scholarly journals Genetic variants in genes involved in the immune response and its allelic transmission for the first and second grade of consanguinity in families of patients with leprosy.

2015 ◽  
Vol 6 ◽  
Author(s):  
Cardona Pemberthy Viviana ◽  
Bedoya Berrio Gabriel ◽  
Cardona-Castro Nora
Keyword(s):  
Immune Response ◽  
Genetic Variants ◽  
Second Grade ◽  
Allelic Transmission

Abstract 161: Identification of Genetic Variants Associated with Kidney Injury That Leads to Increased Blood Pressure

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Ashlyn C Harmon ◽  
Ashley C Johnson ◽  
Santosh Atanur ◽  
Klio Maratou ◽  
Tim Aitman ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Bone Marrow ◽  
Immune Response ◽  
Renal Function ◽  
Kidney Disease ◽  
Kidney Function ◽  
Genetic Variants ◽  
Kidney Injury ◽  
Chromosome 11 ◽  
Genomic Locus

Hypertension, diabetes and obesity, along with genetic predisposition, contribute to the growing number of chronic kidney disease patients. Our novel congenic model [S.SHR(11)] was developed through genetic modification of the Dahl salt-sensitive (S) rat, a model of hypertension related renal disease. The S.SHR(11) strain exhibits accelerated kidney injury compared to the already highly susceptible S rat. On either a low or high-salt diet, the S.SHR(11) model predominately exhibited more tubulointerstitial fibrosis compared to the S rat (17.1±1.29% vs. 12.9±1.22%). Increased α-SMA and macrophage infiltration was also observed. The S and S.SHR(11) had similar blood pressure (week 12), despite an early reduction in renal function in the S.SHR(11); however at an advanced age the S.SHR(11) demonstrated significantly higher blood pressure than the S (215±6.6 mm Hg vs. 183±5.9, respectively). This suggests that increased kidney injury is driving the development of hypertension later in life. Since these two animal models are identical with exception of chromosome 11, the causative genetic variants contributing to decreased renal function must reside within this region. The Dahl S and SHR genomes have been sequenced; this data provides a catalog of all the genetic variants between the two models. The 95% confidence interval of the genomic locus contains 28 non-synonymous SNP, with 15 of these SNP occurring within only three genes: Retnlg , Trat1 and Myh15. Two of these genes, Retnlg and Trat1, are known to play a role in immune response leading to our hypothesis that genetic variants in these genes alter protein function and lead to an increased immune response. Bone marrow transplant studies have been initiated to test our hypothesis and preliminary data shows that S rats who receive S.SHR(11) bone marrow have kidney function measurements similar to the S.SHR(11). The sequencing information has also lead to the development of nine new, more refined congenic strains. Through functional analysis of these new congenic animals, identification of the causative genetic variations will be expedited. In summary, we are employing a model of accelerated kidney disease to identify genes or genetic variants responsible for reduced kidney function and hypertension.

scholarly journals Genetic polymorphisms mediating behavioural and immune response to pathogens may moderate the impact of the COVID-19 pandemic: a pilot study

2020 ◽  
Author(s):  
Ravi Philip Rajkumar
Keyword(s):  
Immune Response ◽  
Pilot Study ◽  
Immune Responses ◽  
Genetic Variants ◽  
Mortality Rates ◽  
Therapeutic Strategies ◽  
Published Data ◽  
Entire World ◽  
S Allele ◽  
The Impact

AbstractBackgroundThe COVID-19 pandemic has affected the entire world, but there are wide variations in prevalence and mortality across nations. Genetic variants which influence behavioural or immune responses to pathogens, selected for by pathogen pressure, may influence this variability. Two relevant polymorphisms in this context are the s allele of the serotonin transporter promoter (5-HTTLPR) and the G allele of the interleukin-6 gene (IL-6 rs1800795).MethodsThe frequencies of the 5-HTTLPR s allele and IL-6 rs1800795 G allele were obtained from published data. The correlations between these allele frequencies and the prevalence and mortality rates of COVID-19 were examined across 44 nations.ResultsThe IL-6 rs1800795 G allele was negatively correlated with COVID-19 prevalence (ρ = −0.466, p < 0.01) and mortality (ρ = −0.591, p<0.001) across nations. The 5-HTTLPR s allele was negatively correlated with COVID-19 mortality rates (ρ = −0.437, p = 0.023).ConclusionsThese results suggest that a significant relationship exists between genetic variants that influence behavioural and immune responses to pathogens and indices of the impact of COVID-19 across nations. Further investigation of these variants and their correlates may permit the development of better preventive or therapeutic strategies in the management of the COVID-19 pandemic.

