Interleukin-23 receptor gene polymorphisms in Iranian patients with juvenile systemic lupus erythematosus

Introduction and objectives: Considering the possible roles of interleukin-23 receptor (IL-23R) gene in the pathogenesis of juvenile systemic lupus erythematosus (JSLE), the objective of this study was to elucidate whether polymorphisms of the IL23R are associated with susceptibility to JSLE in an Iranian population. Materials and methods: A case-control study on 62 patients with JSLE and 78 healthy controls was performed to investigate the associations of four single nucleotide polymorphisms (SNPs) in IL-23R gene, namely, rs7517847, rs10489629, rs11209026, and rs1343151, with susceptibility to JSLE, using real-time polymerase chain reaction Taqman genotyping technique. Results: Analysis of allele and genotype frequency of four selected SNPs revealed statistically significant positive association between homozygous variant of rs7517847 (TT) (P, 0.02) and T allele at the same position (P, 0.01) with JSLE vulnerability. There was no significant association between other evaluated SNPs and JSLE susceptibility. Conclusion: These findings suggest that particular IL-23R gene variants could affect individual susceptibility to JSLE

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Interleukin-23 receptor gene polymorphisms in Iranian patients with juvenile systemic lupus erythematosus.

INTRODUCTION AND OBJECTIVES: Considering the possible roles of interleukin-23 receptor (IL-23R) gene in the pathogenesis of juvenile systemic lupus erythematosus (JSLE), the objective of this study was to elucidate whether polymorphisms of the IL23R are associated with susceptibility to JSLE in an Iranian population. MATERIALS AND METHODS: A case-control study on 62 patients with JSLE and 78 healthy controls was performed to investigate the associations of four single nucleotide polymorphisms (SNPs) in IL-23R gene, namely, rs7517847, rs10489629, rs11209026, and rs1343151, with susceptibility to JSLE, using real-time polymerase chain reaction Taqman genotyping technique. RESULTS: Analysis of allele and genotype frequency of four selected SNPs revealed statistically significant positive association between homozygous variant of rs7517847 (TT) (P, 0.02) and T allele at the same position (P, 0.01) with JSLE vulnerability. There was no significant association between other evaluated SNPs and JSLE susceptibility. CONCLUSION: These findings suggest that particular IL-23R gene variants could affect individual susceptibility to JSLE.

Novel AICDA mutation in a case of autosomal recessive hyper-IgM syndrome, growth hormone deficiency and autoimmunity

BACKGROUND: The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders, which have been rarely reported to be associated with growth hormone deficiency (GHD). METHODS AND RESULTS: A nine-year-old girl with recurrent urinary tract infections, diarrhoea, sinopulmonary infections, and failure to thrive since the age of six months had normal CD3+, CD4+, CD8 + T lymphocytes, and CD19 + B lymphocytes and natural killer (NK) cells, but extremely elevated IgM and significantly decreased IgG and IgA. In view of the patient's short stature, growth hormone evaluation was carried out and growth hormone deficiency established. The patient underwent Ig replacement therapy and received growth hormone therapy in addition to antibiotics and responded well. Furthermore, the patient developed benign cervical lymphadenopathy, as well as elevated erythrocyte sedimentation rate, positive autoantibodies to SSA-Ro, and severely dry eyes, which partially responded to both the punctate occlusion and systemic corticosteroids, at the age of seven years. Sequencing analysis of the exons from activation-induced cytidine deaminase (AICDA) gene revealed that the patient was homozygous for a single T to C transversion at position 455 in exon 4, which replaces a Valine with an Alanine. CONCLUSIONS: To our knowledge, this is a new AICDA mutation, which has not been reported previously in HIGM. The mutation analysis could improve diagnosis of HIGM patients and also elaborating on the spectrum of AICDA mutations

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Novel AICDA mutation in a case of autosomal recessive hyper-IgM syndrome, growth hormone deficiency and autoimmunity.

