Genetic and Epigenetic Factors of Takotsubo Syndrome: A Systematic Review.

Takotsubo syndrome (TTS), recognized as stress's cardiomyopathy, or as left ventricular apical balloon syndrome in recent years, is a rare pathology, described for the first time by Japanese researchers in 1990. TTS is characterized by an interindividual heterogeneity in onset and progression, and by strong predominance in postmenopausal women. The clear causes of these TTS features are uncertain, given the limited understanding of this intriguing syndrome until now. However, the increasing frequency of TTS cases in recent years, and particularly correlated to the SARS-CoV-2 pandemic, leads us to the imperative necessity both of a complete knowledge of TTS pathophysiology for identifying biomarkers facilitating its management, and of targets for specific and effective treatments. The suspect of a genetic basis in TTS pathogenesis has been evidenced. Accordingly, familial forms of TTS have been described. However, a systematic and comprehensive characterization of the genetic or epigenetic factors significantly associated with TTS is lacking. Thus, we here conducted a systematic review of the literature before June 2021, to contribute to the identification of potential genetic and epigenetic factors associated with TTS. Interesting data were evidenced, but few in number and with diverse limitations. Consequently, we concluded that further work is needed to address the gaps discussed, and clear evidence may arrive by using multi-omics investigations.

Genome-Wide Association Study Identifies Eight Novel Loci for Susceptibility of Scrub Typhus and Highlights Immune-Related Signaling Pathways in Its Pathogenesis.

Scrub typhus is a fatal zoonotic disease caused by Orientia tsutsugamushi. This disease is accompanied by systemic vasculitis, lymphadenopathy, headache, myalgia, and eschar. In recent studies, a novel strain that is resistant to current medical treatment was identified in Thailand. Thus, the development of new specific drugs for scrub typhus is needed. However, the exact molecular mechanism governing the progression of scrub typhus has not been fully elucidated. To understand disease-related genetic factors and mechanisms associated with the progression of scrub typhus, we performed a genome-wide association study (GWAS) in scrub typhus-infected patients and found a scrub typhus-related signaling pathway by molecular interaction search tool (MIST) and PANTHER. We identified eight potent scrub typhus-related single nucleotide polymorphisms (SNPs) located on the PRMT6, PLGLB2, DTWD2, BATF, JDP2, ONECUT1, WDR72, KLK, MAP3K7, and TGFBR2 genes using a GWAS. We also identified 224 genes by analyzing protein-protein interactions among candidate genes of scrub typhus and identified 15 signaling pathways associated with over 10 genes by classifying these genes according to signaling pathways. The signaling pathway with the largest number of associated genes was the gonadotropin-releasing hormone receptor pathway, followed by the TGF-beta signaling pathway and the apoptosis signaling pathway. To the best of our knowledge, this report describes the first GWAS in scrub typhus.

Perspectives on the Genetic Associations of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a common form of inflammatory spinal arthritis with a complex polygenic aetiology. Genome-wide association studies have identified more than 100 loci, including some involved in antigen presentation (HLA-B27, ERAP1, and ERAP2), some in Th17 responses (IL6R, IL23R, TYK2, and STAT3), and others in macrophages and T-cells (IL7R, CSF2, RUNX3, and GPR65). Such observations have already helped identify potential new therapies targeting IL-17 and GM-CSF. Most AS genetic associations are not in protein-coding sequences but lie in intergenic regions where their direct relationship to particular genes is difficult to assess. They most likely reflect functional polymorphisms concerned with cell type-specific regulation of gene expression. Clarifying the nature of these associations should help to understand the pathogenic pathways involved in AS better and suggest potential cellular and molecular targets for drug therapy. However, even identifying the precise mechanisms behind the extremely strong HLA-B27 association with AS has so far proved elusive. Polygenic risk scores (using all the known genetic associations with AS) can be effective for the diagnosis of AS, particularly where there is a relatively high pre-test probability of AS. Genetic prediction of disease outcomes and response to biologics is not currently practicable.

Causal Relationship and Shared Genetic Loci between Psoriasis and Type 2 Diabetes through Trans-Disease Meta-Analysis.