Association Between Genetic Variants in Immune Response Genes and Outcomes After Hematopoietic Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3049-3049
Author(s):  
Bharat Thyagarajan ◽  
Scott Jackson ◽  
Saonli Basu ◽  
Pamala A. Jacobson ◽  
Myron D Gross ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Genetic Variants ◽  
Acute Gvhd ◽  
Cytokine Response ◽  
Innate Immune ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Allogeneic Hct ◽  
Increased Risk

Abstract Abstract 3049 Background: Despite rapid advances in allogeneic hematopoietic cell transplant (HCT) techniques, the procedure continues to be associated with a high morbidity and mortality with transplant related mortality (TRM) ranging from 15% to as high as 50%. Acute graft versus host disease (GvHD) remains a major cause of morbidity and an important cause of early TRM in patients undergoing allogeneic HCT. Though variations in major histocompatibiliy (MHC) genes are well known determinants of acute GvHD, there is increasing evidence that genetic variation in immune/cytokine response pathways also contributes significantly to the pathogenesis of acute GvHD. Methods: We evaluated the association of single nucleotide polymorphisms (SNPs) in non-MHC dependent immune/cytokine response pathways (n= 77 SNPs in recipients and donors) with acute GvHD and TRM at one year in a cohort of 425 recipient-donor pairs who underwent allogeneic HCT for treatment of hematologic malignancies at the University of Minnesota between 1998 and 2007. We used a Fine and Gray proportional hazards model adjusted for competing risk to evaluate the association between the genetic variants and time to acute GvHD and time to TRM. Results: After adjustment for recipient age at transplant, race, diagnosis, disease status at transplant, gender mismatch, CMV serostatus of recipient and donor, recipient and donor sex, donor type, conditioning regimen (myeloablative or reduced intensity) and year of transplant, one recipient SNP, rs646005 in the TIRAP gene and one donor SNP, rs2232596 in the LBP gene were marginally associated with increased risk for grade II-IV acute GvHD (Hazard ratio (HR) = 1.33 (95% Confidence interval (CI): 1.07 – 1.62) and 1.32 (1.07 – 1.66) respectively; p =0.01). Similar analyses for TRM showed recipient SNP rs5498 in the ICAM1 gene was associated with a decreased risk of TRM (HR: 0.67(95% CI: 0.50 – 0.89); p=0.0006) while recipient SNPs rs1739654 in the LBP gene and rs3804100 in the TLR2 gene were associated with an increased TRM risk (HR: 1.86 (95% CI: 1.16 – 2.97) and 1.66 (95% CI: 1.11 – 2.48) respectively; p =0.01). Conclusions: These findings are consistent with previous reports that support a role for genetic variants in the innate immune response pathways among both recipients and donors can influence the risk of acute GvHD and TRM among patients undergoing allogeneic HCT. These findings indicate that a systematic search for genetic variants in the innate immune response pathways may identify novel biomarkers that can be used to identify patients at high risk for acute GvHD and TRM. Disclosures: Weisdorf: Genzyme: Consultancy, Research Funding.

scholarly journals Novel TNIP2 and TRAF2 Variants Are Implicated in the Pathogenesis of Pulmonary Arterial Hypertension

2021 ◽  
Vol 8 ◽  
Author(s):  
Shaun Pienkos ◽  
Natalia Gallego ◽  
David F. Condon ◽  
Alejandro Cruz-Utrilla ◽  
Nuria Ochoa ◽  
...  
Keyword(s):  
Immune Response ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Vascular Remodeling ◽  
Biliary Cirrhosis ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial ◽  
The Impact ◽  
Healthy Lung