BACKGROUND: The Hyper-immunoglobulin M syndromes (HIGM) are a heterogeneous group of genetic disorders, which have been rarely reported to be associated with growth hormone deficiency (GHD). METHODS AND RESULTS: A nine-year-old girl with recurrent urinary tract infections, diarrhoea, sinopulmonary infections, and failure to thrive since the age of six months had normal CD3+, CD4+, CD8+T lymphocytes, and CD19+B lymphocytes and natural killer (NK) cells, but extremely elevated IgM and significantly decreased IgG and IgA. In view of the patient's short stature, growth hormone evaluation was carried out and growth hormone deficiency established. The patient underwent Ig replacement therapy and received growth hormone therapy in addition to antibiotics and responded well. Furthermore, the patient developed benign cervical lymphadenopathy, as well as elevated erythrocyte sedimentation rate, positive autoantibodies to SSA-Ro, and severely dry eyes, which partially responded to both the punctate occlusion and systemic corticosteroids, at the age of seven years. Sequencing analysis of the exons from activation-induced cytidine deaminase (AICDA) gene revealed that the patient was homozygous for a single T to C transversion at position 455 in exon 4, which replaces a Valine with an Alanine. CONCLUSIONS: To our knowledge, this is a new AICDA mutation, which has not been reported previously in HIGM. The mutation analysis could improve diagnosis of HIGM patients and also elaborating on the spectrum of AICDA mutations.

Association of interleukin-1 family gene polymorphisms with juvenile idiopathic arthritis in Iranian population

BACKGROUND: Cytokines, including interleukin-1 (IL-1), seem to contribute towards the pathogenesis of juvenile idiopathic arthritis (JIA), so this study was designed to evaluate the associations of IL-1 gene cluster and IL-1 receptor (IL-1R) gene single nucleotide polymorphisms (SNPs) with JIA proneness in Iranian population. MATERIALS AND METHODS: Genomic DNA of 55 Iranian patients with JIA and 140 controls were extracted and typed for IL-1alpha gene at position −889, IL-1beta gene at positions −511 and +3962, IL-1R gene at position Pst-I 1970, and interleikin-1 receptor antagonist (IL-1Ra) gene at position Mspa-I 11100, using polymerase chain reaction with sequence-specific primers method, and compared between patients and controls. RESULTS: The CC genotype of IL-1Ra at Mspa-I 11100 position was found to be more frequent in patients with JIA compared to healthy individuals (P=0.03), although the CT genotype at the same position was significantly higher in the control group in comparison with patients with JIA (P=0.02). No significant differences were observed between the two groups of case and control for IL-1alpha (−889 C/T), IL-1beta (−511 C/T and +3962 C/T) and IL-1R (Pst-1 1970 C/T). CONCLUSION: The results of the present investigation suggest that certain IL-1Ra gene variants are associated with individuals' susceptibility to JIA. Nevertheless, further studies are required to establish the results of the current study

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Association of tumour necrosis factor-alpha G/A -238 and G/A -308 single nucleotide polymorphisms with juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is a heterogeneous autoimmune disorder of unknown origin. As proinflammatory cytokines are known to contribute towards the pathogenesis of JIA, this case-control study was performed to examine the associations of certain single nucleotide polymorphisms (SNPs) of tumour necrosis factor-α (TNF-α) gene. Fifty-three patients with JIA participated in this study as patients group and compared with 137 healthy unrelated controls. Genotyping was performed for TNF-α gene at positions -308 and -238, using polymerase chain reaction with sequence-specific primers method. Results of the analysed data revealed a significant positive association for TNF-α gene at positions -308 and -238 for A allele in patients group compared with controls (P < 0.01). At the genotypic level, the frequency of TNF-α gene at positions -308 and -238 for GG genotype was discovered to be higher in the patients with JIA compared to the healthy controls (P < 0.01), while GA genotype at the same positions was observed to be less frequent in the case group than the controls (P < 0.01). At the haplotypic level, a significant positive association for TNF-α GG haplotype (positions -308, -238) together with a notable negative association for TNF-α AG and GA haplotypes at the same positions were detected in the patients group in comparison with the healthy individuals (P < 0.01). Cytokine gene polymorphisms might affect the development of JIA. Particular TNF-α gene variants could render individuals more susceptible to JIA..

