Variants In Immune Response Genes Research Articles

Identifying Rare Genetic Variants of Immune Mediators as Risk Factors for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects more than 1% of children, and there is no viable pharmacotherapeutic agent to treat the core symptoms of ASD. Studies have shown that children with ASD show changes in their levels of immune response molecules. Our previous studies have shown that ASD is more common in children with folate receptor autoantibodies. We also found that children with ASD have abnormal gut immune function, which was characterized by a significant increase in the content of immunoglobulin A and an increase in gut-microbiota-associated epitope diversity. These studies suggest that the immune mechanism plays an important role in the occurrence of ASD. The present study aims to systematically assess gene mutations in immune mediators in patients with ASD. We collected genetic samples from 72 children with ASD (2–12 years old) and 107 healthy controls without ASD (20–78 years old). We used our previously-designed immune gene panel, which can capture cytokine and receptor genes, the coding regions of MHC genes, and genes of innate immunity. Target region sequencing (500×) and bioinformatics analytical methods were used to identify variants in immune response genes associated with patients with ASD. A total of 4 rare variants were found to be associated with ASD, including HLA-B: p.A93G, HLA-DQB1: p.S229N, LILRB2: p.R322H, and LILRB2: c.956-4C>T. These variants were present in 44.44% (32/72) of the ASD patients and were detected in 3.74% (4/107) of the healthy controls. We expect these genetic variants will serve as new targets for the clinical genetic assessment of ASD, and our findings suggest that immune abnormalities in children with ASD may have a genetic basis.

Immune Response and Lipid Metabolism Gene Polymorphisms Are Associated with the Risk of Obesity in Middle-Aged and Elderly Patients.

More than two billion people around the world are overweight or obese. Even in apparently healthy people, obesity has a potent effect on their quality of life. Experimental data indicate the role of infectious agents in systemic inflammation, revealing a correlation between the dietary habits of people with obesity and the level of systemic inflammation mediators, serum lipid concentration, and hormonal and immune status. This study aimed to determine the association of immune response and lipid metabolism gene polymorphisms with the risk of obesity. This study included 560 Caucasian participants living in Western Siberia (Russian Federation). A total of 52 polymorphic sites in 20 genes were analyzed using the 5′ TaqMan nuclease assay. Four risk-associated polymorphic variants were discovered—two variants in immune response genes (IL6R rs2229238, OR = 1.92, 95% CI = 1.36–2.7, p = 0.0002 in the dominant model; IL18 rs1946518, OR = 1.45, 95% CI = 1.03–2.04, p = 0.033 in the over-dominant model) and two variants in lipid metabolism genes (LPA rs10455872, OR = 1.86, 95% CI = 1.07–3.21, p = 0.026 in the log-additive model; LEPR rs1137100, OR = 2.88, 95% CI = 1.52–5.46, p = 0.001 in the recessive model). Thus, polymorphisms in immune response and lipid metabolism genes are potentially associated with the modification of obesity risk in the Caucasian population.

Single nucleotide variants in immune-response genes and the tumor microenvironment composition predict progression of mantle cell lymphoma

BackgroundThere is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients’ samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL.MethodsWe assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models.ResultsHigh FOXP3/CD3 ratios (p = 0.001), high IL17A levels (p = 0.003) and low IL2 levels (p = 0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p = 0.02). In the SNV model, the CC haplotype of IL10 (p < 0.01), the GG genotype of IL2 rs2069762 (p = 0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p < 0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGFβ levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients’ survival.ConclusionsOur results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations.

An Immunological Perspective to Non-syndromic Sensorineural Hearing Loss.