Psoriasis and type 2 diabetes (T2D) are complex conditions with significant impacts on health. Patients with psoriasis have a higher risk of T2D (∼1.5 OR) and vice versa, controlling for body mass index; yet, there has been a limited study comparing their genetic architecture. We hypothesized that there are shared genetic components between psoriasis and T2D. Trans-disease meta-analysis was applied to 8,016,731 well-imputed genetic markers from large-scale meta-analyses of psoriasis (11,024 cases and 16,336 controls) and T2D (74,124 cases and 824,006 controls), adjusted for body mass index. We confirmed our findings in a hospital-based study (42,112 patients) and tested for causal relationships with multivariable Mendelian randomization. Mendelian randomization identified a causal relationship between psoriasis and T2D (P = 1.6 × 10‒4, OR = 1.01) and highlighted the impact of body mass index. Trans-disease meta-analysis further revealed four genome-wide significant loci (P < 5 × 10‒8) with evidence of colocalization and shared directions of effect between psoriasis and T2D not present in body mass index. The proteins coded by genes in these loci (ACTR2, ERLIN1, TRMT112, and BECN1) are connected through NF-κB signaling. Our results provide insight into the immunological components that connect immune-mediated skin conditions and metabolic diseases, independent of confounding factors.

IMGT® Biocuration and Comparative Analysis of Bos taurus and Ovis aries TRA/TRD Loci.

The adaptive immune response provides the vertebrate immune system with the ability to recognize and remember specific pathogens to generate immunity, and mount stronger attacks each time the pathogen is encountered. T cell receptors are the antigen receptors of the adaptive immune response expressed by T cells, which specifically recognize processed antigens, presented as peptides by the highly polymorphic major histocompatibility (MH) proteins. T cell receptors (TR) are divided into two groups, αß and γδ, which express distinct TR containing either α and ß, or γ and δ chains, respectively. The TRα locus (TRA) and TRδ locus (TRD) of bovine (Bos taurus) and the sheep (Ovis aries) have recently been described and annotated by IMGT® biocurators. The aim of the present study is to present the results of the biocuration and to compare the genes of the TRA/TRD loci among these ruminant species based on the Homo sapiens repertoire. The comparative analysis shows similarities but also differences, including the fact that these two species have a TRA/TRD locus about three times larger than that of humans and therefore have many more genes which may demonstrate duplications and/or deletions during evolution.

Common genetic susceptibility loci link PFAPA syndrome, Behçet's disease, and recurrent aphthous stomatitis.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. The disease appears to cluster in families, but the pathogenesis is unknown. We queried two European-American cohorts and one Turkish cohort (total n = 231) of individuals with PFAPA for common variants previously associated with two other oropharyngeal ulcerative disorders, Behçet's disease and recurrent aphthous stomatitis. In a metaanalysis, we found that a variant upstream of IL12A (rs17753641) is strongly associated with PFAPA (OR 2.13, P = 6 × 10-9). We demonstrated that monocytes from individuals who are heterozygous or homozygous for this risk allele produce significantly higher levels of IL-12p70 upon IFN-γ and LPS stimulation than those from individuals without the risk allele. We also found that variants near STAT4, IL10, and CCR1-CCR3 were significant susceptibility loci for PFAPA, suggesting that the pathogenesis of PFAPA involves abnormal antigen-presenting cell function and T cell activity and polarization, thereby implicating both innate and adaptive immune responses at the oropharyngeal mucosa. Our results illustrate genetic similarities among recurrent aphthous stomatitis, PFAPA, and Behçet's disease, placing these disorders on a common spectrum, with recurrent aphthous stomatitis on the mild end, Behçet's disease on the severe end, and PFAPA intermediate. We propose naming these disorders Behçet's spectrum disorders to highlight their relationship. HLA alleles may be factors that influence phenotypes along this spectrum as we found new class I and II HLA associations for PFAPA distinct from Behçet's disease and recurrent aphthous stomatitis.

The current landscape of psoriasis genetics in 2020.