Association of interleukin-1 family gene polymorphisms with juvenile idiopathic arthritis in Iranian population.

BACKGROUND: Cytokines, including interleukin-1 (IL-1), seem to contribute towards the pathogenesis of juvenile idiopathic arthritis (JIA), so this study was designed to evaluate the associations of IL-1 gene cluster and IL-1 receptor (IL-1R) gene single nucleotide polymorphisms (SNPs) with JIA proneness in Iranian population. MATERIALS AND METHODS: Genomic DNA of 55 Iranian patients with JIA and 140 controls were extracted and typed for IL-1α gene at position -889, IL-1ß gene at positions -511 and +3962, IL-1R gene at position Pst-I 1970, and interleikin-1 receptor antagonist (IL-1Ra) gene at position Mspa-I 11100, using polymerase chain reaction with sequence-specific primers method, and compared between patients and controls. RESULTS: The CC genotype of IL-1Ra at Mspa-I 11100 position was found to be more frequent in patients with JIA compared to healthy individuals (P=0.03), although the CT genotype at the same position was significantly higher in the control group in comparison with patients with JIA (P=0.02). No significant differences were observed between the two groups of case and control for IL-1α (-889 C/T), IL-1ß (-511 C/T and +3962 C/T) and IL-1R (Pst-1 1970 C/T). CONCLUSION: The results of the present investigation suggest that certain IL-1Ra gene variants are associated with individuals' susceptibility to JIA. Nevertheless, further studies are required to establish the results of the current study.

Association of interleukin-2 and interferon-γ single nucleotide polymorphisms with Juvenile systemic lupus erythematosus

Purpose: Juvenile systemic lupus erythematosus (JSLE) is a severe and chronic autoimmune disease of unknown origin. Inflammatory cytokines can play a pivotal role in the pathogenesis of JSLE, while their secretion is under genetic control. The current investigation was performed to analyse the associations of particular single nucleotide polymorphisms (SNPs) of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) genes in a case control study. Materials and methods: The allele, genotype and haplotype frequencies of the polymorphic IL-2 (G/T at −330, rs2069762, and G/T at +166, rs2069763) and IFN-γ (A/T at +874, rs2430561) genes were estimated in 59 patients with JSLE by contrast with 140 healthy controls using polymerase chain reaction with sequence-specific primers method. Results: Results of the analysed data revealed a negative allelic association for JSLE in IL-2 −330/T (P=0.02), as well as a positive allelic association for IL-2 −330/G (P=0.02). IL-2 GG genotype (−330) in the patient group was also significantly overrepresented (P<0.001), while IL-2 GT genotype (−330) was notably decreased in the patients with JSLE (P<0.001). Additionally, the frequency of IL-2 (−330, +166) GT haplotype was significantly higher in the patient group (P<0.001). Conclusion: IL-2 cytokine gene polymorphisms could affect individual susceptibility to JSLE and can take on the role of possible genetic markers for vulnerability to JSLE

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Association of interleukin 1 gene cluster and interleukin 1 receptor gene polymorphisms with ischemic heart failure.

BACKGROUND: Proinflammatory cytokines have been known to play a considerable part in the pathomechanisms of chronic heart failure (CHF). Given the importance of proinflammatory cytokines in the context of the failing heart, we assessed whether the polymorphisms of interleukin (IL)-1 gene cluster, including IL-1α, IL-1ß, and IL-1 receptor antagonist (IL-1RA) and IL-1R gene are predictors of CHF due to ischemic heart disease. METHODS: Forty- three patients with ischemic heart failure were recruited in this study as patients group and compared with 140 healthy unrelated control subjects. Using polymerase chain reaction with sequence-specific primers method, the allele and genotype frequency of 5 single nucleotide polymorphisms (SNPs) within the IL-1α (-889), IL-1ß (-511, +3962), IL-1R (psti 1970), and IL-1RA (mspa1 11100) genes were determined. RESULTS: The frequency of the IL-1ß -511/C allele was significantly higher in the patient group compared to that in the control group (p = 0.031). The IL-1ß (-511) C/C genotype was significantly overrepresented in patients compared to controls (p = 0.022). CONCLUSIONS: Particular allele and genotype in IL-1ß gene were overrepresented in patients with ischemic heart failure, possibly affecting the individual susceptibility to this disease (Tab. 1, Ref. 27).

