HLA alleles: important pieces to the COVID-19 puzzle.

Research on human leukocyte antigen (HLA) molecules in coronavirus disease 2019 (COVID-19) raised high expectations but has yielded limited results. Augusto et al.'s recent study in Nature unveils a strong association of HLA-B*15:01 with asymptomatic COVID-19, representing an important contribution to genetics in COVID-19.

Pharmacogenetic Variation and Its Clinical Relevance in a Latin American Rural Population.

Latin-American populations have been largely underrepresented in genomic studies of drug response and disease susceptibility. In this paper, we present a genome-wide Chilean dataset from Talca based on the Illumina Global Screening Array. This let us to compare the frequency of gene variants involved in response to drugs among our population and others, taking data from the 1000 Genomes Project. We found four single-nucleotide polymorphisms with low prevalence in Chileans when compared with African, Amerindian, East and South Asian, and European populations: rs2819742 (RYR2), rs2631367 (SLC22A5), rs1063320 (HLA-G), and rs1042522 (TP53). Moreover, two markers showed significant differences between lower and higher proportion of Mapuche ancestry groups: rs1719247 (located in an intergenic region in chromosome 15; p-value = 6.17 × 10-5, Bonferroni corrected p-value = 0.02) and rs738409 (A nonsynonymous gene variant in the PNPLA3 gene; p-value = 9.02 × 10-5, Bonferroni corrected p-value = 0.04). All of these polymorphisms have been shown to be associated with diverse pathologies, such as asthma, cancer, or chronic hepatitis B, or to be involved in a different response to drugs, such as metformin, HMG-CoA reductase inhibitors, or simvastatin. The present work provides a pharmacogenetic landscape of an understudied Latin American rural population and supports the notion that pharmacogenetic studies in admixed populations should consider ancestry for a higher accuracy of the results. Our study stresses the relevance of the pharmacogenomic research to provide guidance for a better choice of the best treatment for each individual in a population with admixed ancestry.

Genomics, proteomics and metabolomics: their emerging roles in the discovery and validation of rheumatoid arthritis biomarkers.

Rheumatoid arthritis (RA) is an autoimmune inflammatory rheumatic disease which affects several organs and tissues, predominantly the synovial joints. Despite major advances, the aetiology of this disease is not completely understood. Although several biomarkers are routinely used in RA management and some of them can be detected even prior to the onset of the clinical disease, there is a high demand for novel biomarkers to further improve the early diagnosis of RA. The '-omics' techniques that have emerged and have been developed in recent years have allowed researchers to improve their knowledge of the aetiopathology of RA. At the same time, advances in screening technologies offer an excellent opportunity to find new biomarkers potentially useful for early diagnosis, stratification of patients, and even prediction of a better response to a specific therapy. This review describes what is known about the methodologies used in the discovery of novel biomarkers in RA, along with the findings of these methodologies, with specific attention to recent advances in the fields of genomics, proteomics and metabolomics.

Th17 response and autophagy--main pathways implicated in the development of inflammatory bowel disease by genome-wide association studies.

Inflammatory bowel disease (IBD) is an entity that mainly includes ulcerative colitis (UC) and Crohn´s disease (CD). Improved health care, diet changes, and higher industrialization are associated with an increase in IBD prevalence. This supports the central role of environmental factors in the pathology of this disease. However, IBD also shows a relevant genetic component as shown by high heritability. Classic genetic studies showed relevant associations between IBD susceptibility and genes involved in the immune response. This is consistent with prior theories about IBD development. According to these, contact of the immune system with a high number of harmless antigens from the diet and the bacterial flora should originate tolerance while preserving response against pathogens. Failure to achieve this balance may originate the typical inflammatory response associated with IBD. Recently, genome-wide association studies (GWASs) have confirmed the implication of the immune system, particularly the Th17 immune response, previously associated to other autoimmune diseases, and of autophagy. In this paper, the mechanisms involved in these two relevant pathways and their potential role in the pathogenesis of IBD are reviewed.

[Genetics of ankylosing spondylitis]. / Genética, HLA-B27 y espondilitis anquilosante: 40 años.

Ankylosing spondylitis (AS) is a prototypical inflammatory disease of the locomotor system affecting axial skeleton. It is part of the general group of spondyloarthopathies (SpA). Its strong association with histocompatibility antigen HLA-B27 is known since 1973. However, HLA-B27 contribution to AS genetic risk is approximately 16%. Therefore, other genes are necessarily involved in the pathogenesis of the disease. Genomic development and the possibility of making genome wide screening have contributed enormously to the study of the disease. In this paper, we describe the actual knowledge about AS genetic risk, which has contributed to understand the influence of HLA-B27 on the etiology and pathogenesis of the disease. We also intend to foresee how these findings will result in an improvement of patients'’ quality of life.

