Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women

Suppiah, Vijayaprakash; Rooney, Mary; Vandenbroeck, Koen

doi:10.1016/j.yexmp.2006.02.001

Cited by 9 publications

(5 citation statements)

References 38 publications

(40 reference statements)

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“…Interestingly, an IL-1α signature was found in the remaining ILAR subtypes, suggesting a mechanistic answer to differences in the efficacy of IL-1 blockade (IL-1 receptor antagonism versus specific anti–IL-1β therapy) in some children with nonsystemic arthritis (48,49). The key role of IL-4 in defining patient groups by sensitivity analysis supports earlier studies implicating Th2-related cytokines in moderating the pathogenesis of childhood arthritis (50,51). Using data alone, our analytical framework recovered important known biomarkers in JIA and provided a means to integrate these known biologic signals with important clinical signals to identify homogeneous patient subpopulations.…”

Section: Discussionsupporting

confidence: 82%

The Biologic Basis of Clinical Heterogeneity in Juvenile Idiopathic Arthritis

Eng

Duong

Rosenberg

et al. 2014

Arthritis & Rheumatology

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ObjectiveChildhood arthritis encompasses a heterogeneous family of diseases. Significant variation in clinical presentation remains despite consensus-driven diagnostic classifications. Developments in data analysis provide powerful tools for interrogating large heterogeneous data sets. We report a novel approach to integrating biologic and clinical data toward a new classification for childhood arthritis, using computational biology for data-driven pattern recognition.MethodsProbabilistic principal components analysis was used to transform a large set of data into 4 interpretable indicators or composite variables on which patients were grouped by cluster analysis. Sensitivity analysis was conducted to determine key variables in determining indicators and cluster assignment. Results were validated against an independent validation cohort.ResultsMeaningful biologic and clinical characteristics, including levels of proinflammatory cytokines and measures of disease activity, defined axes/indicators that identified homogeneous patient subgroups by cluster analysis. The new patient classifications resolved major differences between patient subpopulations better than International League of Associations for Rheumatology subtypes. Fourteen variables were identified by sensitivity analysis to crucially determine indicators and clusters. This new schema was conserved in an independent validation cohort.ConclusionData-driven unsupervised machine learning is a powerful approach for interrogating clinical and biologic data toward disease classification, providing insight into the biology underlying clinical heterogeneity in childhood arthritis. Our analytical framework enabled the recovery of unique patterns from small cohorts and addresses a major challenge, patient numbers, in studying rare diseases.

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Section: Discussionsupporting

confidence: 82%

The Biologic Basis of Clinical Heterogeneity in Juvenile Idiopathic Arthritis

Eng

Duong

Rosenberg

et al. 2014

Arthritis & Rheumatology

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“…Genetic differences between men and women have been implicated in distinct gender-specific patterns of susceptibility to many diseases, including autoimmune disorders [27,28]. Furthermore, some studies revealed female-specific associations between polymorphisms within genes related to the immune system and RA, suggesting the existence of genetic predisposition factors specific for women [29][30][31][32][33][34][35]. In the context of these reports, the present study focused on the female patient population with RA.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms within the human leucocyte antigen-E gene and their associations with susceptibility to rheumatoid arthritis as well as clinical outcome of anti-tumour necrosis factor therapy

Iwaszko

Świerkot

Kolossa³

et al. 2015

Clinical and Experimental Immunology

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Summary Involvement of the non‐classical human leucocyte antigen‐E (HLA‐E) in both innate and acquired immune response suggests its possible role in development of autoimmune pathologies. This study was undertaken to investigate relationships between the HLA‐E gene single nucleotide polymorphisms (SNPs) and a risk of rheumatoid arthritis (RA), as well as to evaluate a potential of these polymorphisms to modulate clinical outcome of anti‐tumour necrosis factor (TNF) treatment in female patients. A total of 223 female patients with RA receiving anti‐TNF biological therapy and 134 female healthy subjects were enrolled into the study. Genotypings for two SNPs within the HLA‐E gene (rs1264457 HLA‐E*01:01/01:03; rs1059510 HLA‐E*01:03:01/01:03:02) were performed using a polymerase chain reaction (PCR) amplification employing LightSNiP assays. Clinical response was evaluated according to the European League Against Rheumatism (EULAR) criteria at 12 and 24 weeks after initiation of the therapy. The frequency of the HLA‐E*01:01/01:01 genotype was decreased significantly in RA patients in comparison to controls (P = 0·031). The presence of the HLA‐E*01:01/01:01 genotype in patients correlated with better EULAR response after 12 weeks of anti‐TNF treatment, while 01:03 allele carriers were generally unresponsive to the treatment (P = 0·014). The HLA‐E*01:03/01:03 genotype was also over‐represented among non‐responding patients in comparison to HLA‐E*01:01/01:01 homozygotes (P = 0·021). With respect to the HLA‐E rs1059510 variation, a better response after 12 weeks was observed more frequently in patients carrying the HLA‐E*01:03:01/01:03:01 genotype than other genotypes (P = 0·009). The results derived from this study imply that HLA‐E polymorphisms may influence RA susceptibility and affect clinical outcome of anti‐TNF therapy in female RA patients.

