Publications by authors named "Augusto D"

62 Publications

Behçet disease, new insights in disease associations and manifestations: a next-generation sequencing study.

Clin Exp Immunol 2021 Apr 3;204(1):144-151. Epub 2021 Feb 3.

BMT Lab Unit, Clinical Pathology Deptartment, National Cancer Institute, Cairo University, Cairo, Egypt.

Behçet disease is a multi-system disease associated with human leukocyte antigen (HLA) class I polymorphism. High-resolution next-generation sequencing (NGS) with haplotype analysis has not been performed previously for this disease. Sixty Egyptian patients diagnosed according to the International Study Group (ISG) criteria for Behçet disease and 160 healthy geographic and ethnic-matched controls were genotyped for HLA class I loci (HLA-A, B, C). For HLA class II loci (DRB1, DRB3/4/5, DQA1, DQB1, DPA1, DPB1), 40 control samples were genotyped. High-resolution HLA genotyping was performed using NGS and the results were analyzed. Clinical manifestations were oral ulcers (100%), genital ulcers (100%), eye (55%) and neurological (28%) and vascular involvement (35%). HLA-B*51:08 [odds ratio (OR) = 19·75, 95% confidence interval (CI) = 6·5-79; P < 0·0001], HLA-B*15:03 (OR = 12·15, 95% CI = 3·7-50·7; P < 0·0001), HLA-C*16:02 (OR = 6·53, 95% CI = 3-14; P < 0·0001), HLA-A*68:02 (OR = 3·14, 95% CI = 1·1-8·9; P < 0·01) were found to be associated with Behçet disease, as were HLA-DRB1*13:01 and HLA-DQB1*06:03 (OR = 3·39, 95% CI = 0·9-18·9; P = 0·04 for both). By contrast, HLA-A*03:01 (OR = 0·13, 95% CI = 0-0·8; P = 0·01) and HLA-DPB1*17:01 were found to be protective (OR = 0·27, 95% CI = 0·06-1·03; P = 0·02). We identified strong linkage disequilibrium between HLA-B*51:08 and C*16:02 and A*02:01 in a haplotype associated with Behçet disease. HLA-B*51:08 was significantly associated with legal blindness (OR = 2·98, 95% CI = 1·06-8·3; P = 0·01). In Egyptian Behçet patients, HLA-B*51:08 is the most common susceptibility allele and holds poor prognosis for eye involvement.
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http://dx.doi.org/10.1111/cei.13571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944360PMC
April 2021

Genetic variability of immune-related lncRNAs: polymorphisms in LINC-PINT and LY86-AS1 are associated with pemphigus foliaceus susceptibility.

Exp Dermatol 2021 Jan 4. Epub 2021 Jan 4.

Postgraduate Program in Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil.

Pemphigus foliaceus (PF) is an autoimmune blistering disease of the skin, clinically characterized by erosions and, histopathologically, by acantholysis. PF is endemic in the Brazilian Central-Western region. Numerous single nucleotide polymorphisms (SNPs) have been shown to affect the susceptibility for PF, including SNPs at long non-coding RNA (lncRNA) genes, which are known to participate in many physiological and pathogenic processes, such as autoimmunity. Here, we investigated whether the genetic variation of immune-related lncRNA genes affects the risk for endemic and sporadic forms of PF. We analysed 692 novel SNPs for PF from 135 immune-related lncRNA genes in 227 endemic PF patients and 194 controls. The SNPs were genotyped by Illumina microarray and analysed by applying logistic regression at additive model, with correction for sex and population structure. Six associated SNPs were also evaluated in an independent German cohort of 76 sporadic PF patients and 150 controls. Further, we measured the expression levels of two associated lncRNA genes (LINC-PINT and LY86-AS1) by quantitative PCR, stratified by genotypes, in peripheral blood mononuclear cells of healthy subjects. We found 27 SNPs in 11 lncRNA genes associated with endemic PF (p < .05 without overlapping with protein-coding genes). Among them, the LINC-PINT SNP rs10228040*A (OR = 1.47, p = .012) was also associated with increased susceptibility for sporadic PF (OR = 2.28, p = .002). Moreover, the A+ carriers of LY86-AS1*rs12192707 mark lowest LY86-AS1 RNA levels, which might be associated with a decreasing autoimmune response. Our results suggest a critical role of lncRNA variants in immunopathogenesis of both PF endemic and sporadic forms.
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http://dx.doi.org/10.1111/exd.14275DOI Listing
January 2021

Single Nucleotide Polymorphism in Is Associated With HLA-C Expression in Global Populations.

Front Immunol 2020 21;11:1881. Epub 2020 Aug 21.

Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil.

Regulation of NK cell activity is mediated through killer-cell immunoglobulin-like receptors (KIR) ability to recognize human leukocyte antigen (HLA) class I molecules as ligands. Interaction of KIR and HLA is implicated in viral infections, autoimmunity, and reproduction and there is growing evidence of the coevolution of these two independently segregating gene families. By leveraging and data from 1000 Genomes consortium we observed that the variant is associated with lower expression of HLA-C in individuals carrying the ligand HLA-C2 ( = 0.0059). Using flow cytometry, we demonstrated that this variant is also associated with higher expression of KIR2DL1 on the NK cell surface ( = 0.0002). Next, we applied next generation sequencing to analyze sequence variation in 109 Euro and 75 Japanese descendants. Analyzing the extended haplotype homozygosity, we show signals of positive selection for and , which are in linkage disequilibrium with . Our results suggest that lower expression of HLA-C2 ligands might be compensated for higher expression of the receptor KIR2DL1 and bring new insights into the coevolution of and .
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http://dx.doi.org/10.3389/fimmu.2020.01881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478174PMC
April 2021

Variation in genes implicated in B-cell development and antibody production affects susceptibility to pemphigus.