Unveiling the Significance of HLA and KIR Diversity in Underrepresented Populations.

Human leukocyte antigen (HLA) molecules and their relationships with natural killer (NK) cells, specifically through their interaction with killer-cell immunoglobulin-like receptors (KIRs), exhibit robust associations with the outcomes of diverse diseases. Moreover, genetic variations in HLA and KIR immune system genes offer limitless depths of complexity. In recent years, a surge of high-powered genome-wide association studies (GWASs) utilizing single nucleotide polymorphism (SNP) arrays has occurred, significantly advancing our understanding of disease pathogenesis. Additionally, advances in HLA reference panels have enabled higher resolution and more reliable imputation, allowing for finer-grained evaluation of the association between sequence variations and disease risk. However, it is essential to note that the majority of these GWASs have focused primarily on populations of Caucasian and Asian origins, neglecting underrepresented populations in Latin America and Africa. This omission not only leads to disparities in health care access but also restricts our knowledge of novel genetic variants involved in disease pathogenesis within these overlooked populations. Since the KIR and HLA haplotypes prevalent in each population are clearly modelled by the specific environment, the aim of this review is to encourage studies investigating HLA/KIR involvement in infection and autoimmune diseases, reproduction, and transplantation in underrepresented populations.

Utility of polygenic risk scores to aid in the diagnosis of rheumatic diseases.

Rheumatic diseases (RDs) are characterized by autoimmunity and autoinflammation and are recognized as complex due to the interplay of multiple genetic, environmental, and lifestyle factors in their pathogenesis. The rapid advancement of genome-wide association studies (GWASs) has enabled the identification of numerous single nucleotide polymorphisms (SNPs) associated with RD susceptibility. Based on these SNPs, polygenic risk scores (PRSs) have emerged as promising tools for quantifying genetic risk in this disease group. This chapter reviews the current status of PRSs in assessing the risk of RDs and discusses their potential to improve the accuracy of the diagnosis of these complex diseases through their ability to discriminate among different RDs. PRSs demonstrate a high discriminatory capacity for various RDs and show potential clinical utility. As GWASs continue to evolve, PRSs are expected to enable more precise risk stratification by integrating genetic, environmental, and lifestyle factors, thereby refining individual risk predictions and advancing disease management strategies.

HLA-A*11:01 and HLA-C*04:01 are associated with severe COVID-19.

We analyzed the association between HLA polymorphisms and susceptibility to SARS-CoV-2 infection and disease severity. Genotyping data from a total of 9373 COVID-19-positive cases from the Spanish Coalition to Unlock Research on Host Genetics on COVID-19 (SCOURGE) consortium and 5943 population controls were included in the study. We found an association of the alleles HLA-B*14:02 and HLA-C*08:02 with a lower risk to COVID-19 infection (p = 0.006, OR = 0.84, 95% CI = [0.75-0.95], p = 0.024, OR = 0.86, 95% CI = [0.78-0.95], respectively). We also found the alleles HLA-A*11:01 and HLA-C*04:01 associated with disease severity (p = 0.033, OR = 1.16, 95% CI = [1.04-1.31], p = 0.045, OR = 1.14, 95% CI = [1.05-1.25], respectively). These results suggest that an effective presentation of viral peptides by HLA class I alleles involve a faster infection clearance, decreasing the susceptibility and severity of COVID-19.

Advances of Genomic Medicine in Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a common type of inflammatory arthritis found in up to 40% of patients with psoriasis. Although early diagnosis is important for reducing the risk of irreversible structural damage, there are no adequate screening tools for this purpose, and there are no clear markers of predisposition to the disease. Much evidence indicates that PsA disorder is complex and heterogeneous, where genetic and environmental factors converge to trigger inflammatory events and the development of the disease. Nevertheless, the etiologic events that underlie PsA are complex and not completely understood. In this review, we describe the existing data in PsA in order to highlight the need for further research in this disease to progress in the knowledge of its pathobiology and to obtain early diagnosis tools for these patients.

Circulating Free DNA and Its Emerging Role in Autoimmune Diseases.

Liquid biopsies can be used to analyse tissue-derived information, including cell-free DNA (cfDNA), circulating rare cells, and circulating extracellular vesicles in the blood or other bodily fluids, representing a new way to guide therapeutic decisions in cancer. Among the new challenges of liquid biopsy, we found clinical application in nontumour pathologies, including autoimmune diseases. Since the discovery of the presence of high levels of cfDNA in patients with systemic lupus erythaematosus (SLE) in the 1960s, cfDNA research in autoimmune diseases has mainly focused on the overall quantification of cfDNA and its association with disease activity. However, with technological advancements and the increasing understanding of the role of DNA sensing receptors in inflammation and autoimmunity, interest in cfDNA and autoimmune diseases has not expanded until recently. In this review, we provide an overview of the basic biology of cfDNA in the context of autoimmune diseases as a biomarker of disease activity, progression, and prediction of the treatment response. We discuss and integrate available information about these important aspects.