Conventionally the etiology of congenital Non-Syndromic Hearing Loss has been attributed to mutations in the genes involved in ion homeostasis or the structural compartments of the inner ear. However, this contributes to only a part of the problem, as still the determinants for a large majority of the Non-Syndromic Hearing loss seems to be an enigma. Evidences indicate that pathogens like Rubella, Cytomegalovirus, and many other infections can also result in congenital hearing loss. Additionally, there are variety of factors other than the viral mediators, that can act as stressors to trigger an altered immune response, during the gestational period of the mother. It is also known that non-specific stimulation of the immune system can mimic an infection status. This indicates a strong role for environmental factors toward their contribution to the pathology, possibly by influencing the host immune response. These varieties of known or unknown environmental factors interact with the susceptible variants in immune response genes in defining the threshold for protection or infection in an individual. Considering this background we propose to present this perspective that threshold of the host immune response during the prenatal conditions, in response to environmental stimulus, might be determined by the susceptible variants in immune response genes. This in turn can directly or indirectly influence the genes involved in maintaining the structural components or ion homeostasis, resulting in hearing loss. The threshold of immune response alterations may be heavily dependent on the immunogenetic profile of the mother or the fetus.

Polymorphic Variants of Immune Response Genes as a Risk Factor for the Development of Primary Progressive Multiple Sclerosis

Objectives. To analyze the involvement of immune response genes in the pathogenesis of primary progressive multiple sclerosis (PPMS). Materials and methods. A representative cohort of 111 ethnically Russian patients with PPMS took part in a multicenter study. The involvement of immune system genes in the pathogenesis of PPMS was analyzed by investigating the associations of variants of cytokines genes and genes involved in antigen processing and presentation by antigen-presenting cells with the disease. Results and conclusions. Carriership of the IL4 genotype (rs2243250)*C/C and CLEC16A (rs6498169)*G/G was found to have a positive association with the development of PPMS in Russian patients. The association described in studies of other populations, HLA-DRB1*15 with a high risk of developing this form of MS, was confirmed.

Allelic variants of immune response genes in children with infectious complications during the treatment of acute leukemia

Infectious complications that arise during the treatment of children with acute leukemia with chemotherapeutic agents at high doses represent a serious problem in oncohematology. To find genetic conditions that may lead to the development of postchemotherapy infections, the genomes of 12 children with acute leukemia who had severe infectious complications during therapy were examined. At the same time, the coding regions of 17 genes involved in the regulation of the immune response were determined by massive parallel sequencing. The analysis revealed 39 nonsynonymous SNPs that lead to amino acid substitutions, including the following informative genetic markers: PTPN22 c.1858C>T (rs2476601), TLR4 c.896A>G (rs4986790) and TLR4 c.1196C>T (rs4986791), IL7R c.197T>C (rs1494555) and IL7R c.412G>A (rs1494558). The results of massive parallel sequencing were validated by Sanger sequencing. The identification of genetic markers associated with the predisposition to infectious complications may allow one to assess the individual risk of the severe infection development in children with acute leukemia during the treatment with chemotherapeutic agents and to begin the development of personalized approaches to anticancer therapy.

Allelic variants of immune response genes in children with infectious complications during the treatment of acute leukemia

Allelic variants of immune response genes in children with infectious complications during the treatment of acute leukemia

Genetic variants in immune response genes to predict clinical outcome in mCRC patients treated with FOLFIRI/cetuximab (FIRE-3) or with first line cetuximab-based chemotherapy (JACCRO CC-05/06 AR).

3595Background: Cetuximab can exert its anti-tumor mechanisms by stimulating of the immune system via ADCC (antibody-dependent cell-mediated cytotoxicity). Immune response through T-cell activation...