Immunology 2021 Jan 9;162(1):58-67. Epub 2020 Oct 9.

Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brasil.

Pemphigus foliaceus (PF) is an autoimmune blistering skin disease characterized by the presence of pathogenic autoantibodies against desmoglein 1, a component of intercellular desmosome junctions. PF occurs sporadically across the globe and is endemic in some Brazilian regions. Because PF is a B-cell-mediated disease, we aimed to study the impact of variants within genes encoding molecules involved in the different steps of B-cell development and antibody production on the susceptibility of endemic PF. We analysed 3,336 single nucleotide polymorphisms (SNPs) from 167 candidate genes genotyped with Illumina microarray in a cohort of 227 PF patients and 193 controls. After quality control and exclusion of non-informative and redundant SNPs, 607 variants in 149 genes remained in the logistic regression analysis, in which sex and ancestry were included as covariates. Our results revealed 10 SNPs within or nearby 11 genes that were associated with susceptibility to endemic PF (OR >1.56; p < 0.005): rs6657275*G (TGFB2); rs1818545*A (RAG1/RAG2/IFTAP);rs10781530*A (PAXX), rs10870140*G and rs10781522*A (TRAF2); rs535068*A (TNFRSF1B); rs324011*A (STAT6);rs6432018*C (YWHAQ); rs17149161*C (YWHAG); and rs2070729*C (IRF1). Interestingly, these SNPs have been previously associated with differential gene expression, mostly in peripheral blood, in publicly available databases. For the first time, we show that polymorphisms in genes involved in B-cell development and antibody production confer differential susceptibility to endemic PF, and therefore are candidates for possible functional studies to understand immunoglobulin gene rearrangement and its impact on diseases.
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http://dx.doi.org/10.1111/imm.13259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730027PMC
January 2021

Stemness in high-grade serous carcinoma of tubo-ovarian origin causes multiple immunohistochemical pitfalls: a case report.

J Clin Pathol 2020 Dec 4;73(12):845-846. Epub 2020 Aug 4.

Department of Pathology, Site de Jolimont, Centres Hospitaliers Jolimont, Haine-Saint-Paul, Belgium.

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http://dx.doi.org/10.1136/jclinpath-2020-206559DOI Listing
December 2020

Killer Cell Immunoglobulin-like Receptor Variants Are Associated with Protection from Symptoms Associated with More Severe Course in Parkinson Disease.

J Immunol 2020 09 24;205(5):1323-1330. Epub 2020 Jul 24.

Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158;

Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated -allelic polymorphism to interrogate the role of NK cells in PD. We sequenced genes from 1314 PD patients and 1978 controls using next-generation methods and identified genotypes using custom bioinformatics. We examined associations of with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: /HLA-Bw4 from rigidity ( = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and HLA-Bw4i from gait difficulties (p = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity ( = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.
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http://dx.doi.org/10.4049/jimmunol.2000144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484130PMC
September 2020

Exposition to Biological Control Agent Increases the Development of Cancer in Mice Injected With Murine Melanoma.

Front Cell Infect Microbiol 2020 29;10:252. Epub 2020 May 29.

Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil.

Biological control agents (BCA) are an alternative to chemical pesticides and an emerging strategy to safely eliminate plant pathogens. spp. are the most common fungi used as BCAs. They produce spores that are released into the air and can potentially interact with immune system of mammals. We previously showed that affects expression of genes encoding pattern recognition receptors (PRRs) and cytokines in mice. PRRs are involved in the recognition of microorganisms and can lead to pro-tumoral signaling. Here, we evaluated if mice injected with low doses of murine melanoma exhibited increased development of lung tumor when treated with conidia of . Mice treated with and inoculated with B16-F10 melanoma cells exhibited significant increase in tumor uptake ( = 0.006) and increased number of visible nodules in the lungs ( = 0.015). We also analyzed mRNA expression levels of genes encoding PRRs in lung of mice exposed to and demonstrated that mice treated with conidia exhibited lower expression levels of and increased expression of (toll like receptor 4) compared to non-treated controls. The expression levels of and were increased in mice treated with and inoculated with murine melanoma compared to controls only inoculated with melanoma. Our results demonstrate that intranasal exposition to increases tumor in the B16-F10 model, which may raise concerns regarding the safety of its use in agriculture.
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http://dx.doi.org/10.3389/fcimb.2020.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272596PMC
May 2020

Natural killer cell receptor variants and chronic hepatitis B virus infection in the Vietnamese population.

Int J Infect Dis 2020 Jul 16;96:541-547. Epub 2020 May 16.

Programa de Pós-Graduação em Genética, Departamento de Genética, Universidade Federal do Paraná (UFPR), Curitiba, Brazil. Electronic address:

Objectives: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma.

Methods: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis.

Results: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, p = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, p = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, p = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, p = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, p = 0.04).

Conclusions: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.
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http://dx.doi.org/10.1016/j.ijid.2020.05.033DOI Listing
July 2020

A genetic variant in microRNA-146a is associated with sporadic breast cancer in a Southern Brazilian Population.

Genet Mol Biol 2020 3;42(4):e20190278. Epub 2020 Feb 3.

Universidade Federal do Paraná, Departamento de Genética, Curitiba, Paraná, Brazil.

