Interleukin-21 receptor gene polymorphism (rs2285452 A/G) is associated with susceptibility to Behçet's disease.

Behçet's disease (BD) is a chronic auto inflammatory disorder of unknown aetiology. Recently, the dysregulation of interleukin-21 receptor (IL-21R) has been incriminated in different autoimmune and auto-inflammatory diseases, such as systemic lupus erythematous, rheumatoid arthritis, and type 1 diabetes. Herein, we aimed to investigate the association of two Il-21R gene polymorphisms with BD. IL-21R rs2214537 and IL-21R rs2285452 genotypings were investigated in a cohort of 110 adult patients with BD and 116 age and gender unmatched healthy controls. Genotyping was performed by mutagenically separated polymerase chain reaction with newly designed primers. IL-21R rs2285452 genotypes and alleles distribution were statistically different between patients with BD and controls. GA and AA genotypes carrying the minor A allele were more frequent in patients with BD than in healthy controls (37.3% and 11.8% vs. 23.3% and 3.4%, respectively). The minor A allele was associated with an increased BD risk (odds ratios = 2.42, 95% confidence interval = 1.214.87, p = .005). IL-21R rs2214537 GG genotype was found to be associated with susceptibility to BD in the recessive model (GG vs. CC + CG; p = .046, OR =  1.91, 95% CI =  1.003.650. IL-21R rs2285452 and IL-21R rs2214537 were not in linkage disequilibrium (D' = 0.42). The AG haplotype was more frequently observed in patients with BD than in controls (0.247 vs. 0.056, p =  .0001). This study for the first time reports the association of IL-21R rs2285452 and IL-21R rs2214537 with BD. Functional studies are required to elucidate the exact role of these genetic variants.

IRAK2 is associated with systemic lupus erythematosus risk.

INTRODUCTION: Interleukin-1 receptor-associated kinases (IRAKs) are serine-threonine kinases involved in toll-like receptor and interleukin-1 signaling pathways. They play a key role in inflammation and innate immunity. IRAKs have been previously incriminated in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis and inhibition of IRAKs has been recently regarded as a potential therapeutic strategy for SLE. OBJECTIVES: The aim of the present study was to test the association between IRAK2 rs708035 and rs3844283 with SLE. MATERIAL AND METHODS: IRAK2 rs708035 and rs3844283 were genotyped by mutagenically separated polymerase chain reaction (MS-PCR) in 142 SLE patients and 149 age- and gender-matched controls. RESULTS: The hyperfunctional IRAK2 rs708035 A allele was more frequent among SLE patients than controls (62.9% versus 54.7%, p = 0.046). IRAK2 rs3844283 C allele was present in 66.5% of patients and 75.5% of controls. The CC genotype was the most frequently exhibited genotype. It was carried by 45.1% of patients with SLE and 57.7% of controls. The G allele was associated with an increased risk of SLE (OR = 1.54, 95%, CI = 1.07-2.22, p = 0.017). IRAK2 rs708035 and IRAK2 rs3844283 were in linkage disequilibrium (D' = 0.64). The AG haplotype was more frequently observed in SLE patients than in controls (0.292 versus 0.194, p = 0.008). CONCLUSION: This study for the first time ever reveals the association of IRAK2 rs708035 and IRAK2 rs3844283 and the corresponding haplotypes with SLE. Our findings give additional rationale to target IRAKs in the treatment of SLE.Key Points• IRAK2 rs708035 A allele is more frequent in SLE patients than in controls and IRAK2 rs3844283 G allele is associated with SLE susceptibility.• These two alleles are in linkage disequilibrium.• The AG haplotype is associated with SLE.

The Cu/Zn superoxide dismutase +35A/C (rs2234694) variant correlates with altered levels of protein carbonyls and glutathione and associates with severity of COPD in a Tunisian population.

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality that has been associated with inflammation and oxidative stress. The purpose of the present case-control study was to determine the relationships between oxidative stress-related genetic variants and the risk and severity of COPD, as well as, the influence of these variants on inflammatory and oxidative stress parameters. Genotyping of superoxide dismutase 1 (SOD1) + 35 A/C (rs2234694), catalase [A-21T (rs7943316), C-262T (rs1001179)] and glutathione peroxidase 1 (reduced glutathione (GSH)-Px1) 198Pro/Leu (rs1050450) was carried out in 143 patients with COPD and 216 healthy controls using PCR-RFLP. Serum levels of IL-6 and TNF-α were determined by enzyme-linked immunosorbent assays (ELISA), while the levels of reduced GSH, total antioxidant status (TAS), H2O2, lipid peroxides (TBARS) and protein carbonyls (PCs) were determined using spectrophotometric methods. We also evaluated the activities of GSH-Px, catalase, and superoxide dismutase (SOD) in both plasma and erythrocytes. We did not observe significant differences in the genotype and allele frequencies of chosen variants between COPD patients and healthy controls. A significant correlation was retrieved between the SOD1 + 35A/C variant and disease severity (odds ratios (OR) = 0.15, p = 0.04). In addition, patients having the +35AC genotype presented increased plasma levels of GSH and a reduced level of PCs (p = 0.03, p = 0.04, respectively). The present data highlighted the important role of antioxidant enzymes and their genetic variants in the oxidative stress-mediated pathogenesis and progression of COPD.

