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Two single nucleotide polymorphisms in IL13 and IL13RA1 from individuals with idiopathic Parkinson's disease increase cellular susceptibility to oxidative stress.

ABSTRACT: The human genes for interleukin 13 (IL-13) and its receptor alpha 1 (IL-13Rα1) are in chromosomal regions associated with Parkinson's disease (PD). The interaction of IL-13 with its receptor increases the susceptibility of mouse dopaminergic neurons to oxidative stress. We identified two rare single SNPs in IL13 and IL13RA1 and measured their cytotoxic effects. rs148077750 is a missense leucine to proline substitution in IL13. It was found in individuals with early onset PD and no other known monogenic forms of the disease and is significantly linked with PD (Fisher's exact test: p-value = 0.01, odds ratio = 14.2). rs145868092 is a leucine to phenylalanine substitution in IL13RA1 affecting a residue critical for IL-13 binding. Both mutations increased the cytotoxic activity of IL-13 on human SH-SY5Y neurons exposed to sublethal doses of hydrogen peroxide, t-butyl hydroperoxide or RLS3, an inducer of ferroptosis. Our data show that both rs148077750 and rs145868092 conferred a gain-of-function that may increase the risk of developing PD.

SUBMITTER: Aguirre CA

PROVIDER: S-EPMC9012133 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TLR4 polymorphisms may increase susceptibility to periodontitis in Pg-positive individuals.

Project description:ObjectiveTo investigate the correlation between the single nucleotide polymorphisms (SNPs) in the toll-like receptor 4 (TLR4) gene and the susceptibility to chronic periodontitis.Design241 Chinese subjects from the cohort of Beijing Shijingshan Community were recruited. Buccal swab samples, the whole unstimulated saliva and periodontal clinical parameters were collected. Human DNA extracted from buccal swab samples were used for genotyping eight SNPs of the TLR4 gene (rs11536889, rs1927906, rs1927911, rs2149356, rs4986790, rs4986791, rs2737190, rs787384) by the Sequenom MassARRAY system. Porphyromonas gingivalis (P. gingivalis) was detected from the deposition of the whole unstimulated saliva through polymerase chain reaction (PCR) method based on 16S rRNA. The correlation between SNPs of TLR4 and chronic periodontitis susceptibility in the whole subjects and the patients detected with P. gingivalis was investigated.ResultsThe variants of rs4986790 and rs4986791 were not found in 241 Chinese subjects. Moreover, there was no significant difference in the distribution of theother6 SNPs of TLR4 between groups of none/mild -periodontitis and moderate/severe-periodontitis subjects. When combined with P. gingivalis infection, rs1927911 (TT/CC+CT), rs2149356 (TT/GG+GT) and rs2737190 (GG/AA+AG) were independent risk factors of chronic periodontitis.ConclusionThree SNPs of TLR4, i.e., rs1927911 (TT/CC+CT), rs2149356 (TT/GG+GT) and rs2737190 (GG/AA+AG), were associated with moderate/severe chronic periodontitis in Chinese population infected with P. gingivalis. P. gingivalis, which interacted with TLR4 gene plays an important role in the pathogenesis of periodontitis.

| S-EPMC6875378 | biostudies-literature

Single nucleotide polymorphisms of let-7-related genes increase susceptibility to breast cancer.

Project description:BackgroundLet-7 is a microRNA (miRNA) that targets the β2 adrenergic receptor (ADRB2), hypoxia inducible factor 1 subunit alpha inhibitor (HIF1AN), and claudin 12 (CLDN12) genes. Single nucleotide polymorphisms (SNPs) in the structural or regulatory regions of these miRNA let-7-related genes may be associated with breast cancer carcinogenesis and prognosis. Low let-7 expression may increase breast cancer risk. We investigated the effects of let-7-related gene SNP (mirSNPs) on breast cancer risk and clinical outcomes.MethodsThe distribution frequencies of the three SNPs were genotyped in patients with breast cancer and controls. Multivariate logistic regression analysis was used to evaluate the association between the SNPs and susceptibility to breast cancer. We investigated the effects of these mirSNPs prospectively on disease-free survival (DFS) using the Kaplan-Meier method and the extended multivariate Cox model.ResultsWe found that rs1042713 in the ADRB2 gene and rs11292 in the 3'-UTR of the HIF1AN gene were associated with breast cancer susceptibility (P<0.05). The CLDN12 rs1017105 genotype was associated with estrogen receptor (P=0.031) and progesterone receptor status (P=0.007). The number of risk alleles was associated with estrogen receptor (P=0.034) status in breast cancer patients. In the survival analysis, the extended Cox model demonstrated that rs1042713 (P=0.000) and rs1017105 (P=0.004) were independent predictors of DFS. The number of risk alleles of the ADRB2, HIF1AN, and CLDN12 genes was an independent predictor of DFS (P<0.001).ConclusionLet-7-related mirSNPs might be associated with carcinogenesis and clinical outcome in breast cancer, suggesting that variants of miRNA let-7-related gene networks coregulate breast cancer characteristics.

| S-EPMC6456510 | biostudies-literature

Single nucleotide polymorphisms and cancer susceptibility.