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“…Our data indicate that the IL‐4 haplotypes tagged by the −589T allele reduce the risk of premature MI. Because atherosclerosis is classically considered to be a Th1‐mediated disease, the observed protective effect of the −589T allele would be in accordance with the delayed progression of other Th1‐type diseases such as rheumatoid arthritis and multiple sclerosis in carriers of the −589T allele or 33T allele [12–14,17]. Interestingly, the same haplotypes seem to enhance the severity of the disease in Th2‐type diseases such as severe asthma and IgA nephropathy [4,7], and were recently found to enhance the risk of stroke in a nested case–control study (OR 1.40; 95% CI 1.13–1.73) [22].…”

Section: Discussionmentioning

confidence: 97%

“…The role of IL‐4 in the development and progression of complex diseases has been studied using single nucleotide polymorphisms (SNPs) in the IL‐4 gene ( IL‐4 ) which are associated with IL‐4 expression. The rare alleles of these polymorphisms were found to be associated with high IL‐4 expression [3], elevated total serum IgE [4–6], increased severity and progression of asthma [3,7], IgA nephropathy [8], certain carcinomas [9,10], late onset disease in AIDS (however, not in all studies) [11–13] and Th1‐type diseases, such as multiple sclerosis [14,15] and rheumatoid arthritis [16,17].…”

Section: Introductionmentioning

confidence: 99%

The −589C>T polymorphism in the interleukin‐4 gene (IL‐4) is associated with a reduced risk of myocardial infarction in young individuals

Paffen

Medina²,

Visser

et al. 2008

Journal of Thrombosis and Haemostasis

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To cite this article: Paffen E, Medina P, de Visser MCH, van Wijngaarden A, Zorio E, Estellé s A, Rosendaal FR, Españ a F, Bertina RM, Doggen CJM.The )589C>T polymorphism in the interleukin-4 gene (IL-4) is associated with a reduced risk of myocardial infarction in young individuals. J Thromb Haemost 2008; 6: 1633-8.Summary. Background: Inflammatory reactions contribute to the development of arterial disease. We investigated the role of interleukin-4 (IL-4) in the development of myocardial infarction (MI) by genotyping patients with MI and control subjects for the )589C>T (rs2243250) single nucleotide polymorphism (SNP), which tags a functional haplotype of IL-4. Methods and results: Study of Myocardial Infarctions Leiden (SMILE) included 560 men with a first MI and 646 control subjects. The Valencia study included 305 patients with MI at £52 years (men and women) and 310 control subjects. In SMILE no clear overall association with the )589C>T genotype was found [odds ratio (OR) 0.84; 95% CI 0.37-1.95 for )589TT and 0.82; 95% CI 0.62-1.07 for )589CT compared with )589CC]. In patients younger than 50 years, carriership of one or two )589T alleles was associated with a reduced risk of MI (OR 0.57: 95% CI 0.34-0.95). This result was replicated in the Valencia study, where carriers of one or two )589T alleles had a reduced risk of MI , with a strong protective effect of the )598T allele in homozygous )589T (OR 0.33: 95% CI 0.10-1.05). In the control subjects of the Valencia study, the )589T allele was associated with reduced levels of F1+2. Conclusion: Our data indicate that the IL-4 haplotype tagged by the )589T allele reduces the risk of MI in young individuals.

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Polymorphisms in the interleukin-4 and IL-4 receptor genes modify risk for chronic inflammatory arthropathies in women

Cited by 9 publications

References 38 publications

The Biologic Basis of Clinical Heterogeneity in Juvenile Idiopathic Arthritis

The Biologic Basis of Clinical Heterogeneity in Juvenile Idiopathic Arthritis

Polymorphisms within the human leucocyte antigen-E gene and their associations with susceptibility to rheumatoid arthritis as well as clinical outcome of anti-tumour necrosis factor therapy

The −589C>T polymorphism in the interleukin‐4 gene (IL‐4) is associated with a reduced risk of myocardial infarction in young individuals

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