Abstract T P154: Association of Common Variants in Immune Response Genes with Severity of Familial Cerebral Cavernous Malformation Type 1

Objective: Familial Cerebral Cavernous Malformation type 1 (fCCM1) is an autosomal dominant disease caused by KRIT1 mutations and characterized by brain lesions, which increase in number over time for unknown reasons. Inflammation and altered expression of immune response genes have been observed in human CCM lesions. We investigated whether common variants in immune response genes are associated with fCCM1 disease severity, as manifested by greater lesion burden. Methods: Lesion burden was assessed on susceptibility-weighted MR imaging for 178 fCCM1 subjects, all carriers of the founder common Hispanic mutation (CHM, Q455X in KRIT1 ) and recruited as part of the Brain Vascular Malformation Consortium study. We selected 321 variants in 12 immune response genes up-regulated in human CCM lesions and represented on the Affymetrix Axiom® Genome-Wide LAT-1 Human Array. Linear regression analyses under an additive model were performed to assess association of genotype with log-lesion burden residuals, after adjustment for age at enrollment and gender. P -values were generated using 100,000 permutations to account for family structure and multiple testing. Results: Lesion burden (range: 0-713; mean ± SD: 60.5 ± 116.3) was highly variable. The minor alleles at rs2272022 ( CD200 ), rs75223220 ( CD68 ), rs57767447 and rs12587347 ( IGH ), and rs13053345 ( IGL ) were associated with more lesions (≥32%, P &lt;0.05) at baseline, independent of age and gender. The minor alleles at rs7639471 ( CD200 ), rs9901675 ( CD68 ), rs5759959 ( GUSP11 ), rs10147756 and rs7144404 ( IGH ), and rs987710 ( IGL ) were associated with fewer lesions (≤45%, P &lt;0.05). Variants in CD247 , CD3G , HLA-DRB1 , IGJ , LOC390714 , MS4A1 and SDC1 were not significantly associated with lesion burden. Conclusions: Several common variants in immune response genes are associated with lesion burden in fCCM1-CHM subjects. Further studies are needed to confirm whether CD200, CD68, GUSP11, IGH and IGL genes influence fCCM1 disease severity.

Use of genetic variants in immune response genes to predict clinical outcome in mCRC patients treated with cetuximab-based therapy.

3567 Background: Cetuximab is a monoclonal antibody targeting the EGF receptor. One of its anti-tumor mechanisms is the stimulation of the immune system via ADCC (Antibody-Dependent-Cell mediated Cytotoxicity). Immune response through T-cell activation may also play a role in antitumor efficacy of chemotherapy. CTLA4, PDL1, IDO1 and CD24 are inhibitory co-receptors or ligands that may downregulate the immune system through suppression of T-cell response. We tested whether Germline polymorphisms in these genes are involved in the cetuximab dependent immune response pathway and thus predict outcome in mCRC patients treated with cetuximab. Methods: DNA was isolated from blood of 108 patients with mCRC treated with either irinotecan+cetuximab (n=73) or single agent cetuximab (n=35). Twelve prospectively functionally relevant SNPs; IDO1(rs9657182, rs3739319, rs1010866), PD1(rs2227981, rs7421861), PDL1(rs2297137, rs2297136, rs10122089, G&gt;C), CTLA4(rs231777, rs231775), and CD24(rs8734) were analyzed by PCR-based direct sequencing and evaluated for association with tumor response, overall survival (OS), and progression free survival (PFS). Results: Results are attached. There were 65 men and 43 women with a median PFS of 3.7 (95%CI: 2.8, 4.6) months and a median OS of 10.5 (95%CI:7.7, 13.3) months. Median follow up was 16.3 (range:1.2, 42.4) months. Conclusions: Our results show that immune response related SNPs may predict efficacy of cetuximab treatment in patients with mCRC. To the best of our knowledge this is the first data linking PDL1(rs2297137) to cetuximab efficacy in mCRC patients. [Table: see text]

Common SNPs within or near Three Immune Response Genes Implicated in the Risk of FVIII Immunogenicity in Hemophilia A Do Not Influence Steady-State Levels of Their Encoded mRNAs

