Relevance of IL7R genotype and mRNA expression in Dutch patients with multiple sclerosis

2011 ◽  
Vol 17 (8) ◽  
pp. 922-930 ◽  
Author(s):  
MH Sombekke ◽  
LF van der Voort ◽  
JJ Kragt ◽  
JM Nielsen ◽  
H Guzel ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mrna Expression ◽  
Mrna Level ◽  
Susceptibility Gene ◽  
Disease Phenotype ◽  
Single Nucleotide ◽  
Relative Expression ◽  
Interleukin 7 ◽  
Membrane Bound ◽  
Magnetic Resonance Imaging Mri

Background: The interleukin 7 receptor (IL7R) has been recognized as a susceptibility gene for Multiple Sclerosis (MS). Analysis of rs6897932 (the most strongly MS-associated single nucleotide polymorphism (SNP)), showed effects of genotype on the relative expression of membrane-bound to total amount of IL7R mRNA. Objective: We assessed the relevance of IL7R on MS phenotype (including clinical and magnetic resonance imaging (MRI) parameters) at DNA and mRNA level in Dutch patients with MS. Methods: The genotype of rs6897932 was analyzed in 697 patients with MS and 174 healthy controls. The relevance of genotype and carriership of the C allele on MS phenotype (disease activity and severity, using clinical and MRI parameters) was assessed. In addition, relative gene expression of membrane-bound to total IL7R mRNA was analyzed with respect to disease phenotype in a subgroup of 95 patients with early relapsing MS. Results: In particular, homozygosity for the risk allele is a risk factor for MS in our population (ORCC vs CT and TT = 1.65 (95% CI: 1.18–2.30), two-sided p = 0.004). However, no effect of genotype or the relative expression of membrane-bound IL7R (presence of exon 6–7) to total amount of IL7R mRNA (presence of exon 4–5) was found on MS phenotype. Discussion: Homozygosity for the IL7R exon 6 rs6897932 C allele is associated with a higher risk for MS in our Dutch population. No effect was found of genotype or mRNA expression on disease phenotype.

TACE mRNA expression in peripheral mononuclear cells precedes new lesions on MRI in multiple sclerosis

2002 ◽  
Vol 8 (6) ◽  
pp. 447-451 ◽  
Author(s):  
T Seifert ◽  
B C Kieseier ◽  
S Ropele ◽  
S Strasser-Fuchs ◽  
F Quehenberger ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mrna Expression ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Brain Magnetic Resonance Imaging ◽  
Peripheral Blood Mononuclear ◽  
Relapsing Remitting ◽  
Membrane Bound ◽  
Magnetic Resonance Imaging Mri ◽  
A Disintegrin And Metalloproteinase

Tumor necrosis factor-a (TNF-a) is involved in the pathogenesis of multiple sclerosis (MS). It has to be released from its cell membrane-bound precursor by proteolytic cleavage. This is mainly performed by a member of the ADAM (a disintegrin and metalloproteinase) family of enzymes, TNF-a-converting enzyme (TACE, ADAM 17). In a longitudinal study on 11 relapsing-remitting MS patients, we qualitatively determined mRNA expression of TNF-a and TACE in peripheral blood mononuclear cells (PBMCs) without ex vivo stimulation. mRNA expression was related to disease activity as assessed by monthly gadolinium (Gd)-enhanced brain magnetic resonance imaging (MRI). Patients found positive for TACE mRNA in PBMCs showed a significantly higher mean number of new Gd-enhancing lesions per scan one month following PBMC sampling.

CD46 in a Spanish cohort of multiple sclerosis patients: genetics, mRNA expression and response to interferon-beta treatment

2010 ◽  
Vol 17 (5) ◽  
pp. 513-520 ◽  
Author(s):  
Roberto Alvarez-Lafuente ◽  
Fiona Blanco-Kelly ◽  
Marta Garcia-Montojo ◽  
Alfonso Martínez ◽  
Virginia De Las Heras ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mrna Expression ◽  
Interferon Beta ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Multiple Sclerosis Patients ◽  
Spanish Cohort ◽  
Independent Cohort