Project description:A large number of genes associated with various cancer types contain single nucleotide polymorphisms (SNPs). SNPs are located in gene promoters, exons, introns as well as 5'- and 3'- untranslated regions (UTRs) and affect gene expression by different mechanisms. These mechanisms depend on the role of the genetic elements in which the individual SNPs are located. Moreover, alterations in epigenetic regulation due to gene polymorphisms add to the complexity underlying cancer susceptibility related to SNPs. In this systematic review, we discuss the various genetic and epigenetic mechanisms involved in determining cancer susceptibility related to various SNPs located in different genetic elements. We also discuss the diagnostic potential of these SNPs and the focus for future studies.

| S-EPMC5746410 | biostudies-other

Single Nucleotide Polymorphisms in Pediatric Idiopathic Nephrotic Syndrome.

Project description:Polymorphic variants in several molecules involved in the glomerular function and drug metabolism have been implicated in the pathophysiology of pediatric idiopathic nephrotic syndrome (INS), but the results remain inconsistent. We analyzed the association of eleven allelic variants in eight genes (angiopoietin-like 4 (ANGPTL4), glypican 5 (GPC5), interleukin-13 (IL-13), macrophage migration inhibitory factor (MIF), neural nitric oxide synthetase (nNOS), multidrug resistance-1 (MDR1), glucocorticoid-induced transcript-1 (GLCCI1), and nuclear receptor subfamily-3 (NR3C1)) in 100 INS patients followed up till adulthood. We genotyped variants using PCR and direct sequencing and evaluated estimated haplotypes of MDR1 variants. The analysis revealed few differences in SNP genotype frequencies between patients and controls, or in clinical parameters among the patients. Genotype distribution of MDR1 SNPs rs1236, rs2677, and rs3435 showed significant (p < 0.05) association with different medication regimes (glucocorticoids only versus glucocorticoids plus additional immunosuppressives). Some marginal association was detected between ANGPTL4, GPC5, GLCCI1, and NR3C1 variants and different medication regimes, number of relapses, and age of onset. Conclusion. While MDR1 variant genotype distribution associated with different medication regimes, the other analyzed gene variants showed only little or marginal clinical relevance in INS.

| S-EPMC4876225 | biostudies-literature

CHL1 gene polymorphisms increase lung cancer susceptibility.

Project description:Lung cancer represents a complex and malignant cancer. Close Homologue of L1 (CHL1) gene plays a crucial role in the progress of cancer. The aim of this study is to explore the association between CHL1 rs425366 polymorphism and lung cancer susceptibility in northeast of China. A hospital-based case-control study was carried out to collect relative characteristics. Logistic regression analysis was conducted to analyze the relationship between single nucleotide polymorphisms and lung cancer susceptibility. The results suggested that there was statistically significant difference between GT genotype and TT genotype of rs425366 and lung cancer susceptibility. In stratified analysis, TT genotype of rs425366 may increase the risk of lung adenocarcinoma. We also found that non-smoking individuals carrying T allele were more likely to develop lung cancer. Overall, our study may indicate that CHL1 gene may increase lung cancer susceptibility in northeast of China.

| S-EPMC5862597 | biostudies-literature

Single nucleotide polymorphisms and prostate cancer susceptibility.

Project description: Not available

| S-EPMC2615108 | biostudies-literature

Association of IL13 polymorphisms with susceptibility to myocardial infarction: A case-control study in Chinese population.

Project description:Inflammatory cytokines play a major role in the pathogenesis of myocardial infarction (MI). Although information on the importance of interleukin 13 (IL13) in human MI is limited, it has been well documented in the mouse model. Genetic variation in the IL13 gene has been associated with the structure and expression of the IL13. In the present study, we hypothesized that IL13 common genetic variants would be associated with a predisposition to the development of MI. The present study enrolled 305 MI patients and 310 matched healthy controls. Common genetic polymorphisms in the IL13 gene (rs20541, rs1881457, and rs1800925) were genotyped using the TaqMan SNP genotyping method. Plasma levels of IL13 were measured using an enzyme-linked immunosorbent assay (ELISA). In MI patients, minor alleles of the IL13 rs1881457 and rs1800925 polymorphisms were less common than in healthy controls [rs1881457: AC (P = 0.004, OR = 0.61), C (P = 0.001, OR = 0.66); rs1800925: CT (P = 0.006, OR = 0.59)]. Further haplotype analysis of three studied SNPs revealed a significant association with predisposition to MI. Interestingly, IL13 rs1881457 and rs1800925 were linked to plasma levels of IL13: the reference genotype had higher levels, heterozygotes were intermediate, and the alternate genotype had the lowest levels. In the Chinese population, IL13 (rs1881457 and rs180092) variants are associated with different plasma IL13 levels and offer protection against MI development. However, additional research is required to validate our findings in different populations, including descent samples.

| S-EPMC11293651 | biostudies-literature

Toll-like receptor 4 gene polymorphisms and susceptibility to juvenile idiopathic arthritis.