Acquisition of New Migratory Properties by Highly Differentiated CD4+CD28null T Lymphocytes in Rheumatoid Arthritis Disease.

Expanded CD4+CD28null T lymphocytes are found in the tissues and peripheral blood of patients with many autoimmune diseases, such as rheumatoid arthritis (RA). These highly differentiated cells present potent inflammatory activity and capability to induce tissue destruction, which has been suggested to predispose to the development of more aggressive disease. In fact, preferential migration to inflammatory sites has been proposed to be a contributing factor in the progression of autoimmune and cardiovascular diseases frequently found in these patients. The functional activity of CD4+CD28null T lymphocytes is largely dependent on interleukin 15 (IL-15), and this cytokine may also act as a selective attractor of these cells to local inflammatory infiltrates in damaged tissues. We have analysed, in RA patients, the migratory properties and transcriptional motility profile of CD4+CD28null T lymphocytes compared to their counterparts CD28+ T lymphocytes and the enhancing role of IL-15. Identification of the pathways involved in this process will allow us to design strategies directed to block effector functions that CD4+CD28null T lymphocytes have in the target tissue, which may represent therapeutic approaches in this immune disorder.

Lanthanum activates calcium-sensing receptor and enhances sensitivity to calcium.

BACKGROUND: The aim of this study was to investigate whether nanomolar concentrations of lanthanum could influence the calcium-sensing receptor (CaSR) response. METHODS: Embryonic kidney (HEK-293) cells transiently transfected with the human CaSR were used to test the ability of lanthanum to activate the CaSR, either alone or in combination with calcium. CaSR activation was measured by flow cytometry. Parathyroid glands from 4-month-old male Wistar rats with normal renal function (n = 60) were also cultured ex vivo with different concentrations of lanthanum to measure parathyroid hormone (PTH) secreted to the medium and PTH mRNA. RESULTS: The maximal CaSR activation induced by 1 muM lanthanum chloride (LaCl(3)) was similar to that induced by 16 mM calcium chloride (CaCl(2) 16 mM: 294 +/- 14%; LaCl(3) 1 muM: 303 +/- 11%). Lanthanum half effective concentration (EC(50)) was 77.28 nM, lower than the 2.30 mM obtained for calcium, supporting the concept that this metal is a strong agonist of the CaSR. Moreover, lanthanum was also able to enhance CaSR sensitivity to calcium. The presence of 1 nM LaCl(3) significantly left-shifted the CaSR response curve, changing the EC(50) value for calcium from 2.30 mM (calcium alone) to 1.26 mM (calcium + 1 nM lanthanum). The parathyroid glands cultured with lanthanum showed a trend to secrete less PTH compared to the control glands: 1.51 +/- 0.23 (control), 0.91 +/- 0.17 (La 100 nM) and 1.04 +/- 0.18 (La 400 nM) [(pg/h)/(pg/h), mean +/- SEM] (ANOVA P = 0.0145). A similar trend was also observed in PTH synthesis measured by PTH mRNA levels. CONCLUSIONS: These in vitro findings demonstrate that lanthanum, at nanomolar concentrations, is an agonist of the CaSR able to activate it in the absence of calcium. In addition, it can also enhance CaSR sensitivity to calcium, modulating PTH synthesis and secretion.

Contribution of Multiplex Immunoassays to Rheumatoid Arthritis Management: From Biomarker Discovery to Personalized Medicine.

Rheumatoid arthritis (RA) is a multifactorial, inflammatory and progressive autoimmune disease that affects approximately 1% of the population worldwide. RA primarily involves the joints and causes local inflammation and cartilage destruction. Immediate and effective therapies are crucial to control inflammation and prevent deterioration, functional disability and unfavourable progression in RA patients. Thus, early diagnosis is critical to prevent joint damage and physical disability, increasing the chance of achieving remission. A large number of biomarkers have been investigated in RA, although only a few have made it through the discovery and validation phases and reached the clinic. The single biomarker approach mostly used in clinical laboratories is not sufficiently accurate due to its low sensitivity and specificity. Multiplex immunoassays could provide a more complete picture of the disease and the pathways involved. In this review, we discuss the latest proposed protein biomarkers and the advantages of using protein panels for the clinical management of RA. Simultaneous analysis of multiple proteins could yield biomarker signatures of RA subtypes to enable patients to benefit from personalized medicine.

Latin American Genes: The Great Forgotten in Rheumatoid Arthritis.