MicroRNAs (miRNAs) play an essential role in gene expression and affect the development of tumours, including breast cancer (BC). Polymorphisms in miRNA genes can affect the interaction of miRNAs with their target messenger RNA by interfering, creating or disrupting target sites. The single nucleotide polymorphism (SNP) rs2910164, located in the seed region of miR146a, was shown to be associated with BC among different populations. In the present study, we investigated whether rs2910164 is associated with BC in 326 patients and 411 controls from a Brazilian population of predominantly European ancestry. The presence of the allele rs2910164*C was associated with an increased risk of BC (OR=1.4, 95% CI=1.03-1.85, p = 0.03). We also analysed publicly available RNA-seq data to evaluate if miR146a is differentially expressed in different subtypes of BC. Genotyping was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP). By leveraging public data from TCGA database, we analysed 461 patients and found that miR146a is significantly more expressed in BC than in non-tumor tissue (1.47 fold, p = 0.02) and is expressed to a greater degree in aggressive BC subtypes.
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http://dx.doi.org/10.1590/1678-4685-GMB-2019-0278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198002PMC
February 2020

c-MET as a Potential Resistance Mechanism to Everolimus in Breast Cancer: From a Case Report to Patient Cohort Analysis.

Target Oncol 2020 02;15(1):139-146

Medical Oncology Unit, Hopital de Jolimont, Rue Ferrer 159, 7100, Haine Saint Paul, Belgium.

Background: We describe in a patient with breast cancer the change in c-MET expression during everolimus treatment, opening a better understanding of the resistance to everolimus and a role for cabozantinib.

Objective: The objective of this study was to evaluate c-MET as a potential predictive biomarker for everolimus efficacy in breast cancer.

Methods: We first selected a patient with breast cancer with a long-lasting response to everolimus and retrospectively profiled biopsies that were taken before everolimus initiation (Biopsy 1) and at progression on everolimus (Biopsy 2) using amplicon sequencing and immunohistochemistry. We then retrospectively evaluated c-MET expression in a cohort of patients with breast cancer treated with everolimus.

Results: While not expressed in Biopsy 1, c-MET was highly expressed in Biopsy 2, suggesting a role for c-MET in breast cancer progression. Cabozantinib resulted in a rapid radiological response in this patient. Twenty-nine patients were included (12 c-MET-positive and 17 c-MET-negative patients) in the second part of the study. Baseline c-MET expression was associated with higher tumor grade, higher frequency of visceral metastases, and lower endocrine sensitivity. The c-MET-positive patients presented with a shorter progression-free survival (6.1 vs 10.5 months, respectively; p = 0.002) and a lower response rate (0% vs 12%) to everolimus, compared with c-MET-negative patients.

Conclusions: c-MET could play a role in the resistance to everolimus and its inhibition should be evaluated in breast cancer.
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http://dx.doi.org/10.1007/s11523-020-00704-2DOI Listing
February 2020

Characterization of serum cytokines and circulating microRNAs that are predicted to regulate inflammasome genes in cutaneous leishmaniasis patients.

Exp Parasitol 2020 Mar 28;210:107846. Epub 2020 Jan 28.

Department of Biological Sciences, Universidade Estadual de Santa Cruz (UESC), Ilhéus, BA, Brazil. Electronic address:

Leishmaniasis is a neglected disease caused by an intracellular protozoan parasite of the genus Leishmania. Infection starts when this protozoan replicates in a phagolysosomal compartment in macrophages, after evading host immune responses. The balance of Th1 and Th2 immune responses is crucial in leishmaniasis because it will determine whether the infection will be under control or if clinical complications will occur. The inflammasome, which is activated during Leishmania infection, involves the action of caspase-1 and release of the proinflammatory cytokines interleukin-1β and interleukin-18. Together, they contribute to the maintenance of an inflammatory response and pyroptosis. Here, we evaluated the serum levels of cytokines and the expression of circulating microRNAs related to inflammasome regulation in twenty-seven patients with cutaneous leishmaniasis in comparison to nine healthy individuals, in the context of the inflammasome activation. Evaluation of serum cytokines activation (IL-1β, IL-2, IL-4, IL-6, IL-10, and IL-17) was performed by flow cytometry using CBA kits (cytometric beads array) while the expression of circulating microRNAs (miR-7, miR-133a, miR-146b, miR-155, miR-223, miR-328, and miR-342) in plasma was measured by quantitative polymerase chain reaction. Our results showed an increase of the expression of miR-7-5p (p < 10), miR-133a (p = 0.034), miR-146b (p = 0.003), miR-223-3p (p = 10), and miR-328-3p (p = 0.002), and cytokine levels for IL-1β (p = 0.0005), IL-6 (p = 0.001), and IL-17 (p = 0.001) in patients with cutaneous leishmaniasis compared to the controls. These results suggest that microRNAs and cytokines can play an important role in regulating the human immune responses to Leishmania infection. Our findings may contribute to the understanding of the mechanisms of the gene regulation during the cutaneous leishmaniasis and to the identification of possible biomarkers of the infection.
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http://dx.doi.org/10.1016/j.exppara.2020.107846DOI Listing
March 2020

Condemned or Not to Die? Gene Polymorphisms Associated With Cell Death in Pemphigus Foliaceus.

Front Immunol 2019 18;10:2416. Epub 2019 Oct 18.

Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil.