Association of Interleukin-2, but not Interferon-Gamma, single nucleotide polymorphisms with juvenile idiopathic arthritis

BACKGROUND: Cytokines, including interleukin-2 (IL-2) and interferon-gamma (IFN-γ), seem to play a role in the pathogenesis of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate the associations of IL-2 and IFN-γ single nucleotide polymorphisms (SNPs) with susceptibility to JIA in an Iranian population. METHODS: enomic DNA of 54 Iranian patients with JIA and 139 healthy unrelated controls were typed for IL-2 (G/T at −330 and +166) as well as IFN-γ gene (A/T at +874), using polymerase chain reaction with sequence-specific primers method, and compared between patients and controls. RESULTS: A significantly higher frequency of the IL-2 −330 GG genotype (p < 0.01) was found in the JIA patients compared to the controls. However, the GT genotype at the same position was notably lower than in controls (p < 0.01). Moreover, IL-2 (−330, +166) GT haplotype was more frequent in patients with JIA in comparison with controls. No significant differences was observed between the two groups of case and control for IL-2 (G/T at +166) and IFN-γ (A/T at +874) SNPs. CONCLUSION: The results of the current study suggest that certain SNPs of IL-2 gene have association with individuals' susceptibility to JIA. However, further investigations are required to confirm the results of this study

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Association of interleukin-2 and interferon-γ single nucleotide polymorphisms with Juvenile systemic lupus erythematosus.

PURPOSE: Juvenile systemic lupus erythematosus (JSLE) is a severe and chronic autoimmune disease of unknown origin. Inflammatory cytokines can play a pivotal role in the pathogenesis of JSLE, while their secretion is under genetic control. The current investigation was performed to analyse the associations of particular single nucleotide polymorphisms (SNPs) of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) genes in a case control study. MATERIALS AND METHODS: The allele, genotype and haplotype frequencies of the polymorphic IL-2 (G/T at -330, rs2069762, and G/T at +166, rs2069763) and IFN-γ (A/T at +874, rs2430561) genes were estimated in 59 patients with JSLE by contrast with 140 healthy controls using polymerase chain reaction with sequence-specific primers method. RESULTS: Results of the analysed data revealed a negative allelic association for JSLE in IL-2 -330/T (P=0.02), as well as a positive allelic association for IL-2 -330/G (P=0.02). IL-2 GG genotype (-330) in the patient group was also significantly overrepresented (P<0.001), while IL-2 GT genotype (-330) was notably decreased in the patients with JSLE (P<0.001). Additionally, the frequency of IL-2 (-330, +166) GT haplotype was significantly higher in the patient group (P<0.001). CONCLUSION: IL-2 cytokine gene polymorphisms could affect individual susceptibility to JSLE and can take on the role of possible genetic markers for vulnerability to JSLE.

Interleukin 10 and transforming growth factor beta 1 gene polymorphisms in juvenile idiopathic arthritis.

OBJECTIVES: The aim of this study is to identify the associations between interleukin 10 (IL-10) and transforming growth factor beta 1 (TGF-ß1) gene polymorphisms and individual susceptibility to juvenile idiopathic arthritis (JIA) in a group of Iranian patients. BACKGROUND: Cytokine genes, including IL-10 and TGF-ß1, are known to play important roles in the pathogenesis of JIA. METHODS: Using polymerase chain reaction with sequence-specific primers method, the frequency of alleles, genotypes and haplotypes of IL-10 (positions -1082, -819, -592) and TGF-ß1 (codon 10, codon 25) single-nucleotide polymorphisms (SNPs) were investigated in 55 patients with JIA as a case group and compared with 140 healthy unrelated controls. RESULTS: The G allele was significantly less frequent at TGF-ß1 codon 25 in patients with JIA than in the controls (p < 0.01). The frequency of CT genotype at TGF-ß1 codon 10 was found to be higher in healthy individuals in comparison with that in patients group (p = 0.04). We observed no differences in the frequency of alleles, genotypes and haplotypes of IL-10 gene between the groups of patients and controls. CONCLUSIONS: Considering the low frequency of existence of TGF-ß1 G allele at codon 25 as well as TGF-ß1 CT genotype at codon 10 in patients with JIA, it seems that these cytokine gene polymorphisms could play role as the protective factors against JIA.