Background: In a prior study of our group we found an up-regulation of CD46 expression in a cohort of Spanish multiple sclerosis (MS) patients. Objective: To evaluate the potential role of CD46 in the response to interferon-beta treatment in MS patients through the analysis of five tagging single nucleotide polymorphisms (SNPs) and measurement of mRNA. Methods: A total of 406 MS patients and 513 control patients were analysed for five SNPs at the CD46 locus. Furthermore, 163 MS patients and 163 matched control patients were analysed by RT-PCR for the CD46 mRNA expression in three blood samples (basal, and at 6 and 12 months of interferon-beta treatment) collected in the course of a 1-year follow-up. Results: Two genotypes of rs2724385 polymorphism (AT and TT) could be markers of response to interferon-beta therapy in MS patients ( p = 0.007 and p = 0.006, respectively). Furthermore, the frequency of interferon-beta responders was 44.4% (32/72) in MS patients with an increased CD46 mRNA expression, vs. 65.9% (60/91) in patients with a decreased CD46 mRNA expression ( p = 0.006). Conclusion: The present study shows that CD46 could be associated with the response to interferon-beta therapy; however, the genetic results should be replicated in an independent cohort and further studies are needed to confirm the role of CD46.

Interleukin 7 receptor alpha polymorphism rs6897932 and susceptibility to multiple sclerosis in the Western Balkans

2010 ◽  
Vol 16 (5) ◽  
pp. 533-536 ◽  
Author(s):  
Aleksandra Stanković ◽  
Evica Dinčić ◽  
Smiljana Ristić ◽  
Luca Lovrečić ◽  
Nada Starčević Cizmarević ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Western Balkans ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Receptor Alpha ◽  
Interleukin 7 ◽  
Genome Wide ◽  
Significant Difference ◽  
Polymerase Chain ◽  
Genome Variants

The interleukin 7 receptor alpha single nucleotide polymorphism rs6897932 was identified as a multiple sclerosis susceptibility-modifying polymorphism in genome-wide and gene scan studies, mainly in populations in western countries. The aim of this study was to investigate the association of interleukin 7 receptor alpha rs6897932 with multiple sclerosis in populations from the Western Balkans: Serbia, Croatia, and Slovenia. A total of 678 unrelated white patients and 597 unrelated, ethnically matched healthy controls were included in the study. Genotyping was performed by real-time polymerase chain reaction. We found no significant difference in genotype or allele frequencies between controls and patients with multiple sclerosis either separately in Serbian, Croatian, and Slovenian populations or in the whole sample from the Western Balkans. The odds ratio for multiple sclerosis in this study was 1.04 (0.86—1.25) for the C allele. It is known that demographic as well as environmental factors have a substantial role in multiple sclerosis development, as well as population genetic background. The results of this study indicate that other types of genome variants should be required for the development and/or progression of multiple sclerosis, which may vary among populations.

scholarly journals SCUBE3 Is Likely a Susceptibility Gene for Systemic Lupus Erythematosus for Chinese Populations

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Yuan-yuan Qi ◽  
Ya-fei Zhao ◽  
Ya-ling Zhai ◽  
Xiao-xue Zhang ◽  
Xiao-yang Wang ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Mrna Expression ◽  
Lupus Erythematosus ◽  
Susceptibility Gene ◽  
Nucleotide Polymorphisms ◽  
Systemic Lupus ◽  
Single Nucleotide ◽  
Chinese Populations ◽  
Genetic Susceptibility Factor

Background. Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong genetic disposition with more than 100 susceptibility genes identified until now. However, our knowledge on SLE genetic background is still limited. The present study was aimed at evaluating the role of single nucleotide polymorphisms (SNPs) in SCUBE3, a TGF-β signaling activator, with SLE susceptibility in Chinese populations. Methods. A total of 2801 individuals (490 cases and 493 controls from GWAS cohort and 1003 cases and 815 controls from our cohort) were enrolled, and SNPs located 10 kb up- and downstream of SCUBE3 (chr6:35182190-35218609) were included in the genetic association study. Multiple layers of bioinformatics were conducted, and the levels of SCUBE3 expression were confirmed. Results. Of the 31 SNPs in SCUBE3 tested, 24 SNPs were significantly associated with SLE at p ≤ 0.05 . The top locus was rs1888822 with p = 8.74 ∗ 10 − 6 in the discovery cohort and was confirmed by the replication cohort with p = 0.012 . Additionally, the levels of SCUBE3 mRNA expression were significantly lower in patients with SLE comparing with healthy controls ( p = 4.28 ∗ 10 − 4 ). Further expression data from ArrayExpress showed that the expression of SCUBE3 was also lower in CD3+ T cells and B cells from patients with SLE. Conclusions. Our research revealed that variants in SCUBE3, which encode SCUBE3 as a TGF-β signaling activator, can be considered as a new genetic susceptibility factor for systemic lupus erythematosus. And the reduced mRNA expression of SCUBE3 was first reported in patients with SLE.