Pemphigus foliaceus (PF) is an autoimmune blistering skin disease that occurs sporadically across the globe and is endemic in Brazil. Keratinocyte adhesion loss (acantholysis) is associated with high levels of anti-desmoglein 1 IgG autoantibodies, but the role of cell death is poorly understood in PF. Current evidence disqualifies apoptosis as the major cell death mechanism and no other process has yet been investigated. To approach the role of variation in genes responsible for cell death pathways in pemphigus susceptibility, we systematically investigated the frequencies of 1,167 polymorphisms from genes encoding products of all 12 well-established cell death cascades (intrinsic and extrinsic apoptosis, necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic, NETotic, lysosome-dependent, autophagy-dependent, and immunogenic). By multivariate logistic regression, we compared allelic and genotypic frequencies of 227 PF patients and 194 controls obtained by microarray hybridization. We found 10 variants associated with PF ( < 0.005), belonging to six cell death pathways: apoptosis (, and ), immunogenic cell death (, and ), necroptosis ( and ), necrosis (), parthanatos (), and pyroptosis (). Five polymorphisms were associated with susceptibility: * ( = 1.9, = 0.0003), * ( = 2.14, = 0.0015), * ( = 1.77, = 0.0043), * ( = 2.75, = 0.0009), and * ( = 1.48, = 0.0045). Other five variants were associated with protection: * ( = 0.64, = 0.0014), * ( = 0.48, = 0.0023), * ( = 0.48, = 0.0007), * ( = 0.42, = 0.0040), and * ( = 0.57, = 0.0004). Through functional annotation, we found that all associated alleles, with the exception of *, were previously associated with differential gene expression levels in healthy individuals (mostly in skin and peripheral blood). Further functional validation of these genetic associations may contribute to the understanding of PF etiology and to the development of new drugs and therapeutic regimens for the disease.
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http://dx.doi.org/10.3389/fimmu.2019.02416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813369PMC
November 2020

First Glimpse of Epigenetic Effects on Pemphigus Foliaceus.

J Invest Dermatol 2020 02 31;140(2):488-491.e1. Epub 2019 Jul 31.

Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná, Universidade Federal do Paraná, Curitiba, Paraná, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.jid.2019.07.691DOI Listing
February 2020

[An online dynamic knowledge base in multiple languages on general medicine and primary care].

Pan Afr Med J 2019 5;32:66. Epub 2019 Feb 5.

Département d'Information et d'Informatique Médicale, Université de Rouen, France.

Introduction: The International Classification of Primary Care, Second version (ICPC-2) aligned with the 10th Revision of the International Classification of Disease (ICD-10) is a standard for primary care epidemiology compendium. ICPC-2 has been also intended to identify the clinical topics in family medicine. Contextual field-specific knowledge in family medicine and primary care such as health structures, management, categories of patients, research methods, ethical or environmental features are not standardized and reflect, more often, the views of experts.

Methods: A qualitative research method, applied to the analysis of several Family Medicine congresses, has helped identify, in addition to clinical items, a spectrum of contextual concepts addressed by family doctors during their exchanges at the congresses. Assembled in a hierarchical manner, these concepts were given expression, together with ICPC-2, under the name of Q-codes Version 2.5, in the multilingual multi-terminology semantic server of the Department of Information and medical informatics (D2Im) at the University of Rouen, France. The two classifications are edited under the acronym 3 CGP for Core Content classification of General Practice. This free access server allows you to consult the ICPC-2 in 22 languages and the Q-codes in ten languages.

Results: The result of the joint use of these two classifications, as descriptors in congress to identify the concepts in texts or index the gray literature for family medicine and primary care is presented here in its various pilot uses. The validity and generalizability of 3CGP appears to be good in the light of the translations already carried out by colleagues around the world and of the applicability of the method in the two sides of the Atlantic. However the reproducibility and the inter-coder variations still remain to be tested for Q-codes. Maintenance remains an issue.

Conclusion: This method highlights the conceptual extension, the complexity and the dynamics of the role of general practitioner and family doctor as well as of primary care physician.
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http://dx.doi.org/10.11604/pamj.2019.32.66.15952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560960PMC
July 2019

Unveiling the Diversity of Immunoglobulin Heavy Constant Gamma () Gene Segments in Brazilian Populations Reveals 28 Novel Alleles and Evidence of Gene Conversion and Natural Selection.

Front Immunol 2019 4;10:1161. Epub 2019 Jun 4.

Laboratório de Genética Molecular Humana, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil.

Even though immunoglobulins are critical for immune responses and human survival, the diversity of the immunoglobulin heavy chain gene () is poorly known and mostly characterized only by serological methods. Moreover, this genomic region is not well-covered in genomic databases and genome-wide association studies due to particularities that impose technical difficulties for its analysis. Therefore, the gene has never been systematically sequenced across populations. Here, we deliver an unprecedented and comprehensive characterization of the diversity of the , and gene segments, which encode the constant region of the most abundant circulating immunoglobulins: IgG1, IgG2, and IgG3, respectively. We used Sanger sequencing to analyze 357 individuals from seven different Brazilian populations, including five Amerindian, one Japanese-descendant and one Euro-descendant population samples. We discovered 28 novel alleles and provided evidence that some of them may have been originated by gene conversion between common alleles of different gene segments. The rate of synonymous substitutions was significantly higher than the rate of the non-synonymous substitutions for and ( = 0.01 and 0.03, respectively), consistent with purifying selection. Fay and Wu's test showed significant negative values for most populations ( < 0.001), which indicates that positive selection in an adjacent position may be shaping variation by hitchhiking of variants in the vicinity, possibly the regions that encode the Ig variable regions. This study shows that the variation in the gene is largely underestimated. Therefore, exploring its nucleotide diversity in populations may provide valuable information for comprehension of its evolution, its impact on diseases and vaccine research.
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http://dx.doi.org/10.3389/fimmu.2019.01161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558194PMC
October 2020

Fluctuating and Geographically Specific Selection Characterize Rapid Evolution of the Human Region.

Front Immunol 2019 17;10:989. Epub 2019 May 17.

Department of Neurology, University of California, San Francisco, San Francisco, CA, United States.