Psoriasis is an immune-mediated disease associated with skin and joint inflammation that affects large proportions of populations worldwide. It is a heritable disease: individuals' genetic backgrounds modulate their susceptibility. In genetics, multiple human leukocyte antigen (HLA) genes are most strongly associated with the risk of psoriasis, especially HLA-C*06:02. In the last 10 years, large-scale genome-wide association studies (GWASs) of psoriasis have been conducted in multiple populations, and these have substantially increased the number of genetic loci associated with psoriasis susceptibility (n > 80). Understanding the genetic background of psoriasis is important for understanding the disease's biology, identifying clinical biomarkers, discovering novel drug targets, and accelerating the journey towards personalized medicine. However, the application of whole-genome and long-read sequencing technology in psoriasis genetic analysis is still developing. Moreover, achieving practical strategies for translating psoriasis risk-associated genetic variants into functional annotations and clinical applications remains challenging. In this review, we detail the current and future landscape of psoriasis genetics and introduce the cutting-edge use of large-scale GWAS data, especially in the Japanese population.

Dynamic 3D Locus Organization and Its Drivers Underpin Immunoglobulin Recombination.

A functional adaptive immune system must generate enormously diverse antigen receptor (AgR) repertoires from a limited number of AgR genes, using a common mechanism, V(D)J recombination. The AgR loci are among the largest in the genome, and individual genes must overcome huge spatial and temporal challenges to co-localize with optimum variability. Our understanding of the complex mechanisms involved has increased enormously, due in part to new technologies for high resolution mapping of AgR structure and dynamic movement, underpinning mechanisms, and resulting repertoires. This review will examine these advances using the paradigm of the mouse immunoglobulin heavy chain (Igh) locus. We will discuss the key regulatory elements implicated in Igh locus structure. Recent next generation repertoire sequencing methods have shown that local chromatin state at V genes contribute to recombination efficiency. Next on the multidimensional scale, we will describe imaging studies that provided the first picture of the large-scale dynamic looping and contraction the Igh locus undergoes during recombination. We will discuss chromosome conformation capture (3C)-based technologies that have provided higher resolution pictures of Igh locus structure, including the different models that have evolved. We will consider the key transcription factors (PAX5, YY1, E2A, Ikaros), and architectural factors, CTCF and cohesin, that regulate these processes. Lastly, we will discuss a plethora of recent exciting mechanistic findings. These include Rag recombinase scanning for convergent RSS sequences within DNA loops; identification of Igh loop extrusion, and its putative role in Rag scanning; the roles of CTCF, cohesin and cohesin loading factor, WAPL therein; a new phase separation model for Igh locus compartmentalization. We will draw these together and conclude with some horizon-scanning and unresolved questions.

Genetic variants within ANRIL (antisense non coding RNA in the INK4 locus) are associated with risk of psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory disease which mostly affects skin. Evidences support the role of autoimmune responses in this disorder. The long non-coding RNA (lncRNA) antisense non coding RNA in the INK4 locus (ANRIL) has been shown to participate in modulation of immune response and in the pathogenesis of immune-related disorders. METHODS: We genotyped four single nucleotide polymorphisms (SNPs) with this lncRNA (rs1333045, rs1333048, rs4977574 and rs10757278) in 286 patients with psoriasis and 300 age-/sex-matched controls to identify the role of ANRIL as a risk locus for psoriasis. RESULTS: The C allele of rs1333048 SNP was significantly more prevalent among cases compared with controls (OR (95% CI) = 1.56 (1.23-1.97), adjusted P value = 8.31E-4). The A allele of the rs4977574 had a protective effect against psoriasis (OR (95% CI) = 0.63 (0.49-0.81), adjusted P value = 0.001). The G allele of the rs10757278 conferred risk of psoriasis in the assessed population (OR (95% CI) = 1.9 (1.51-2.4), adjusted P value = 2.18 E-7). The C A G A haplotype (rs1333045, rs1333048, rs4977574 and rs10757278, respectively) was reported to be a protective haplotype against psoriasis (OR (95% CI) = 0.5 (0.35-0.71), adjusted P value = 0.001). The C A G G and T C G G haplotypes conferred risk of psoriasis in the assessed population (OR (95% CI) = 2.37 (1.59-3.54), adjusted P value = 2.4E-4; OR (95% CI) = 5.42 (2.88-10.22), adjusted P value = 1.1E-7, respectively). CONCLUSION: Consequently, ANRIL can be regarded as a risk locus of psoriasis in the assessed population. Future studies are needed to verify whether this contribution is exerted through modulation of immune responses.