The successful implementation of personalized medicine will rely on the integration of information obtained at the level of populations with the specific biological, genetic, and clinical characteristics of an individual. However, because genome-wide association studies tend to focus on populations of European descent, there is a wide gap to bridge between Caucasian and non-Caucasian populations before personalized medicine can be fully implemented, and rheumatoid arthritis (RA) is not an exception. In this review, we discuss advances in our understanding of genetic determinants of RA risk among global populations, with a focus on the Latin American population. Geographically restricted genetic diversity may have important implications for health and disease that will remain unknown until genetic association studies have been extended to include Latin American and other currently under-represented ancestries. The next few years will witness many breakthroughs in personalized medicine, including applications for common diseases and risk stratification instruments for targeted prevention/intervention strategies. Not all of these applications may be extrapolated from the Caucasian experience to Latin American or other under-represented populations.

The Genetics of Spondyloarthritis.

The term spondyloarthritis (SpA) encompasses a group of chronic inflammatory diseases with common features in terms of clinical presentation and genetic predisposition. SpA is characterized by inflammation of the spine and peripheral joints, and is also be associated with extra-articular inflammatory manifestations such as psoriasis, uveitis, or inflammatory bowel disease (IBD). The etiology of SpA is not completely understood, but it is known to have a strong genetic component dominated by the human leukocyte antigen (HLA)-B27. In the last few years, our understanding of genetic susceptibility to SpA, particularly ankylosing spondylitis (AS), has greatly improved thanks to the findings derived from powered genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) arrays. These studies have identified many candidate genes, therefore providing new potential directions in the exploration of disease mechanisms, especially with regard to the key role of the immune system in the pathogenesis of SpA. SpA is a complex disease where genetic variability, environmental factors, and random events interact to trigger pathological pathways. The aim of this review is to summarize current findings on the genetics of SpA, some of which might help to study new treatment approaches.

HLA-DRB1*07:01 and *08:02 Alleles Confer a Protective Effect Against ACPA-Positive Rheumatoid Arthritis in a Latin American Admixed Population.

HLA-DRB1 shared epitope (SE) alleles are important genetic contributors for the risk of developing anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis (RA), particularly in Caucasians. We aimed to analyze the contribution of HLA-DRB1 alleles and single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) region to the susceptibility to develop ACPA-positive RA in a Latin American (LA) population with admixed ancestry. A total of 289 ACPA-positive RA patients and 510 controls were enrolled in this study. The presence of HLA-DRB1*04:01, *09:01 and *10:01 was increased in ACPA-positive RA patients compared with healthy controls (p < 0.0001, p < 0.001 and p < 0.01, respectively), whereas DRB1*07:01 and *08:02 was associated with a decreased risk of ACPA-positive RA (p < 0.001 and p < 0.01, respectively). These results showed a strong correlation with estimates from studies in Asians but not in Caucasian populations. The present study describes the protective effects of the HLA-DRB1*07:01 and *08:02 alleles in ACPA-positive RA patients in a LA population for the first time. Identifying relationships between HLA-DRB1 alleles and RA is important for identifying disease associations in different ethnic groups in order to reach a better understanding of RA worldwide.

Value of measuring plasmatic levels of neurosin in the diagnosis of Alzheimer's disease.

The search for molecular biomarkers for diagnosing and classifying dementias is becoming a high priority need. Neurosin (Kallikrein 6, hk6) is one molecule with promising preliminary results since its levels in brain tissue, cerebrospinal fluid and blood have been found to be abnormal in Alzheimer's disease (AD). In this study, we measured plasmatic levels of neurosin in healthy individuals and patients with cognitive symptoms independently of what the final diagnosis was. We collected plasma samples from 228 controls and 447 patients finally diagnosed with either AD, Mild Cognitive Impairment, Dementia with Lewy Bodies or Parkinson-Dementia, Frontotemporal Dementia, Huntington's disease, Primary Progressive Aphasia, Corticobasal degeneration, Creutzfeldt-Jakob's disease or Pseudodementia. We found that plasmatic levels of neurosin increase with age in healthy individuals and decrease in patients with AD. Plasmatic levels of neurosin differ significantly between AD and Vascular Dementia, Pseudodementia and the control group. Analyses comparing any other form of neurodegenerative dementia to the AD group did not show significant differences. In conclusion, measurement of plasmatic levels of neurosin is useful to distinguish AD patients from subjects without neurodegenerative dementia (either Pseudodementia, Vascular Dementia or controls) although it is not useful to distinguish among neurodegenerative dementias.

Killer cell immunoglobulin-like receptor genotypes in a Chilean population from Talca.

Ninety healthy and unrelated volunteers were randomly selected to study the gene frequencies of Killer-cell immunoglobulin-like receptors (KIRs) in a Chilean (Talca) population. KIR typing was resolved by PCR-single specific primer (SSP), and their gene frequencies were calculated by direct counting of the number of positive and negative loci. The KIR genotype data is publicly available in the Allele Frequencies Net Database under the name "Chile Talca KIR".