The () region comprises a fast-evolving family of genes that encode receptors for natural killer (NK) cells and have crucial role in host defense. Evolution of was examined in the context of the human genome. Gene-content diversity and single nucleotide polymorphisms (SNP) in the genes and flanking regions were compared to >660,000 genome-wide SNPs in over 800 individuals from 52 populations of the human genome diversity panel (HGDP). allelic diversity was further examined using next generation sequencing in a subset of 56 individuals. We identified the SNP located in as a marker of and and, consequently, Cen A and Cen B haplotypes. We also show that combinations of two SNPs ( and ) distinguish from and also define the major high- and low-expressing alleles lineages. Comparing the diversity of the SNPs within the region to remainder of the genome, we observed a high diversity for the centromeric region consistent with balancing selection ( < 0.01); in contrast, centromeric diversity is significantly reduced in East Asian populations ( < 0.01), indicating purifying selection. By analyzing SNP haplotypes in a region spanning ~500 kb that includes the cluster, we observed evidence of strong positive selection in Africa for high-expressing alleles, favored over the low-expressing alleles ( < 0.01). In sharp contrast, the strong positive selection ( < 0.01) that we also observed in the telomeric region in Oceanic populations tracked with a high frequency of . In addition, we demonstrated that worldwide frequency of high-expression alleles was correlated with virus with virus (r = 0.64, < 10) and protozoa (r = 0.69, < 10) loads, which points to selection globally on high-expressing alleles attributable to pathogen exposure.
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http://dx.doi.org/10.3389/fimmu.2019.00989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533848PMC
September 2020

Factors associated with the evaluation of quality of primary health care by older adults living in the Metropolitan Region of Belo Horizonte, Minas Gerais, Brazil, 2010.

Epidemiol Serv Saude 2019 8;28(1):e2018128. Epub 2019 Apr 8.

Fundação Oswaldo Cruz, Instituto René Rachou, Belo Horizonte, MG, Brasil.

Objective: to analyze factors associated with the perception of quality of primary health care (PHC) services by older adults.

Methods: this was a cross-sectional survey with 893 older adults aged 60 years and over living in the Metropolitan Region of Belo Horizonte, MG, Brazil; the study's outcomes were the indicators of the essential attributes of PHC, while explanatory variables included sociodemographic conditions, use of health services and health conditions; Poisson regression with robust variance was used.

Results: older adults aged 80 years and over, women and those with higher education levels gave better evaluations for access and longitudinality, while evaluation was worst among those who reported greater use of health services and chronic health conditions, especially for the PHC attributes of coordination of care and family and community orientation.

Conclusion: poorer health conditions and higher use of services are associated with a more negative perception of PHC attributes among the elderly.
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http://dx.doi.org/10.5123/S1679-49742019000100017DOI Listing
August 2019

The association of HLA-G polymorphisms and the synergistic effect of sMICA and sHLA-G with chronic kidney disease and allograft acceptance.

PLoS One 2019 22;14(2):e0212750. Epub 2019 Feb 22.

Laboratório de Imunogenética e Histocompatibilidade, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Paraná, Brazil.

The HLA-G and MICA genes are stimulated under inflammatory conditions and code for soluble (sMICA and sHLA-G) or membrane-bound molecules that exhibit immunomodulatory properties. It is still unclear whether they would have a synergistic or antagonistic effect on the immunomodulation of the inflammatory response, such as in chronic kidney disease (CKD), contributing to a better prognosis after the kidney transplantation. In this study, we went from genetic to plasma analysis, first evaluating the polymorphism of MICA, NKG2D and HLA-G in a cohort from Southern Brazil, subdivided in a control group of individuals (n = 75), patients with CKD (n = 94), and kidney-transplant (KT) patients (n = 64). MICA, NKG2D and HLA-G genotyping was performed by polymerase chain reaction with specific oligonucleotide probes, Taqman and Sanger sequencing, respectively. Levels of soluble forms of MICA and HLA-G were measured in plasma with ELISA. Case-control analysis showed that the individuals with haplotype HLA-G*01:01/UTR-4 have a lower susceptibility to develop chronic kidney disease (OR = 0.480; p = 0.032). Concerning the group of kidney-transplant patients, the HLA-G genotypes +3010 GC (rs1710) and +3142 GC (rs1063320) were associated with higher risk for allograft rejection (OR = 5.357; p = 0.013 and OR = 5.357, p = 0.013, respectively). Nevertheless, the genotype +3010 GG (OR = 0.136; p = 0.041) was associated with kidney allograft acceptance, suggesting that it is a protection factor for rejection. In addition, the phenotypic analysis revealed higher levels of sHLA-G (p = 0.003) and sMICA (p < 0.001) in plasma were associated with the development of CKD. For patients who were already under chronic pathological stress and underwent a kidney transplant, a high sMICA (p = 0.001) in pre-transplant proved to favor immunomodulation and allograft acceptance. Even so, the association of genetic factors with differential levels of soluble molecules were not evidenced, we displayed a synergistic effect of sMICA and sHLA-G in response to inflammation. This increase was observed in CKD patients, that when undergo transplantation, had this previous amount of immunoregulatory molecules as a positive factor for the allograft acceptance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212750PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386361PMC
November 2019

High-resolution characterization of 12 classical and non-classical HLA loci in Southern Brazilians.

HLA 2019 02;93(2-3):80-88

Laboratório de Genética Molecular Humana, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil.