Dynamic Imprinting of the Treg Cell-Specific Epigenetic Signature in Developing Thymic Regulatory T Cells.

Regulatory T (Treg) cells mainly develop within the thymus and arise from CD25+Foxp3- (CD25+ TregP) or CD25-Foxp3+ (Foxp3+ TregP) Treg cell precursors resulting in Treg cells harboring distinct transcriptomic profiles and complementary T cell receptor repertoires. The stable and long-term expression of Foxp3 in Treg cells and their stable suppressive phenotype are controlled by the demethylation of Treg cell-specific epigenetic signature genes including an evolutionarily conserved CpG-rich element within the Foxp3 locus, the Treg-specific demethylated region (TSDR). Here we analyzed the dynamics of the imprinting of the Treg cell-specific epigenetic signature genes in thymic Treg cells. We could demonstrate that CD25+Foxp3+ Treg cells show a progressive demethylation of most signature genes during maturation within the thymus. Interestingly, a partial demethylation of several Treg cell-specific epigenetic signature genes was already observed in Foxp3+ TregP but not in CD25+ TregP. Furthermore, Foxp3+ TregP were very transient in nature and arose at a more mature developmental stage when compared to CD25+ TregP. When the two Treg cell precursors were cultured in presence of IL-2, a factor known to be critical for thymic Treg cell development, we observed a major impact of IL-2 on the demethylation of the TSDR with a more pronounced effect on Foxp3+ TregP. Together, these results suggest that the establishment of the Treg cell-specific hypomethylation pattern is a continuous process throughout thymic Treg cell development and that the two known Treg cell precursors display distinct dynamics for the imprinting of the Treg cell-specific epigenetic signature genes.

Tomato Natural Resistance Genes in Controlling the Root-Knot Nematode.

The root-knot nematode (RKN) is one of the most dangerous and widespread types of nematodes affecting tomatoes. There are few methods for controlling nematodes in tomatoes. Nature resistance genes (R-genes) are important in conferring resistance against nematodes. These genes that confer resistance to the RKN have already been identified as Mi-1, Mi-2, Mi-3, Mi-4, Mi-5, Mi-6, Mi-7, Mi-8, Mi-9, and Mi-HT. Only five of these genes have been mapped. The major problem is that their resistance breaks down at high temperatures. Some of these genes still work at high temperatures. In this paper, the mechanism and characteristics of these natural resistance genes are summarized. Other difficulties in using these genes in the resistance and how to improve them are also mentioned.

Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility.

Over the last 10 years, genome-wide association studies (GWAS) have identified hundreds of susceptibility loci for autoimmune diseases. However, despite increasing power for the detection of both common and rare coding variants affecting disease susceptibility, a large fraction of disease heritability has remained unexplained. In addition, a majority of the identified loci are located in noncoding regions, and translation of disease-associated loci into new biological insights on the etiology of immune disorders has been lagging. This highlights the need for a better understanding of noncoding variation and new strategies to identify causal genes at disease loci. In this review, I will first detail the molecular basis of gene expression and review the various mechanisms that contribute to alter gene activity at the transcriptional and post-transcriptional level. I will then review the findings from 10 years of functional genomics studies regarding the genetics on gene expression, in particular in the context of infection. Finally, I will discuss the extent to which genetic variants that modulate gene expression at transcriptional and post-transcriptional level contribute to disease susceptibility and present strategies to leverage this information for the identification of causal mechanisms at disease loci in the era of whole genome sequencing.

Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci.

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.

Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis.

OBJETIVE: Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis. METHODS: Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu's arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data. RESULTS: The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression. CONCLUSIONS: Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.

Genetic loci of Staphylococcus aureus associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides.

