P1640: SINGLE NUCLEOTIDE POLYMORPHISMS OF THE HIF1A GENE ARE ASSOCIATED WITH SENSITIVITY OF GLUCOCORTICOID TREATMENT IN PEDIATRIC ITP PATIENTS
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SUBMITTER: Gu H
PROVIDER: S-EPMC9430697 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Project description:Empiric steroid therapy is the first-line therapy for pediatric nephrotic syndrome, but treatment response is variable. There are few predictors of steroid-responsiveness, although evidence for genetic factors does exist. Single nucleotide polymorphisms (SNPs) have been recently identified in the promoter region of glucocorticoid-induced transcript 1 gene (GLCCI1) which affect steroid-responsiveness in asthmatic patients. Independently, GLCCI1 was identified as a podocyte protein, the loss of which disrupts the function of the glomerular filtration barrier. We therefore examined whether SNPs associated with the steroid-responsive expression of GLCCI1 might predict steroid-responsiveness in nephrotic syndrome.A cohort of 211 pediatric patients with nephrotic syndrome and 102 controls were genotyped; among the cases, 117 were initial steroid responders, while 94 did not respond to oral steroids. No statistically significant differences were noted among the groups, although there was a trend based on the comparison of the small subgroups of steroid-responsive and non-responsive patients with biopsy-proven minimal change disease.While larger cohorts are needed to ascertain the possibility of a small effect of GLCCI1 SNPs on the steroid-responsiveness of nephrotic syndrome, the GLCCI1 SNPs associated with steroid-responsiveness in asthmatic patients are unlikely to have a clinically actionable impact in pediatric nephrotic syndrome.
| S-EPMC3408784 | biostudies-literature
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
Project description:BackgroundIn dogs, 6 single-nucleotide polymorphisms (SNPs) have been described in the glucocorticoid receptor gene NR3C1a, 2 of which were nonsynonymous SNPs in exons 2 and 8. The clinical importance of these SNPs is unknown.ObjectivesTo investigate whether SNPs in NR3C1a are associated with clinical outcome in Cocker Spaniels with primary immune thrombocytopenia (pITP).AnimalsTwenty-four Cocker Spaniels with pITP presented to a referral center. Dogs were classified as slow (n = 11) or fast responders (n = 12) based on time required after initiating glucocorticoid treatment to achieve a platelet count >70 000/μL.MethodsDeoxyribonucleic acid was extracted from stored blood samples before amplification by PCR and sequencing of exons 2 and 8 of NR3C1a. Associations between genotype and clinical response variables were investigated.ResultsNeither previously identified nonsynonymous SNPs were identified. The synonymous SNP NR3C1a:c.798C>T in exon 2 was found at an increased prevalence compared to a previous report. No difference was found in prevalence of any genotype at NR3C1a:c.798C>T between fast and slow responders (P = .70).Conclusions and clinical importanceNone of the previously reported nonsynonymous SNPs in exons 2 and 8 of the NR3C1a gene were detected in our cohort of Cocker Spaniels with pITP. The synonymous SNP NR3C1a:c.798C>T in exon 2 was reported at a higher frequency than previously, but was not associated with outcome measures that estimated responsiveness to glucocorticoids.
| S-EPMC9308442 | biostudies-literature
Project description:IntroductionThe glucocorticoid receptor (GR) plays an important regulatory role in the immune system. Four polymorphisms in the GR gene are associated with differences in glucocorticoid (GC) sensitivity; the minor alleles of the polymorphisms N363 S and BclI are associated with relative hypersensitivity to GCs, while those of the polymorphisms ER22/23EK and 9β are associated with relative GC resistance. Because differences in GC sensitivity may influence immune effector functions, we examined whether these polymorphisms are associated with the susceptibility to develop Rheumatoid Arthritis (RA) and RA disease severity.MethodsThe presence of GR polymorphisms was assessed in healthy controls (n = 5033), and in RA patients (n = 368). A second control group (n = 532) was used for confirmation of results. In RA patients, the relationship between GR polymorphisms and disease severity was examined.ResultsCarriers of the N363 S and BclI minor alleles had a lower risk of developing RA: odds ratio (OR) = 0.55 (95% confidence interval (CI) 0.32-0.96, P = 0.032) and OR = 0.73 (95% CI 0.58-0.91, P = 0.006), respectively. In contrast, 9β minor allele carriers had a higher risk of developing RA: OR = 1.26 (95% CI 1.00-1.60, P = 0.050). For ER22/23EK minor allele carriers a trend to an increased risk OR = 1.42 (95% CI 0.95-2.13, P = 0.086) was found. All ER22/23EK carriers (32/32) had erosive disease, while only 77% (259/336) of the non-carriers did (P = 0.008). In addition, ER22/23EK carriers were treated more frequently with anti-tumor necrosis factor-alpha (TNFα) therapy (P < 0.05).ConclusionsThe minor alleles of the 9β and ER22/23EK polymorphisms seem to be associated with increased predisposition to develop RA. Conversely, the minor alleles of the N363 S and BclI polymorphisms are associated with reduced susceptibility to develop RA. These opposite associations suggest that constitutionally determined GC resistance may predispose to development of auto-immunity, at least in RA, and vice versa.