The human leukocyte antigen (HLA) are the most polymorphic genes in the human genome. Because of their importance for antigen recognition, HLA molecules play a central role in host defense and graft rejection upon transplantation. The aim of this study was to characterize allelic diversity of the classical HLA genes HLA-A, -B, -C, -DRA, -DRB1, -DQA1, -DQB1, -DPA1, -DPB1, and the non-classical class I genes HLA-E, -F and -G at high-resolution for a population of predominantly European ancestry from Curitiba, Brazil. Genotyping of 108 individuals was performed by next-generation sequencing on the MiSeq platform and also by Sanger sequencing. The genotype distributions of all loci were in accordance with Hardy-Weinberg equilibrium (P > 0.05) and a total of 202 HLA variants at second field resolution were observed for the 12 loci. The strongest linkage disequilibrium (r = 1.0, P < 10 ) was observed for the following pairs of alleles: HLA-B*42:01:01 ~ HLA-DRB1*03:02:01; HLA-B*14:02:01 ~ HLA-C*08:02:01; B*42:01:01 ~ HLA-C*17:01:01; HLA-DRB1*03:01:01 ~ HLA-DQB1*02:01:01 ~ DRB1*03:01:01 ~ HLA-DQB1*02:01:01; DRB1*13:01:01~ HLA-DQB1*06:03:01 and HLA-DRB1*09:01:02 ~ HLA-DQA1*03:02. This is the first study to characterize all 12 HLA genes at high resolution in a single population. On the basis of the allelic frequencies of worldwide populations and principal component analysis, we confirmed the similarity of the study population to European and other Euro-descendant populations.
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http://dx.doi.org/10.1111/tan.13488DOI Listing
February 2019

Long noncoding RNA polymorphisms influence susceptibility to endemic pemphigus foliaceus.

Br J Dermatol 2019 08 21;181(2):324-331. Epub 2019 Apr 21.

Laboratório de Genética Molecular Humana, Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil.

Background: Pemphigus foliaceus (PF) is an epidermal autoimmune disease, characterized by the presence of autoantibodies against the desmosomal protein desmoglein 1. Genetic and environmental factors contribute to PF, a complex disease that is endemic in Brazil and Colombia and neighbouring countries, and in Tunisia. Long noncoding RNAs (lncRNAs) may participate in gene regulation by interacting with DNA, proteins and other RNAs. Dysregulation of lncRNAs has recently been recognized as an important coplayer in the onset or progression of complex diseases. In addition, single-nucleotide polymorphisms (SNPs) located in lncRNA genes have been associated with differential risk to cancer, autoimmunity and infection.

Objectives: Here, we aimed to investigate whether SNPs in lncRNA genes are associated with differential susceptibility to endemic PF.

Materials And Methods: We integrated data from the lncRNA SNP database with genome-wide genotype data obtained for 229 patients and 6681 controls. We tested the association between endemic PF and 2080 SNPs located in lncRNAs applying logistic regression.

Results: The most significantly associated SNP was rs7144332 (OR = 1·63, P = 2·8 × 10 ), located in the lncRNA gene AL110292·1. Results for five other SNPs were suggestive of association (P < 0·001). In silico analysis indicated that five of the six SNPs impact transcription, three may influence lncRNA's secondary structure, and three may alter microRNA-lncRNA interactions.

Conclusions: We showed, for the first time, that variation in lncRNA genes may influence pemphigus pathogenesis. Our findings highlight the importance of lncRNA variation in autoimmune and possibly other complex diseases and suggest polymorphisms for functional validation.
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http://dx.doi.org/10.1111/bjd.17640DOI Listing
August 2019

Comparative Analysis of Genomic Island Prediction Tools.

Front Genet 2018 12;9:619. Epub 2018 Dec 12.

Department of Bioinformatics, Professional and Technical Education Sector, Federal University of Parana, Curitiba, Brazil.

Tools for genomic island prediction use strategies for genomic comparison analysis and sequence composition analysis. The goal of comparative analysis is to identify unique regions in the genomes of related organisms, whereas sequence composition analysis evaluates and relates the composition of specific regions with other regions in the genome. The goal of this study was to qualitatively and quantitatively evaluate extant genomic island predictors. We chose tools reported to produce significant results using sequence composition prediction, comparative genomics, and hybrid genomics methods. To maintain diversity, the tools were applied to eight complete genomes of organisms with distinct characteristics and belonging to different families. CFT073 was used as a control and considered as the gold standard because its islands were previously curated . The results of predictions with the gold standard were manually curated, and the content and characteristics of each predicted island were analyzed. For other organisms, we created GenBank (GBK) files using Artemis software for each predicted island. We copied only the amino acid sequences from the coding sequence and constructed a multi-FASTA file for each predictor. We used BLASTp to compare all results and generate hits to evaluate similarities and differences among the predictions. Comparison of the results with the gold standard revealed that GIPSy produced the best results, covering ~91% of the composition and regions of the islands, followed by Alien Hunter (81%), IslandViewer (47.8%), Predict Bias (31%), GI Hunter (17%), and Zisland Explorer (16%). The tools with the best results in the analyzes of the set of organisms were the same ones that presented better performance in the tests with the gold standard.
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http://dx.doi.org/10.3389/fgene.2018.00619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315130PMC
December 2018

Cost-effective and fast KIR gene-content genotyping by multiplex melting curve analysis.

HLA 2018 12;92(6):384-391

Laboratório de Genética Molecular Humana, Universidade Federal do Paraná, Curitiba, Brazil.

Killer cell immunoglobulin-like receptor (KIR) genes encode cell surface molecules that recognize HLA molecules and modulate the activity of natural killer (NK) cells. KIR genes exhibit presence and absence polymorphism, which generates a variety of gene-content haplotypes in worldwide populations. KIR gene-content variation is implicated in many diseases and is also important for placentation and transplantation. Because of the complexity of KIR polymorphism, variation in this family is still mostly studied at the gene-content level, even with the advent of next-generation sequencing (NGS) methods. Gene-content determination is generally expensive and/or time-consuming. To overcome these difficulties, we developed a method based on multiplex polymerase chain reaction with specific sequence primers (PCR-SSP) followed by melting curve analysis that allows cost-effective, precise and fast generation of results. Our method was 100% concordant with a gel-based method and 99.9% concordant with presence and absence determination by NGS. The limit of detection for accurate typing was 30 ng of DNA (0.42 μM) with 260/230 and 260/280 ratios as low as 0.19 and of 0.44. In addition, we developed a user-friendly Java-based computational application called killerPeak that interprets the raw data generated by Viia7 or QuantStudio 7 quantitative PCR machines and reliably exports the final genotyping results in spreadsheet file format. The combination of a reliable method that requires low amount of DNA with an automated interpretation of results allows scaling the KIR genotyping in large cohorts with reduced turnaround time.
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http://dx.doi.org/10.1111/tan.13430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6433384PMC
December 2018

Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop.