Association of Interleukin-2, but not Interferon-Gamma, single nucleotide polymorphisms with juvenile idiopathic arthritis.

BACKGROUND: Cytokines, including interleukin-2 (IL-2) and interferon-gamma (IFN-γ), seem to play a role in the pathogenesis of juvenile idiopathic arthritis (JIA). The aim of this study was to investigate the associations of IL-2 and IFN-γ single nucleotide polymorphisms (SNPs) with susceptibility to JIA in an Iranian population. METHODS: Genomic DNA of 54 Iranian patients with JIA and 139 healthy unrelated controls were typed for IL-2 (G/T at -330 and +166) as well as IFN-γ gene (A/T at +874), using polymerase chain reaction with sequence-specific primers method, and compared between patients and controls. RESULTS: A significantly higher frequency of the IL-2 -330 GG genotype (p<0.01) was found in the JIA patients compared to the controls. However, the GT genotype at the same position was notably lower than in controls (p<0.01). Moreover, IL-2 (-330, +166) GT haplotype was more frequent in patients with JIA in comparison with controls. No significant differences was observed between the two groups of case and control for IL-2 (G/T at +166) and IFN-γ (A/T at +874) SNPs. CONCLUSION: The results of the current study suggest that certain SNPs of IL-2 gene have association with individuals' susceptibility to JIA. However, further investigations are required to confirm the results of this study.

Interleukin-4 single nucleotide polymorphisms in juvenile systemic lupus erythematosus.

Juvenile systemic lupus erythematosus (JSLE) is a chronic, recurrent multisystem inflammatory disease, caused by a combination of environmental events and genetic risk factors. As cytokines, including interleukin-4 (IL-4), seem to have a role in the pathogenesis of JSLE, the investigation was performed to evaluate the associations of specific single nucleotide polymorphisms (SNPs) of IL-4 and IL-4RA genes in a case-control study. Fifty-nine patients with JSLE were recruited in this study as patients' group and compared with 140 healthy volunteers. Genotyping was performed for IL-4 gene at positions -1098, -590 and -33, as well as IL-4 receptor α (IL-4RA) gene at position +1902, using polymerase chain reaction with sequence-specific primers method. Following alleles were found to be more common among patients with JSLE: C at -590 and -33 and T at -1098 of IL-4 gene (P value < 0.001; OR = 4.6, P value < 0.001; OR = 2.7 and P value < 0.001; OR = 2.1, respectively). Additionally, significant positive associations for the following genotypes were recognized in JSLE cases, compared with controls: C/C at -33, C/C at -590 and T/T at -1098 of IL-4 gene (P value < 0.001; OR = 5.3, P value < 0.001; OR = 29.5 and P value < 0.001; OR = 3.3, respectively), while following genotypes were less frequent among patients with JSLE: T/C at -33 and -590 and T/G at -1098 of IL-4 gene (P value < 0.001; OR = 0.1, P value < 0.001; OR = 0.03 and P value < 0.001; OR = 0.3, respectively). Furthermore, we noticed an astonishing negative haplotypic association for JSLE for IL-4 (positions -1098, -509 and -33) TTC, GCC and TTT haplotypes (P value < 0.001). There was also a significant relationship between TCC haplotype (IL-4 gene at positions -1098, -590 and -33) and having JSLE (P value < 0.001). On the other hand, we found no significant associations between IL-4R polymorphisms and the susceptibility to JSLE. Cytokine gene polymorphisms may influence susceptibility to JSLE. Particular IL-4 gene variants are associated with JSLE and might have a role in the pathophysiology of disease.