Background: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary vascular remodeling and right heart failure. Specific genetic variants increase the incidence of PAH in carriers with a family history of PAH, those who suffer from certain medical conditions, and even those with no apparent risk factors. Inflammation and immune dysregulation are related to vascular remodeling in PAH, but whether genetic susceptibility modifies the PAH immune response is unclear. TNIP2 and TRAF2 encode for immunomodulatory proteins that regulate NF-κB activation, a transcription factor complex associated with inflammation and vascular remodeling in PAH.Methods: Two unrelated families with PAH cases underwent whole-exome sequencing (WES). A custom pipeline for variant prioritization was carried out to obtain candidate variants. To determine the impact of TNIP2 and TRAF2 in cell proliferation, we performed an MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay on healthy lung pericytes transfected with siRNA specific for each gene. To measure the effect of loss of TNIP2 and TRAF2 on NF-kappa-beta (NF-κB) activity, we measured levels of Phospho-p65-NF-κB in siRNA-transfected pericytes using western immunoblotting.Results: We discovered a novel missense variant in the TNIP2 gene in two affected individuals from the same family. The two patients had a complex form of PAH with interatrial communication and scleroderma. In the second family, WES of the proband with PAH and primary biliary cirrhosis revealed a de novo protein-truncating variant in the TRAF2. The knockdown of TNIP2 and TRAF2 increased NF-κB activity in healthy lung pericytes, which correlated with a significant increase in proliferation over 24 h.Conclusions: We have identified two rare novel variants in TNIP2 and TRAF2 using WES. We speculate that loss of function in these genes promotes pulmonary vascular remodeling by allowing overactivation of the NF-κB signaling activity. Our findings support a role for WES in helping identify novel genetic variants associated with dysfunctional immune response in PAH.

scholarly journals Polymorphisms in STING affect human innate immune responses to poxviruses

2020 ◽  
Author(s):  
Richard B. Kennedy ◽  
Iana H. Haralambieva ◽  
Inna G. Ovsyannikova ◽  
Emily A. Voigt ◽  
Beth R. Larrabee ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Modeling ◽  
Immune Responses ◽  
Genetic Variants ◽  
Innate Immune ◽  
Smallpox Vaccination ◽  
Type I ◽  
Innate Immune Responses ◽  
Dna Viruses

AbstractWe conducted a large genome-wide association study (GWAS) of the immune responses to primary smallpox vaccination in a combined cohort of > 1,600 subjects. We identified a cluster of SNPs on chromosome 5 (5q31.2) that were significantly associated (p-value: 1.3 × 10−12 – 1.5×10−36) with IFNα response to in vitro poxvirus stimulation. Examination of these SNPs led to the functional testing of rs1131769, a non-synonymous SNP in TMEM173 causing an Arg-to-His change at position 232 in the STING protein—a major regulator of innate immune responses to viral infections. Our findings demonstrate important functional differences between the two alleles, where the major allele (R232) more effectively induces IFNα secretion. Molecular modeling of both alleles identified altered ligand binding characteristics between the two variants, providing a potential mechanism underlying differences in inter-individual responses to poxvirus vaccination. Our data demonstrate that possession of the H232 variant impairs STING-mediated innate immunity to poxviruses. These results clarify prior studies evaluating functional effects of genetic variants in TMEM173 and provide novel data regarding genetic control of poxvirus immunity.Contribution to the FieldHere we report that a single nucleotide non-synonymous polymorphism in the TMEM173 gene encodes for a STING variant conferring a reduced IFN stimulated response compared to wild type. Our results suggest that, upon binding of the STING H232 variant to its ligand, activation of downstream signaling proteins is impaired, resulting in decreased production of IFNα and a weaker interferon-stimulated gene response. Molecular modeling indicates that the diminished functional activity of this variant is likely due to an altered physical structure of the STING protein. STING controls the innate, type I IFN response to double-stranded DNA and cyclic dinucleotides. Individuals with the H232 variant of STING have a much weaker innate immune response to vaccinia virus. Our data help resolve ongoing controversies regarding the role of genetic variants in STING function. Because STING plays an important role in our immune response to DNA viruses and bacteria, our results can be used to predict who will and will not respond to vaccines and treatments, and to design more effective vaccine candidates. Given the role of the STING protein in innate responses to DNA viruses and bacterial pathogens, these data may also be useful in developing novel treatment options for multiple infectious diseases.

scholarly journals Immune Checkpoint Molecules—Inherited Variations as Markers for Cancer Risk

2021 ◽  
Vol 11 ◽  
Author(s):  
Marta Wagner ◽  
Monika Jasek ◽  
Lidia Karabon
Keyword(s):  
Immune Response ◽  
Cancer Risk ◽  
Immune Cells ◽  
Genetic Variants ◽  
Expression Patterns ◽  
Predictive Biomarkers ◽  
Amino Acid Sequences ◽  
Immune Checkpoints ◽  
Clinical Effects ◽  
Potential Factors