Hum Immunol 2018 Dec 12;79(12):825-833. Epub 2018 Oct 12.

Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address:

The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3 ∼ KIR3DL1/S1 ∼ KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.
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http://dx.doi.org/10.1016/j.humimm.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322681PMC
December 2018

Southern Bahia, Brazil: KIR gene-content distribution in the highly admixed population from Ilhéus.

Hum Immunol 2018 Dec 22;79(12):823-824. Epub 2018 Sep 22.

Departamento de Genética, Universidade Federal do Paraná, Curitiba, Brazil; Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil. Electronic address:

We here describe the KIR gene-content genotypes in the highly admixed population from Ilhéus, a city located in Bahia State, Northeast Brazil. Bahia is the State with the largest contribution of African ethnicity in comparison to other Brazilian areas and this is the first report of a population from this region. A total of 32 KIR gene-content genotypes have been found, from which 18 were observed in single individuals. The distinct KIR gene-content distribution observed in Ilhéus, along with the elevated diversity of genotypes point to importance of describing KIR polymorphism in unique populations from Brazil.
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http://dx.doi.org/10.1016/j.humimm.2018.09.006DOI Listing
December 2018

Screening the full leucocyte receptor complex genomic region revealed associations with pemphigus that might be explained by gene regulation.

Immunology 2019 01 11;156(1):86-93. Epub 2018 Oct 11.

Laboratory of Human Molecular Genetics, Department of Genetics, Federal University of Paraná, Curitiba, Brazil.

Pemphigus foliaceus (PF) is a blistering autoimmune skin disease rare in most of the world but endemic in certain regions of Brazil. PF is characterized by the detachment of epidermal cells and the presence of autoantibodies against desmoglein 1. In previous studies, we have shown that genetic polymorphisms and variable expression levels of certain leucocyte receptor complex (LRC) genes were associated with PF. However, the role of the LRC on PF susceptibility remained to be investigated. Here, we analysed 527 tag single nucleotide polymorphisms (SNPs) distributed within the 1·5 Mb LRC. After quality control, a total of 176 SNPs were analysed in 229 patients with PF and 194 controls. Three SNPs were associated with differential susceptibility to PF. The intergenic variant rs465169 [odds ratio (OR) = 1·50; P = 0·004] is located in a region that might regulate several immune-related genes, including VSTM1, LILRB1/2, LAIR1/2, LILRA3/4 and LENG8. The rs35336528 (OR = 3·44; P = 0·009) and rs1865097 (OR = 0·57; P = 0·005) SNPs in LENG8 and FCAR genes, respectively, were also associated with PF. Moreover, we found four haplotypes with SNPs within the KIR3DL2/3, LAIR2 and LILRB1 genes associated with PF (P < 0·05), which corroborate previously reported associations. Thus, our results confirm the importance of the LRC for differential susceptibility to PF and reveal new markers that might influence expression levels of several LRC genes, as well as candidates for further functional studies.
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http://dx.doi.org/10.1111/imm.13003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283660PMC
January 2019

Trichoderma asperelloides ethanolic extracts efficiently inhibit Staphylococcus growth and biofilm formation.

PLoS One 2018 24;13(8):e0202828. Epub 2018 Aug 24.

Laboratório de Imunobiologia, Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil.

Fungi from the widely distributed genus Trichoderma are of great biotechnological interest, being currently used in a vast range of applications. Here, we report that high-molecular weight fraction (HWF) derived from Trichoderma asperelloides ethanolic extract exhibits antibiotic activity against staphylococcal biofilms. The antibacterial and anti-biofilm properties of T. asperelloides extracts were evaluated by well-established assays in Staphylococcus aureus ATCC strains (29213 and 6538) and in one clinical isolate from bovine mastitis. The HWF from T. asperelloides eradicated S. aureus by causing substantial matrix de-structuring and biomass reduction (p < 10-5) at concentrations as low as 2.3 μg mL-1. Additionally, we present ultra-structure analysis by the use of scanning electron microscopy as well as transmission microscopy, which showed that T. asperelloides killed cells through cell wall and membrane disturbance. Remarkably, the HWF from T. asperelloides killed S. aureus and eradicated its biofilms in a greater performance than gentamicin (p < 10-5), a known potent antibiotic against S. aureus. Our results indicate that extract from T. asperelloides may represent a promising candidate for the development of new antibiotics against gram-positive bacteria.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202828PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108504PMC
February 2019

Sparking Fire Under the Skin? Answers From the Association of Complement Genes With Pemphigus Foliaceus.

Front Immunol 2018 9;9:695. Epub 2018 Apr 9.

Laboratory of Human Molecular Genetics, Department of Genetics, Universidade Federal do Paraná, Curitiba, Brazil.

