Genetic markers for psoriatic arthritis in patients with psoriasis. Part I: non-HLA genes

Psoriatic arthritis often develops in patients with psoriasis and can lead to joint deformity, stiffness, dysfunction, and disability. Psoriatic arthritis is a polygenic disease. and the issue of personalizing the prognosis of its development can only be resolved taking into account the variability of plenty genomic loci associated with the development of the disease. The personification of the prognosis of the disease can be solved taking into account the variability of the set of genomic loci with which its development is associated. The review examines genomic polymorphisms associated with the development of psoriatic arthritis not psoriasis, except of HLA polymorphisms. Genome regions containing polymorphisms, allelic variants of which are associated both with the development of psoriatic arthritis and reducing the likelihood of its occurrence, are described. It has been reported that the predisposition to the development of psoriatic arthritis in patients with psoriasis is determined by genes encoding proteins involved in inflammation and bone metabolism.

Population structure in the MHC region

In his 1972 "The apportionment of human diversity", Richard Lewontin showed that, when averaged over loci, genetic diversity is predominantly attributable to differences among individuals within populations. However, selection on specific genes and genomic regions can alter the apportionment of diversity. We examine genetic diversity at the HLA loci, located within the MHC region. HLA genes code for proteins that are critical to adaptive immunity and are well-documented targets of balancing selection. The SNPs within HLA genes show strong signatures of balancing selection on large timescales and are broadly shared among populations, with low FST values. However, when we analyze haplotypes defined by these SNPs (i.e., which define "HLA alleles"), we find marked differences in frequencies between geographic regions. These differences are not reflected in the FST values because of the extreme polymorphism at HLA loci, illustrating challenges in interpreting FST. Differences in the frequency of HLA alleles among geographic regions are relevant to bone-marrow transplantation, which requires genetic identity at HLA loci between patient and donor. We explore the case of Brazil's bone-marrow registry, where a deficit of enrolled volunteers with African ancestry reduces the chance of finding donors for individuals with an MHC region of African ancestry.

Evaluation of Human Leukocyte Antigen Class I and Class II in End-Stage Renal Disease Occurrence in Indonesian Transplantation Patients

Background. Genetic studies of end-stage renal disease (ESRD), including those of human leukocyte antigen (HLA) genes, have been reported in several populations but have not yet been evaluated in Indonesia. Some studies have reported that these genes had a substantial role in ESRD. This study aims to analyze the association between HLA genes and ESRD within the Indonesian community. Method. A retrospective study to investigate HLA class I and II alleles to find out the distribution of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 in renal transplant recipients and to ascertain their role in susceptibility to ESRD was performed on totally 149 subjects, consisting of 69 ESRD patients and 80 healthy controls. HLA typing was determined using Luminex techniques. The allele and haplotype frequencies were compared between ESRD patients and controls. Result. High-frequency alleles were HLA-A ∗ 24 (43.6%), B ∗ 15 (38.2%), C ∗ 08 (30.8%), DRB1 ∗ 12 (47.3%), DQB1 ∗ 03 (50.6%), and DPB1 ∗ 13 (22.5%). HLA-A ∗ 24 p = 0.01 and HLA-B ∗ 35 p = 0.02 were associated with a protective effect, with OR 0.537 (95%CI 0.34–0.86) and 0.316 (95%CI 0.11–0.88), respectively. There were some two-locus haplotypes associated with susceptibility to ESRD, such as B ∗ 15-DRB1 ∗ 12, B ∗ 13-DRB1 ∗ 15, A ∗ 02-B ∗ 15, A ∗ 02-C ∗ 08, and B ∗ 13-DQB1 ∗ 05. HLA-A ∗ 02-B ∗ 15-DRB1 ∗ 12 and A ∗ 24-B ∗ 13-DRB1 ∗ 15 appear to be associated with susceptibility to ESRD. Conclusion. The allele groups of HLA-A ∗ 24 and HLA-B ∗ 35 are associated with protection from ESRD. Meanwhile, HLA-B ∗ 13-DRB1 ∗ 15 and A ∗ 24-B ∗ 13-DRB1 ∗ 15 are the most frequent HLAs associated with ESRD in two-locus and three-locus haplotype, respectively.