| S-EPMC2945062 | biostudies-literature
Project description:Predictive biomarkers are needed in immune thrombocytopenia (ITP). Single nucleotide polymorphisms (SNPs) in beta 1 tubulin are potential candidates, as beta 1 tubulin is integral for platelet production and function, and SNPs in beta 1 tubulin have been associated with distinct phenotypes in platelets. We investigated the most prevalent beta 1 tubulin SNP (R307H) as a biomarker in patients with ITP via a retrospective chart review. Allelic frequencies between a group of 191 ITP patients and a healthy control group showed no difference, suggesting no direct aetiological role for the SNP in ITP. However, over similar periods of follow-up, both heterozygote and homozygote minor allele ITP patients were treated with significantly more treatment modalities and had significantly higher risk of failure to immune-modulatory therapies [relative risk (RR) = 1·5, 95% confidence interval (CI) = 1·1-2·1; P = 0·01]; with rituximab, in particular, ITP patients with the SNP experienced a 58% failure rate (RR = 1·6, 95%CI = 1·03-2·5; P = 0·04). Analysis of the absolute immature platelet fraction (A-IPF) as a marker of platelet production showed that SNP patients had significantly higher median A-IPFs compared to non-SNP patients when complete responses were achieved using immune modulatory therapies. The data suggest that the beta 1 tubulin R307H SNP has potential for use as a biomarker in ITP and may affect platelet turnover.
| S-EPMC4001250 | biostudies-literature
Project description:Heat shock protein 90 (HSP90) is an important glucocorticoid receptor (GR) chaperone protein, and is supposed to be the key factor in regulating glucocorticoids (GCs) effects. The aim of the present study was to explore whether single nucleotide polymorphisms (SNPs) within HSP90AA1 gene affect the response of systemic lupus erythematosus (SLE) patients to GCs treatment. Two hundred and forty-five SLE patients were treated with GCs (prednisone) for 12 weeks. SLE disease activity index (SLEDAI) was used to assess the response of SLE patients to GCs treatment, and patients were classified into sensitive group and insensitive group. HapMap database and Haploview software were used to select tag SNPs. Tag SNPs were genotyped by using multiplex SNaPshot method. Univariate and multivariate logistic regression analyses were used to discriminate the impact of SNPs of HSP90AA1 gene on the response of SLE patients to GCs treatment. Two hundred and thirty three SLE patients finished the 12-week follow-up. Of these patients, 128 patients were included in sensitive group, and 105 patients were included in insensitive group. Seven tag SNPs were selected within HSP90AA1 gene. We detected significant associations for rs7160651 (dominant model: crude OR 0.514, 95 % CI 0.297-0.890, P = 0.018; adjusted OR 0.518, 95 % CI 0.293-0.916, P = 0.024), rs10873531 (dominant model: crude OR 0.516, 95 % CI 0.305-0.876, P = 0.014; adjusted OR 0.522, 95 % CI 0.304-0.898, P = 0.019) and rs2298877 (dominant model: crude OR 0.543, 95 % CI 0.317-0.928, P = 0.026, adjusted OR 0.558, 95 % CI 0.323-0.967, P = 0.037) polymorphisms, but not for other polymorphisms (P > 0.05). The present study demonstrates that HSP90AA1 gene SNPs may affect the response of SLE patients to GCs treatment.
| S-EPMC4771663 | biostudies-literature
Project description:AimPain in sickle cell disease patients is heterogeneous and genetic polymorphisms may predispose an individual to varied vulnerability to painful events. We studied the association of SNPs in the glucocorticoid receptor gene (NR3C1) with pain in sickle cell disease.MethodAcute pain was scored as the number of utilizations due to crisis pain in a 12-month period. Chronic pain was calculated as the Composite Pain Index score.Results & conclusionrs33389 T allele (IRR = 1.53, p = 0.014 additive; IRR = 1.64, p = 0.011 recessive), rs2963155 G allele (IRR = 1.80, p < 0.001 additive; IRR = 2.25, p = 0.021 dominant; IRR = 2.07, p < 0.001 recessive) and rs9324918 C allele (IRR = 1.43, p = 0.021 additive) were associated with higher utilization rates, indicating the potential contribution of NR3C1 polymorphisms to acute pain heterogeneity in sickle cell disease.