Skin blisters of pemphigus foliaceus (PF) present concomitant deposition of autoantibodies and components of the complement system (CS), whose gene polymorphisms are associated with susceptibility to different autoimmune diseases. To investigate these in PF, we evaluated 992 single-nucleotide polymorphisms (SNPs) of 44 CS genes, genotyped through microarray hybridization in 229 PF patients and 194 controls. After excluding SNPs with minor allele frequency <1%, out of Hardy-Weinberg equilibrium in controls or in strong linkage disequilibrium ( ≥ 0.8), 201 SNPs remained for logistic regression. Polymorphisms of 11 genes were associated with PF. encodes a crucial serine protease of the lectin pathway (rs13094773: OR = 0.5,  = 0.0316; rs850309: OR = 0.23,  = 0.03; rs3864098: OR = 1.53,  = 0.0383; rs698104: OR = 1.52,  = 0.0424; rs72549154: OR = 0.55,  = 0.0453). (rs187875: OR = 1.46,  = 0.0189; rs700218: OR = 0.12,  = 0.0471) and (rs11206934: OR = 4.02,  = 0.0323) encode proteins of the membrane attack complex (MAC) and (rs10404456: OR = 1.43,  = 0.0155), a potent anaphylatoxin-receptor. Two encode complement regulators: MAC-blocking CD59 (rs1047581: OR = 0.62,  = 0.0152) and alternative pathway-blocking CFH (rs34388368: OR = 2.57,  = 0.0195). One encodes opsonin: (rs4807895: OR = 2.52,  = 0.0239), whereas four encode receptors for C3 fragments: (haplotype with rs6656401: OR = 1.37,  = 0.0382), (rs2182911: OR = 0.23,  = 0.0263), (CR3, rs12928810: OR = 0.66,  = 0.0435), and (CR4, rs11574637: OR = 0.63,  = 0.0056). Associations reinforced former findings, regarding differential gene expression, serum levels, C3, and MAC deposition on lesions. Deregulation of previously barely noticed processes, e.g., the lectin and alternative pathways and opsonization-mediated phagocytosis, also modulate PF susceptibility. The results open new crucial avenues for understanding disease etiology and may improve PF treatment through additional therapeutic targets.
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http://dx.doi.org/10.3389/fimmu.2018.00695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5900433PMC
June 2019

KIR-HLA distribution in a Vietnamese population from Hanoi.

Hum Immunol 2018 Feb 27;79(2):93-100. Epub 2017 Nov 27.

Laboratório de Genética Molecular Humana, Universidade Federal do Paraná, Curitiba, Brazil; Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Brazil. Electronic address:

The KIR (killer cell immunoglobulin-like receptors) gene family codifies a group of receptors that recognize human leukocyte antigens (HLA) and modulate natural killer (NK) cells response. Genetic diversity of KIR genes and HLA ligands has not yet been deeply investigated in South East Asia. Here, we characterized KIR gene presence and absence polymorphism of 14 KIR genes and two pseudogenes, as well as the frequencies of the ligands HLA-Bw4, HLA-C1 and HLA-C2 in a Vietnamese population from Hanoi (n = 140). Genotyping was performed by polymerase chain reaction with specific sequence primers (PCR-SSP). We compared KIR frequencies and performed principal component analysis with 43 worldwide populations of different ancestries. KIR carrier frequencies in Vietnamese were similar to those reported for Thai and Chinese Han, but differed significantly from other geographically close populations such as Japanese and South Korean. This similarity was also observed in KIR gene-content genotypes and is in accordance with the origin from Southern China and Thailand proposed for the Vietnamese population. The frequencies of HLA ligands observed in Vietnamese did not differ from those reported for other East-Asian populations (p > .05). Studies regarding KIR-HLA in populations are of prime importance to understand their evolution, function and role in diseases.
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http://dx.doi.org/10.1016/j.humimm.2017.11.011DOI Listing
February 2018

Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for Class I Genes.

J Immunol 2017 03 1;198(6):2320-2329. Epub 2017 Feb 1.

Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702;

Polymorphisms located within the have been linked to many disease outcomes by mechanisms not yet fully understood in most cases. Variants located within untranslated regions of genes are involved in allele-specific expression and may therefore underlie some of these disease associations. We determined sequences extending nearly 2 kb upstream of the transcription start site for 68 alleles from 57 major lineages of classical class I genes. The nucleotide diversity within this promoter segment roughly follows that seen within the coding regions, with showing the highest (∼1.9%), followed by (∼1.8%), and showing the lowest diversity (∼0.9%). Despite its greater diversity, mRNA expression levels determined in 178 European Americans do not vary in an allele- or lineage-specific manner, unlike the differential expression levels of or reported previously. Close proximity of promoter sequences in phylogenetic trees is roughly reflected by similarity of expression pattern for most and loci. Although promoter sequence divergence might impact promoter activity, we observed no clear link between the phylogenetic structures as represented by pairwise nucleotide differences in the promoter regions with estimated differences in mRNA expression levels for the classical class I loci. Further, no pair of class I loci showed coordinated expression levels, suggesting that distinct mechanisms across loci determine their expression level under nonstimulated conditions. These data serve as a foundation for more in-depth analysis of the functional consequences of promoter region variation within the classical class I loci.
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http://dx.doi.org/10.4049/jimmunol.1601679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340644PMC
March 2017

The Impact of KIR Polymorphism on the Risk of Developing Cancer: Not as Strong as Imagined?

Front Genet 2016 28;7:121. Epub 2016 Jun 28.

Laboratório de Genética Molecular Humana, Departamento de Genética, Universidade Federal do Paraná Curitiba, Brazil.

The polymorphism of killer cell immunoglobulin-like receptors (KIR) has been associated with several diseases, including infection, autoimmunity and cancer. KIR molecules are a family of receptors expressed on the surface of natural killer cells (NK), frontline defense of innate immunity against microorganisms and neoplastic cells. Some studies have shown conflicting results concerning the role that KIR polymorphism plays in tumor susceptibility, particularly in leukemia and lymphoma. Interestingly, the presence of HLA ligands is sometimes strongly associated with several types of cancer and apparently is not related with their interaction with KIR. This manuscript briefly reviews the uncommon polymorphism of KIR and critically summarizes the recent findings with regards of the importance of KIR variation for cancer susceptibility.
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http://dx.doi.org/10.3389/fgene.2016.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923111PMC
July 2016