Improved Characterization of Balancing Selection Genome Wide and a Detailed Look at HLA Genes

Balancing selection occurs when different evolutionary pressures impact the fitness of multiple alleles, resulting in increased allelic diversity in the population. A new statistical method was developed to test for selection, improving inference by using efficient Bayesian techniques to test for density and strength of linkage disequilibrium. Evolutionary simulation studies showed that the method consistently outperformed existing methods. Using this methodology, we tested for novel signals of balancing selection genome wide in 500 samples from phased trios. Several novel signals of selection appeared in CYP2A7, GPC6, and CNR2 across multiple ancestries. Additionally, tests in SIRPA demonstrate dramatically strong selection signal, significantly higher than previously observed. Well-known signals around olfactory genes and the MHC, containing HLA genes associated with the immune response, also demonstrated strong signatures of selection. So, utilizing data from the 17th IHIW, a follow up analysis was then performed by leveraging over seven thousand HLA typed samples by NGS; in contrast, the genome wide scan did not include a detailed characterization of the HLA genes. The strongest signals observed in the IHIW samples were in DQA1 and DQB1 in or around exon 2, the portion of the gene responsible for antigen presentation and most likely to be under environmental and evolutionary pressure. Our new statistical approach and analysis suggest novel evolutionary pressure in new regions and additionally highlight the importance of improved sequencing and characterization of variation across the extended MHC and other critical regions.

Next generation sequencing HLA-typing of recipients and donors of allogeneic haematopoietic stem cells

Introduction. The patient survival after allogeneic haematopoietic stem cell transplantation (allo-HSCT) from an unrelated or related haploidentical donor is improved in a donor–recipient match resolution at the level of non-coding region identity of HLA genes. Next-generation sequencing (NGS) allows detection of point substitutions in HLA non-coding regions.Aim — assessment of the NGS-based HLA-typing performance.Materials and methods. An NGS-based HLA-typing of 1,056 DNA samples from allo-HSCT recipients, their related and registry donors was performed with AllTypekit chemistry (OneLambda, USA). A parallel HLA-typing assay of 96 samples by 8 genes (A/B/C/DRB1/DRB3/DRB4/DRB5/DQB1) was accomplished within one working week.Results. HLA class I genes were typed at a 4-field (allelic), and HLA class II genes — 2–4-field (high to allelic) resolution. An allelic-resolution typing of HLA class I genes in a Russian population (657 registry donors) was conducted for the first time. The most frequent HLA alleles have been identified: А*02:01:01:01 in HLA-A (26.9 %), B*07:02:01:01 in HLA-B (12.5 %) and C*07:02:01:03 in HLA-C (12.6 %). The most frequent HLA class II variants were DRB1*07:01:01 (14.1 %), DRB3*02:01:01 (18.0 %), DRB4*01:03:01 (18.9 %), DRB5*01:01:01 (13.5 %), DQB1*03:01P (17.4 %).Conclusion. An NGS-geared HLA-typing has yielded low-ambiguity allelic and high-level resolution results in a parallel sequencing assay with a large number of samples. The method implemented detects genetic polymorphisms also in non-exonic non-coding regions of HLA genes and facilitates typing in candidate HSCT recipients, related and unrelated donors.

Morphea and Autoimmunity: HLA behind the scene?

We read with deep attention the case report recently published about the peculiar association of morphea, celiac disease, dermatitis herpetiformis and dermatomyositis , and we would discuss the particular genetics that lay behind morphea and related autoimmune disorders, with a focus on HLA genes.

High Resolution Haplotype Analyses of Classical HLA Genes in Families With Multiple Sclerosis Highlights the Role of HLA-DP Alleles in Disease Susceptibility