The proteinase 3 (PR3)-positive anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis (GPA) has been associated with chronic nasal S. aureus carriage, which is a risk factor for disease relapse. The present study was aimed at comparing the genetic make-up of S. aureus isolates from PR3-ANCA-positive GPA patients with that of isolates from patients suffering from myeloperoxidase (MPO)-ANCA-positive AAV, and isolates from healthy controls. Based on a DNA microarray-based approach, we show that not only PR3-ANCA-positive GPA patients, but also MPO-ANCA-positive AAV patients mainly carried S. aureus types that are prevalent in the general population. Nonetheless, our data suggests that MPO-ANCA-associated S. aureus isolates may be distinct from healthy control- and PR3-ANCA-associated isolates. Furthermore, several genetic loci of S. aureus are associated with either PR3-ANCA- or MPO-ANCA-positive AAV, indicating a possible role for pore-forming toxins, such as leukocidins, in PR3-ANCA-positive GPA. Contrary to previous studies, no association between AAV and superantigens was detected. Our findings also show that a lowered humoral immune response to S. aureus is common for PR3-ANCA- and MPO-ANCA-positive AAV. Altogether, our observations imply that the presence or absence of particular virulence genes of S. aureus isolates from AAV patients contributes to disease progression and/or relapse.

Population genetics of immune-related multilocus copy number variation in Native Americans.

While multiallelic copy number variation (mCNV) loci are a major component of genomic variation, quantifying the individual copy number of a locus and defining genotypes is challenging. Few methods exist to study how mCNV genetic diversity is apportioned within and between populations (i.e. to define the population genetic structure of mCNV). These inferences are critical in populations with a small effective size, such as Amerindians, that may not fit the Hardy-Weinberg model due to inbreeding, assortative mating, population subdivision, natural selection or a combination of these evolutionary factors. We propose a likelihood-based method that simultaneously infers mCNV allele frequencies and the population structure parameter f, which quantifies the departure of homozygosity from the Hardy-Weinberg expectation. This method is implemented in the freely available software CNVice, which also infers individual genotypes using information from both the population and from trios, if available. We studied the population genetics of five immune-related mCNV loci associated with complex diseases (beta-defensins, CCL3L1/CCL4L1, FCGR3A, FCGR3B and FCGR2C) in 12 traditional Native American populations and found that the population structure parameters inferred for these mCNVs are comparable to but lower than those for single nucleotide polymorphisms studied in the same populations.

Primary Immunodeficiencies and Inflammatory Disease: A Growing Genetic Intersection.

Recent advances in genome analysis have provided important insights into the genetic architecture of infectious and inflammatory diseases. The combined analysis of loci detected by genome-wide association studies (GWAS) in 22 inflammatory diseases has revealed a shared genetic core and associated biochemical pathways that play a central role in pathological inflammation. Parallel whole-exome sequencing studies have identified 265 genes mutated in primary immunodeficiencies (PID). Here, we examine the overlap between these two data sets, and find that it consists of genes essential for protection against infections and in which persistent activation causes pathological inflammation. Based on this intersection, we propose that, although strong or inactivating mutations (rare variants) in these genes may cause severe disease (PIDs), their more subtle modulation potentially by common regulatory/coding variants may contribute to chronic inflammation.

On the organization of human T-cell receptor loci: log-periodic distribution of T-cell receptor gene segments.

The human T-cell repertoire is complex and is generated by the rearrangement of variable (V), diversity (D) and joining (J) segments on the T-cell receptor (TCR) loci. The T-cell repertoire demonstrates self-similarity in terms clonal frequencies when defined by V, D and J gene segment usage; therefore to determine whether the structural ordering of these gene segments on the TCR loci contributes to the observed clonal frequencies, the TCR loci were examined for self-similarity and periodicity in terms of gene segment organization. Logarithmic transformation of numeric sequence order demonstrated that the V and J gene segments for both T-cell receptor α (TRA) and ß (TRB) loci are arranged in a self-similar manner when the spacing between the adjacent segments was considered as a function of the size of the neighbouring gene segment, with an average fractal dimension of approximately 1.5. Accounting for the gene segments occurring on helical DNA molecules with a logarithmic distribution, sine and cosine functions of the log-transformed angular coordinates of the start and stop nucleotides of successive TCR gene segments showed an ordered progression from the 5' to the 3' end of the locus, supporting a log-periodic organization. T-cell clonal frequency estimates, based on V and J segment usage, from normal stem cell donors were plotted against the V and J segment on TRB locus and demonstrated a periodic distribution. We hypothesize that this quasi-periodic variation in gene-segment representation in the T-cell clonal repertoire may be influenced by the location of the gene segments on the periodic-logarithmically scaled TCR loci. Interactions between the two strands of DNA in the double helix may influence the probability of gene segment usage by means of either constructive or destructive interference resulting from the superposition of the two helices.