNA; ECO: Evidence & Conclusion Ontology; EFO: Experimental Factor Ontology; FDR: false discovery rate; GO: Gene Ontology; GWAS: genome wide association studies; HPO: Human Phenotype Ontology; ICGC: International Cancer Genome Consortium; lncRNA: long noncoding RNA; miRNA: micro RNA; ncRNA: noncoding RNA; NGS: next generation sequencing; OMIM: Online Mendelian Inheritance in Man; piRNA: piwi-interacting RNA; snoRNA: small nucleolar RNA; TCGA: The Cancer Genome Atlas.

Gender Differences in Inflammatory Bowel Disease.

Immune-mediated diseases typically show a female preponderance. Looking at all autoimmune diseases combined, 8 of 10 patients are females. Although not as prominent, gender differences in inflammatory bowel disease (IBD) have been reported for epidemiology, disease presentation, disease course and complications, medical and surgical therapies, adherence, psychosocial functioning, and psychiatric co-disorders. While for some factors evidence is rather good, for others data are conflicting. Gastroenterologists dealing with IBD patients in daily clinical practice should be aware of gender-specific issues for the following reasons: (1) misperception of disease presentation potentially delays IBD diagnosis, which has been shown to have deleterious effects, and (2) awareness of gender-specific symptoms and disease severity allows initiation of early and adequately tailored treatment. This might prevent development of complications. And (3) insights into gender-specific differences in terms of treatment and adherence to treatment can improve disease management and foster a more individualized treatment approach. In this review, we summarize current knowledge about gender-specific differences in IBD and highlight the most clinically relevant aspects.

Analysis of disease organ as a novel phenotype towards disease genetics understanding.

Discerning the modular nature of human diseases through computational approaches calls for diverse data. The finding sites of diseases, like other disease phenotypes, possess rich information in understanding disease genetics. Yet, analysis of the rich knowledge of disease finding sites has not been comprehensively investigated. In this study, we built a large-scale disease organ network (DON) based on 76,561 disease-organ associations (for 37,615 diseases and 3492 organs) extracted from the United Medical Language System (UMLS) Metathesaurus. We investigated how phenotypic organ similarity among diseases in DON reflects disease gene sharing. We constructed a disease genetic network (DGN) using curated disease-gene associations and demonstrated that disease pairs with higher organ similarities not only are more likely to share genes, but also tend to share more genes. Based on community detection algorithm, we showed that phenotypic disease clusters on DON significantly correlated with genetic disease clusters on DGN. We compared DON with a state-of-art disease phenotype network, disease manifestation network (DMN), that we have recently constructed, and demonstrated that DON contains complementary knowledge for disease genetics understanding.

SMALLa AIRWAY DISEASE IN COPD ASSOCIATED TO BIOMASS EXPOSURE.

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous entity that may result from different causative agents and risk factors and may follow diverse clinical courses, including COPD secondary to biomass smoke exposure. At present, this phenotype is becoming more important for two reasons: first, because at least almost half of the world's population is exposed to biomass smoke, and second, because the possibility of it being diagnosed is increasing. Biomass smoke exposure COPD affects primarily women and is related with insults to the airways occurred during early life. Although constituents of biomass smoke and tobacco smoke are similar, the physiopathological changes they induce differ depending not only on the chemical composition (related with the type of fuel used) but also on the particle size and the inhalation pattern. Evidence has shown that biomass smoke exposure affects the airway, predominantly the small airways causing anthracofibrosis and peribronchiolar fibrosis changes that will clinically translate into chronic bronchitis symptoms, with a high impact on the quality of life. In this review, we focus especially on the main epidemiological and clinical differences between COPD secondary to biomass exposure and COPD caused by tobacco exposure.

Insights into Mutation Effect in Three Poikiloderma with Neutropenia Patients by Transcript Analysis and Disease Evolution of Reported Patients with the Same Pathogenic Variants.

PURPOSE: Poikiloderma with neutropenia (PN) is a genodermatosis currently described in 77 patients, all presenting with early-onset poikiloderma, neutropenia, and several additional signs. Biallelic loss-of-function mutations in USB1 gene are detected in all molecularly tested patients but genotype-phenotype correlation remains elusive. Cancer predisposition is recognized among PN features and pathogenic variants found in patients who developed early in life myelodysplasia (n = 12), acute myeloid leukemia (n = 2), and squamous cell carcinoma (n = 2) should be kept into account in management and follow-up of novel patients. This will hopefully allow achieving data clustered on specific mutations relevant to oncological surveillance of the carrier patients. METHODS: We describe the clinical features of three unreported PN patients and characterize their USB1 pathogenic variants by transcript analysis to get insights into the effect on the overall phenotype and disease evolution. RESULTS: A Turkish boy is homozygous for the c.531delA deletion, a recurrent mutation in Turkey; an adult Italian male is compound heterozygous for two nonsense mutations, c.243G>A and c.541C>T, while an Italian boy is homozygous for the splicing c.683_693+1del variant. The identified mutations have already been reported in PN patients who developed hematologic or skin cancer. Aberrant mRNAs of all four mutated alleles could be identified confirming that transcripts of USB1 main isoform either carrying stop codons or mis-spliced may at least partially escape nonsense-mediated decay. CONCLUSIONS: Our study addresses the need of gathering insights on genotype-phenotype correlations in newly described PN patients, by transcript analysis and information on disease evolution of reported patients with the same pathogenic variants.

Clinical and genetic heterogeneity in a large cohort of Armenian patients with late-onset familial Mediterranean fever.

PURPOSE: This work aimed at investigating demographic, clinical, and genetic characteristics of individuals experiencing their first familial Mediterranean fever (FMF) attack at age ≥40 years in a very large cohort of Armenian FMF patients. METHODS: In total, 10,370 Armenian patients diagnosed with FMF based on the Tel Hashomer criteria and carrying at least one MEFV mutant allele were included in this study. RESULTS: A total of 354 (3.40%) patients had late-onset FMF. Of these, 194 (54.80%) were female and 160 (45.20%) were male. The following genotypes were significantly associated with the late-onset variant: M680I/E148Q (P = 0.004), M694V/E148Q (P < 0.001), and V726A/V726A (P< 0.001). Of note, 12/354 (3.40%) patients were found to be homozygous for the M694V mutation. Individuals with late-onset FMF had a milder disease phenotype presenting significantly less frequent fever, skin manifestation, and chest pain compared to individuals with a disease onset before 40 years of age. Abdominal pain was found more often in the late-onset FMF group, whereas arthritis, proteinuria, and amyloidosis did not differ significantly between the two groups. CONCLUSION: Our data suggest that late-onset FMF is more prevalent in women and is of greater clinical as well as genetic heterogeneity than previously reported.