AbstractAbstract 3366 Background/Aims:The hemophilia A (HA)-causing Factor (F)VIII gene (F8) mutation type is a well-established determinant of risk for the development of alloimmune inhibitors that neutralize replacement FVIII proteins in ∼20% of all HA patients. Studies have investigated variants of immune response genes to determine if they may account for the inter-individual variability in FVIII immunogenicity observed in patients with the same F8 abnormality, e.g., the intron-22 inversion. While some studies have found associations between inhibitor status and promoter polymorphisms in CTLA4, TNFA and/or IL10, others have not. If these promoter polymorphisms are indeed functional and truly influence inhibitor development, their alleles could modulate transcription initiation rates. The goal of this study was to investigate the possibility of cis-acting genotype-specific differences in mean steady-state mRNA levels encoded by CTLA4, TNFA and IL10. Methods:We examined the relationship of lymphocyte CTLA4, TNFA and IL10 mRNA levels with the genotypes of 265 SNPs located across their structural loci in 1189 Mexican American subjects in the San Antonio Family Heart Study. Expression profiles were generated using Illumina’s HWG-6 BeadChips and genotypes came from the Illumina OmniExpress-12 BeadChip. Measured genotype association analyses that accounted for non-independence of family members and employed an additive model (in which testing to determine whether gene expression varies by genotype, with the model constrained so that each “dose” of the minor allele raises or lowers gene expression by an equal amount “beta”) were performed using the software package SOLAR. P-values were calculated using a 1 degree-of-freedom chi-square test comparing the likelihood of a model where the change in expression levels by genotype is estimated to the likelihood of a model where beta is constrained to zero. Results:None of the 265 genotyped SNPs within or near these three genes (i.e., 49 SNPs in IL10, 35 SNPs in CTLA4 & 181 SNPs in TNFA) function as cis-acting regulatory variants, as no significant genotype-specific associations with these genes’ transcript levels were identified. Conclusions:We observed no evidence for cis-regulation of CTLA4, TNFA or IL10 in Mexican Americans, the largest and most rapidly growing minority population in the United States, despite having genotyped directly the previously implicated promoter polymorphisms in the current analysis (e.g., see Figure). Although Hispanic American HA patients were recently found to have a significantly higher risk for inhibitor development than White HA patients, it is possible that cis-acting functional variants in this minority population are rare and not well-represented by the common GWAS SNPs used for these analyses. Since linkage disequilibrium patterns between markers are population-specific, we are also currently genotyping these SNPs in a large cohort of African and Caucasian American HA patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

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

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.

Parental smoking impairs vaccine responses in children with atopic genotypes

Gene-environment interactions play central roles in controlling postnatal maturation of immune function, but their effects on infant vaccine responses are unknown. Genetic variants associated with atopy and the environmental factor of exposure to parental smoking (PS) of tobacco independently alter immune responses. We sought to investigate the hypothesis that genetic variants associated with atopy and their interaction with PS influence infant vaccine responsiveness. In 200 infants with parental atopic history, relationships were sought between polymorphisms in the IL-4, IL-4 receptor alpha (IL-4Ralpha), and IL-13 genes; PS; and immune responses to diphtheria/tetanus vaccination. Analyses stratified by PS unmasked negative associations between atopic alleles of these genes and vaccine outcomes. The most consistent involved the IL-4Ralpha 551 QR/QQ genotypes, which were associated with reduced IgG levels (P = .02) and T-cell responses (IFN-gamma, P = .002; IL-10, P = .01; 1L-13, P = .01; IL-5, P = .06) to tetanus toxoid and parallel reductions in polyclonal T-cell responses and innate immune responses in PS-exposed infants. PS potentiates suppressive effects of variants in immune response genes in children. These effects are not observed in the absence of this exposure. Ultimately, this finding might have implications for infant vaccination in countries with high smoking rates. It might also have broader implications in relation to environmental toxicology because it demonstrates specific mechanisms through which the developing immune system might be differentially sensitive to low-level toxicant exposures. PS interacts with genes associated with atopy to impair vaccine responses. These interactions might have vaccine design and public health implications.