Project description:To determine if polymorphisms within the Toll-like receptor 4 (TLR4) gene are associated and linked with juvenile idiopathic arthritis (JIA). To investigate any possible gene-gene (epistatic) interaction between TLR4 and macrophage migration inhibitory factor (MIF) gene polymorphisms.313 simplex families (each containing one affected JIA proband) were genotyped. Two known functionally important single nucleotide polymorphisms (SNPs) within the TLR4 gene (Asp299Gly and Thr399Ile) were typed by SNaPshot ddNTP primer extension and capillary electrophoresis. Single point and multipoint transmission disequilibrium tests (TDT) were carried out through the extended TDT and TDT phase packages for the two TLR4 SNPs. Epistatic interaction between TLR4 haplotypes and the previously JIA associated MIF CATT(7)-MIF-173*C promoter haplotype was investigated by chi(2) test and unconditional logistic regression in Stata version 7.No distortion from random inheritance was observed by single point analysis for TLR4 Asp299Gly (p = 0.89) or TLR4 Thr399Ile (p = 0.40). Similarly, no distortion in transmission was seen when the TLR4 haplotypes were studied (p = 0.54). Additionally, no evidence for gene-gene interaction between TLR4 polymorphisms and the previously associated MIF gene polymorphisms was found (p = 0.40).No linkage or association was seen for Asp299Gly or Thr399Ile SNPs of TLR4 with JIA susceptibility. No evidence of an epistatic interaction between these TLR4 polymorphisms and MIF polymorphisms was found.

| S-EPMC1755476 | biostudies-other

TRPC6 single nucleotide polymorphisms and progression of idiopathic membranous nephropathy.

Project description:BackgroundActivating mutations in the Transient Receptor Potential channel C6 (TRPC6) cause autosomal dominant focal segmental glomerular sclerosis (FSGS). TRPC6 expression is upregulated in renal biopsies of patients with idiopathic membranous glomerulopathy (iMN) and animal models thereof. In iMN, disease progression is characterized by glomerulosclerosis. In addition, a context-dependent TRPC6 overexpression was recently suggested in complement-mediated podocyte injury in e.g. iMN. Hence, we hypothesized that genetic variants in TRPC6 might affect susceptibility to development or progression of iMN.Methods & resultsGenomic DNA was isolated from blood samples of 101 iMN patients and 292 controls. By direct sequencing of the entire TRPC6 gene, 13 single nucleotide polymorphisms (SNPs) were identified in the iMN cohort, two of which were causing an amino acid substitution (rs3802829; Pro15Ser and rs36111323, Ala404Val). No statistically significant differences in genotypes or allele frequencies between patients and controls were observed. Clinical outcome in patients was determined (remission n?=?26, renal failure n?=?46, persistent proteinuria n?=?29, follow-up median 80 months {range 51-166}). The 13 identified SNPs showed no association with remission or renal failure. There were no differences in genotypes or allele frequencies between patients in remission and progressors.ConclusionsOur data suggest that TRPC6 polymorphisms do not affect susceptibility to iMN, or clinical outcome in iMN.

| S-EPMC4096511 | biostudies-literature

CHD7 gene polymorphisms are associated with susceptibility to idiopathic scoliosis.

Project description:Idiopathic scoliosis (IS) is the most common spinal deformity in children, and its etiology is unknown. To refine the search for genes underlying IS susceptibility, we ascertained a new cohort of 52 families and conducted a follow-up study of genomewide scans that produced evidence of linkage and association with 8q12 loci (multipoint LOD 2.77; P=.0028). Further fine mapping in the region revealed significant evidence of disease-associated haplotypes (P<1.0 x 10-4) centering over exons 2-4 of the CHD7 gene associated with the CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) syndrome of multiple developmental anomalies. Resequencing CHD7 exons and conserved intronic sequence blocks excluded coding changes but revealed at least one potentially functional polymorphism that is overtransmitted (P=.005) to affected offspring and predicts disruption of a caudal-type (cdx) transcription-factor binding site. Our results identify the first gene associated with IS susceptibility and suggest etiological overlap between the rare, early-onset CHARGE syndrome and common, later-onset IS.

| S-EPMC1852746 | biostudies-literature

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