scholarly journals An algorithm using clinical data to predict the optimal individual glucocorticoid dosage to treat multiple sclerosis relapses

2021 ◽  
Vol 14 ◽  
pp. 175628642110200
Author(s):  
Judit Gili-Kovács ◽  
Robert Hoepner ◽  
Anke Salmen ◽  
Maud Bagnoud ◽  
Ralf Gold ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Optic Neuritis ◽  
Immune Therapy ◽  
Serum Vitamin ◽  
Multivariate Regression Analysis ◽  
Pulse Therapy ◽  
Clinical Routine ◽  
Hydroxyvitamin D ◽  
Serum Vitamin D ◽  
Magnetic Resonance Imaging Mri

Background: Glucocorticoid (GC) pulse therapy is used for multiple sclerosis (MS) relapse treatment; however, GC resistance is a common problem. Considering that GC dosing is individual with several response-influencing factors, establishing a predictive model, which supports clinicians to estimate the maximum GC dose above which no additional therapeutic value can be expected presents a huge clinical need. Method: We established two, independent retrospective cohorts of MS patients. The first was an explorative cohort for model generation, while the second was established for its validation. Using the explorative cohort, a multivariate regression analysis with the GC dose used as the dependent variable and serum vitamin D (25D) concentration, sex, age, EDSS, contrast enhancement on cranial magnetic resonance imaging (MRI), immune therapy, and the involvement of the optic nerve as independent variables was established. Results: In the explorative cohort, 113 MS patients were included. 25-hydroxyvitamin D (25D) serum concentration and the presence of optic neuritis were independent predictors of the GC dose needed to treat MS relapses [(25D): −25.95 (95% confidence interval (CI)): −47.40 to −4.49; p = 0.018; optic neuritis: 2040.51 (95% CI: 584.64–3496.36), p = 0.006]. Validation of the multivariate linear regression model was performed within a second cohort. Here, the predicted GC dose did not differ significantly from the dose administered in clinical routine (mean difference: −843.54; 95% CI: −2078.08–391.00; n = 30, p = 0.173). Conclusion: Our model could predict the GC dose given in clinical, routine MS relapse care, above which clinicians estimate no further benefit. Further studies should validate and improve our algorithm to help the implementation of predictive models in GC dosing.

scholarly journals Postnatal Smoke Exposure Further Increases the Hepatic Nicotine Metabolism in Prenatally Smoke Exposed Male Offspring and Is Linked with Aberrant Cyp2a5 Methylation

2020 ◽  
Vol 22 (1) ◽  
pp. 164
Author(s):  
Khosbayar Lkhagvadorj ◽  
Zhijun Zeng ◽  
Karolin F. Meyer ◽  
Laura P. Verweij ◽  
Wierd Kooistra ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mrna Expression ◽  
Nicotine Dependence ◽  
Susceptibility Gene ◽  
Smoke Exposure ◽  
Adverse Outcomes ◽  
Male Offspring ◽  
Adult Offspring ◽  
Mrna Levels ◽  
Nicotine Metabolism

Prenatal smoke exposure (PreSE) is a risk factor for nicotine dependence, which is further enhanced by postnatal smoke exposure (PostSE). One susceptibility gene to nicotine dependence is Cytochrome P450 (CYP) 2A6, an enzyme responsible for the conversion of nicotine to cotinine in the liver. Higher CYP2A6 activity is associated with nicotine dependence and could be regulated through DNA methylation. In this study we investigated whether PostSE further impaired PreSE-induced effects on nicotine metabolism, along with Cyp2a5, orthologue of CYP2A6, mRNA expression and DNA methylation. Using a mouse model where prenatally smoke-exposed adult offspring were exposed to cigarette smoke for 3 months, enzyme activity, mRNA levels, and promoter methylation of hepatic Cyp2a5 were evaluated. We found that in male offspring, PostSE increased PreSE-induced cotinine levels and Cyp2a5 mRNA expression. In addition, both PostSE and PreSE changed Cyp2a5 DNA methylation in male groups. PreSE however decreased cotinine levels whereas it had no effect on Cyp2a5 mRNA expression or methylation. These adverse outcomes of PreSE and PostSE were most prominent in males. When considered in the context of the human health aspects, the combined effect of prenatal and adolescent smoke exposure could lead to an accelerated risk for nicotine dependence later in life.

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