In recent years, immunotherapy has been revolutionized by a new approach that works by blocking receptors called immune checkpoints (IC). These molecules play a key role in maintaining immune homeostasis, mainly by suppressing the immune response and by preventing its overactivation. Since inhibition of the immune response by IC can be used by cancer to avoid recognition and destruction by immune system, blocking them enhances the anti-tumor response. This therapeutic approach has brought spectacular clinical effects. The ICs present heterogeneous expression patterns on immune cells, which may affect the effectiveness of immunotherapy. The inherited genetic variants in regulatory regions of ICs genes can be considered as potential factors responsible for observed inter-individual differences in ICs expression levels on immune cells. Additionally, polymorphism located in exons may introduce changes to ICs amino acid sequences with potential impact on functional properties of these molecules. Since genetic variants may affect both expression and structure of ICs, they are considered as risk factors of cancer development. Inherited genetic markers such as SNPs may also be useful in stratification patients into groups which will benefit from particular immunotherapy. In this review, we have comprehensively summarized the current understanding of the relationship between inherited variations of CTLA-4, PDCD1, PD-L1, BTLA, TIM-3, and LAG-3 genes in order to select SNPs which can be used as predictive biomarkers in personalized evaluation of cancer risk development and outcomes as well as possible response to immunotherapy.

scholarly journals Genes of different molecular classes and their relationship with type 1 diabetes an age of manifestation

2020 ◽  
pp. 89-91
Author(s):  
Н.В. Тарасенко ◽  
И.А. Гончарова ◽  
А.В. Марков ◽  
Е.И. Кондратьева ◽  
Л.В. Спирина ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Immune Response ◽  
Type 1 Diabetes ◽  
Genetic Variants ◽  
Metabolic Pathways ◽  
Age Of Onset ◽  
Healthy Population ◽  
Sequenom Massarray ◽  
Different Ages

В работе изучена генетическая составляющая возраста манифестации сахарного диабета 1-го типа (СД1). В общей группе больных СД1 (n=330), а также в подгруппах с разным возрастом манифестации СД1 (до 30 лет, n=269, с 31 года, n=61) и популяционной выборке (n=289) изучено 58 однонуклеотидных полиморфизмов (SNPs), локализованных в 47 генах, продукты которых участвуют в различных метаболических путях и вовлечены в процессы фиброгенеза, эндотелиальную дисфункцию, иммунный ответ и воспаление. Генотипирование выполнено методом масс-спектрометрии на приборе «Sequenom MassARRAY» (США). В результате выявлена ассоциация с возрастом манифестации СД1 до 30 лет rs1007856 гена ITGB5 (генотип TT, р=0,02), rs3765124 гена ADAMDEC1 (генотип AA, р=0,01). При сравнении подгрупп СД1 с разным возрастом манифестации отличия получены для rs1107946 гена COL1A1 (генотип AA, р=0,03) и rs514921 гена MMP1 (генотип AA, р=0,03). Гены, SNPs которых показали ассоциацию с возрастом манифестации СД1, кодируют белковые продукты, вовлеченные в метаболизм экстрацеллюлярного матрикса и коллагена. Данные варианты могут рассматриваться в качестве маркеров возраста дебюта СД1. We have studied the genetic component of the age of onset of type 1 diabetes (T1D). We examined a group of patients with T1D (n = 330), which was divided into subgroups with different ages of manifestation of T1D (up to 30 years, n = 269, from 31 years old, n=61). A total of 289 healthy population individuals were enrolled in this study. We studied 58 SNPs of 47 genes whose products are involved in various metabolic pathways as well as fibrogenesis, endothelial dysfunction, the immune response and inflammation. We performed genotyping by mass spectrometry using a Sequenom MassARRAY (USA). As a result, we identified an association with the manifestation age of T1D up to 30 years for rs1007856 of the gene ITGB5 (genotype TT, p=0,02), rs3765124 of the gene ADAMDEC1 (genotype AA, p=0,01). Differences received when comparing subgroups of T1D with different ages of manifestation: for rs1107946 of the gene COL1A1 (genotype AA, p=0,03) and rs514921 of the gene MMP1 (genotype AA, p=0,03). Genes whose SNPs have been associated with an age of manifestation of T1D are involved in the metabolism of extracellular matrix and collagen. Identified genetic variants can be considered as markers of the age of onset of T1D.

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