| S-EPMC6275559 | biostudies-literature
Project description:Nasal polyposis (NP) is a chronic inflammatory disease. Several genes play major roles in the pathophysiology of the disease. We analyzed RYD5 gene polymorphisms to determine the effect of these variants or their genetic combinations on NP. We genotyped the RYD5 gene in 434 participants (196 patients with NP and 238 controls). Data were analyzed with SPSS, SNPStats, and multifactor dimensionality reduction (MDR) software. We genotyped 10 single-nucleotide polymorphisms (SNPs) in the RYD5 gene. RYD5 (+152G>T) (p.Gly51Va) has not been reported previously. The PolyPhen and PROVEAN predicted the missense mutation as deleterious, but sorting intolerant from tolerant (SIFT) did not. In the genotype analysis, we found that four SNPs (RYD5 [-264A>G], [-103G>A], [+57-14C>T], and [+66A>G]) were significantly associated with NP. The individuals with combined genotypes of six risk alleles (RYD5-264G, -103A, +13C, +57-14T, +66G, and +279T) had significantly higher risks for NP compared with the ones with one or four risk alleles. Haplotype analysis revealed that the two haplotypes were associated with risk of NP. As indicated by MDR analysis, RYD5 (-264A>G and -103G>A) and RYD5 (-264A>G, -177C>A, and -103G>A) were the best predictive combinations and they had the highest synergistic interaction on NP. In addition, RYD5 (+13C>T) was significantly associated with increased risk of both NP with asthma and NP with allergy and asthma. Some SNPs and their combinations in the RYD5 gene are associated with increased probability for developing NP. We emphasize the importance of genetic factors on NP and NP-related clinical phenotypes.
| S-EPMC4593873 | biostudies-literature
Project description:AimTo investigate the relationship between c.343A>G and c.2216A>C polymorphism sites in the CDH17 gene and colorectal carcinoma.MethodsNinety-three non-consanguineous colorectal carcinoma patients admitted to the Department of Oncology at the First Affiliated Hospital of Zhengzhou University were included in this study. Ninety-three peripheral venous blood samples, of approximately one milliliter from each patient, were collected between December 2009 and August 2010. The genomic DNA of these peripheral venous blood samples were extracted and purified using a Fermentas Genomic DNA Purification Kit (Fermentas, CA) according to the manufacturer's protocol. The single nucleotide polymorphisms (SNPs) of the liver-intestine cadherin (CDH17) gene c.343A>G and c.2216A>C were determined by the polymerase chain reaction-single strand conformation polymorphism method (PCR-SSCP) in 93 peripheral venous blood samples from patients suffering with colorectal carcinoma. Typical samples that showed different migration bands in SSCP were confirmed by sequencing. Directed DNA sequencing was used to check the correctness of the genotype results from the PCR-SSCP method.ResultsThere was a significant association between the c.2216 A>C SNPs of the CDH17 gene and the tumor-node-metastasis (TNM) grade, as well as with lymph node status, in 93 peripheral venous blood samples from colorectal carcinoma patients. The genotype frequencies of A/C, A/A, and C/C were 12.90%, 33.33% and 53.76%, respectively. There was a significant correlation between lymph node metastasis, TNM grade, and the genotype distribution (P < 0.05). The C/C genotype raised the risk of lymph node metastasis and the TNM grade. There was a significant difference in the TNM grade and lymph node metastasis between the A/A and C/C genotypes (P = 0.003 and P = 0.013, respectively). Patients with colorectal carcinoma carrying the C allele tended to have a higher risk of lymph node metastasis and have a higher TNM grade. The difference between the TNM grades, as well as the lymph node metastasis of the two alleles, was statistically significant (P < 0.01).ConclusionThe SNPs of the CDH17 gene c.2216 A>C might be clinically important in the prognosis of colorectal carcinoma.
| S-EPMC3544027 | biostudies-literature
Project description:The vitamin D/Vitamin D receptor (VDR) axis is crucial for human health as it regulates the expression of genes involved in different functions, including calcium homeostasis, energy metabolism, cell growth and differentiation, and immune responses. In particular, the vitamin D/VDR complex regulates genes of both innate and adaptive immunity. Autoimmune diseases are believed to arise from a genetic predisposition and the presence of triggers such as hormones and environmental factors. Among these, a role for Vitamin D and molecules correlated to its functions has been repeatedly suggested. Four single nucleotide polymorphisms (SNPs) of the VDR gene, ApaI, BsmI, TaqI, and FokI, in particular, have been associated with autoimmune disorders. The presence of particular VDR SNP alleles and genotypes, thus, was observed to modulate the likelihood of developing diverse autoimmune conditions, either increasing or reducing it. In this work, we will review the scientific literature suggesting a role for these different factors in the pathogenesis of autoimmune conditions and summarize evidence indicating a possible VDR SNP involvement in the onset of these diseases. A better understanding of the role of the molecular mechanisms linking Vitamin D/VDR and autoimmunity might be extremely useful in designing novel therapeutic avenues for these disorders.
| S-EPMC10376382 | biostudies-literature