Multiple sclerosis (MS) susceptibility shows strong genetic associations with HLA alleles and haplotypes. We genotyped 11 HLA genes in 477 non-Hispanic European MS patients and their 954 unaffected parents using a validated next-generation sequencing (NGS) methodology. HLA haplotypes were assigned unequivocally by tracing HLA allele transmissions. We explored HLA haplotype/allele associations with MS using the genotypic transmission disequilibrium test (gTDT) and multiallelic TDT (mTDT). We also conducted a case-control (CC) study with all patients and 2029 healthy unrelated ethnically matched controls. We performed separate analyses of 54 extended multi-case families by reviewing transmission of haplotype blocks. The haplotype fragment including DRB5*01:01:01~DRB1*15:01:01:01 was significantly associated with predisposition (gTDT: p < 2.20e-16; mTDT: p =1.61e-07; CC: p < 2.22e-16) as reported previously. A second risk allele, DPB1*104:01 (gTDT: p = 3.69e-03; mTDT: p = 2.99e-03; CC: p = 1.00e-02), independent from the haplotype bearing DRB1*15:01 was newly identified. The allele DRB1*01:01:01 showed significant protection (gTDT: p = 8.68e-06; mTDT: p = 4.50e-03; CC: p = 1.96e-06). Two DQB1 alleles, DQB1*03:01 (gTDT: p = 2.86e-03; mTDT: p = 5.56e-02; CC: p = 4.08e-05) and DQB1*03:03 (gTDT: p = 1.17e-02; mTDT: p = 1.16e-02; CC: p = 1.21e-02), defined at two-field level also showed protective effects. The HLA class I block, A*02:01:01:01~C*03:04:01:01~B*40:01:02 (gTDT: p = 5.86e-03; mTDT: p = 3.65e-02; CC: p = 9.69e-03) and the alleles B*27:05 (gTDT: p = 6.28e-04; mTDT: p = 2.15e-03; CC: p = 1.47e-02) and B*38:01 (gTDT: p = 3.20e-03; mTDT: p = 6.14e-03; CC: p = 1.70e-02) showed moderately protective effects independently from each other and from the class II associated factors. By comparing statistical significance of 11 HLA loci and 19 haplotype segments with both untruncated and two-field allele names, we precisely mapped MS candidate alleles/haplotypes while eliminating false signals resulting from ‘hitchhiking’ alleles. We assessed genetic burden for the HLA allele/haplotype identified in this study. This family-based study including the highest-resolution of HLA alleles proved to be powerful and efficient for precise identification of HLA genotypes associated with both, susceptibility and protection to development of MS.

AB0408 SYSTEMIC SCLERODERMA AND ENVIRONMENTAL RISK FACTORS: IDENTIFYING ASSOCIATIONS MINING THE BIOMEDICAL LITERATURE

Background:A debate still exists concerning the role of occupational and environmental factors in the pathogenesis of systemic scleroderma (SSc).Objectives:Our aim was to explore associations between SSc and environmental factors utilizing an automatic semantic interpretation of PubMed results.Methods:The literature search string: (“systemic sclerosis” OR “scleroderma”) AND (“occupational exposure” OR “environmental” OR “risk factor”) was used to retrieve abstracts from the entire PubMed database, using Semantic MEDLINE 2, on 6/14/2020. This application represents a network of semantic predications (triples of the form subject-predicate (or relation) -object, e.g. Occupational Exposure causes Systemic Scleroderma) on a knowledge graph. Subject and object arguments of each predication are concepts from the Unified Medical Language System (UMLS) Metathesaurus and the relation is taken from the UMLS Semantic Network. The system allows for choosing the central topic (“Systemic Scleroderma”), the length of the network (3 nodes), and automatic summarization, eliminating the less informative predications.Results:The search string retrieved 864 citations and identified 6,397 predications by using 34 types of relations. Initially, we focused our attention on the ‘CAUSES’ type of relation (Figure 1), displaying a network with 59 nodes and 57 edges.The central concepts of this network, identified as having causal relationship with SSc are autoimmune diseases/autoimmunity, chemicals such as bleomycin, occupational and environmental exposure, especially silica, vinyl chloride and trichloroethylene, genes, including HLA and non-HLA genes, genetic polymorphisms, transcription factors (TFs) such as Fli1 and KLF5, and fibrosis. Eosinophilia-myalgia syndrome, toxic oil syndrome and infection were all causally linked to autoimmune diseases. Minerals were associated with occupational exposure and with autoimmune diseases. Concepts causally linked to fibrosis were rare diseases, HLA genes, other non-HLA genes, such as STAT4, IR4, IR5, TLR4, TLR7 and Rho-associated Kinase, and vinyl chloride monomer. Pathogenic factors associated with SSc were endothelial dysfunction and extracellular matrix proteins. Many of the papers in the network also suggested that hormonal factors are involved.Conclusion:Inspection on the knowledge graphs reveals concepts central to research on the etiopathogenesis of SSc. The relations in which these concepts participate, provide more specific information. The Semantic MEDLINE graph supports the kind of patterns that underpin literature-based discovery.Although the pathogenesis of SSc remains elusive, it is accepted that initial vascular damage driven by autoimmunity and environmental factors causes abnormalities in the vasculature resulting in the activation of fibroblasts in various organs. Silica and solvents such as trichloroethylene seem to be the most consistently suspected environmental agents in SSc.References:[1]Rindflesch TC,et al. Semantic MEDLINE: An advanced information management application for biomedicine. Information Services & Use 2011;31:15-21.Figure 1.Semantic Network of Casual Relationships of Systemic Scleroderma.Disclosure of Interests:None declared