Molecular characterisation of a mosaicism with a complex chromosome rearrangement: evidence for coincident chromosome healing by telomere capture and neo-telomere formation.

BACKGROUND: Broken chromosomes must acquire new telomeric "caps" to be structurally stable. Chromosome healing can be mediated either by telomerase through neo-telomere synthesis or by telomere capture. AIM: To unravel the mechanism(s) generating complex chromosomal mosaicisms and healing broken chromosomes. METHODS: G banding, array comparative genomic hybridization (aCGH), fluorescence in-situ hybridisation (FISH) and short tandem repeat analysis (STR) was performed on a girl presenting with mental retardation, facial dysmorphism, urogenital malformations and limb anomalies carrying a complex chromosomal mosaicism. RESULTS & DISCUSSION: The karyotype showed a de novo chromosome rearrangement with two cell lines: one cell line with a deletion 9pter and one cell line carrying an inverted duplication 9p and a non-reciprocal translocation 5pter fragment. aCGH, FISH and STR analysis enabled the deduction of the most likely sequence of events generating this complex mosaic. During embryogenesis, a double-strand break occurred on the paternal chromosome 9. Following mitotic separation of both broken sister chromatids, one acquired a telomere vianeo-telomere formation, while the other generated a dicentric chromosome which underwent breakage during anaphase, giving rise to the del inv dup(9) that was subsequently healed by chromosome 5 telomere capture. CONCLUSION: Broken chromosomes can coincidently be rescued by both telomere capture and neo-telomere synthesis.

IRAK2 is associated with susceptibility to rheumatoid arthritis.

This study was performed to investigate the association of the single nucleotide polymorphisms of interleukin-1 receptor-associated kinase 2 (IRAK2) rs3844283 and rs708035 with rheumatoid arthritis (RA). IRAK2 rs3844283 and rs708035genotyping was determined by mutagenically separated PCR with specifically designed primers in a cohort of 222 (30 men, 192 women, mean age 49 years) adult RA patients and 224 matched controls. IRAK2 rs3844283 C allele was detected in 66% of RA patients and 74% of controls. The CC genotype was the most frequent genotype in both RA patients (45.5%) and the controls (56.3%). The G allele was found to be associated with RA susceptibility (OR = 1.47, 95% CI = 1.10-1.96, p = 0.008). The GG genotype was found to be associated with RA in the co-dominant and the dominant models (OR = 2.03, 95% CI = 1.08-3.81, p = 0.042 and OR = 1.54, 95% CI = 1.06-2.23, p = 0.023, respectively). IRAK2 rs708035 was found not to be in the Hardy-Weinberg equilibrium. The hyperfunctional IRAK2 rs708035 A allele was more frequent in RA patients than in controls (69.9 versus 62.2%, respectively, p = 0.015). Moreover, IRAK2 rs708035 and IRAK2 rs3844283 were in linkage disequilibrium and the GA haplotype was significantly more frequent in RA patients than in controls (p = 0.034). This study for the first time ever reports the association of IRAK2 rs3844283, IRAK2 rs708035, and the corresponding haplotypes with RA. Functional studies are recommended to elucidate the risk posed by the GA haplotype for the development of RA.

The role of enterovirus infections in type 1 diabetes in Tunisia.

BACKGROUND: Enteroviral infections have long been suspected in having a role in ß cell destruction and therefore leading to the onset of clinical type 1 diabetes (T1D). The frequency of enterovirus (EV)-related T1D in North Africa is still unknown. The aim of the present study was to investigate the relationship between infection with EV and T1D in Tunisia. METHODS: A total of 95 T1D patients (41 children and 54 adults) and 141 healthy control subjects (57 children and 84 adults) were tested for the presence of EV-RNA by a highly sensitive nested reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS: EV-RNA was detected more frequently in plasma from diabetic patients than in plasma of controls (31.6% vs. 7.8%, p<0.0001; OR=5.45; 95% CI 2.44-12.43). RT-PCR revealed positive in 53.7% of T1D children and 14.8% of T1D adults. There was a statistically significant difference between children and adults with T1D (p<0.0001). Positivity of EV-RNA according to the time after the occurrence of the disease did not show any significant difference (p=0.34). Anti-glutamic acid decarboxylase (GAD) antibodies were not associated with EV-RNA (p=0.65). CONCLUSIONS: EV-RNA is associated with T1D mellitus in the Tunisian population especially in children. These results support the hypothesis that EV act as environmental risk factors for T1D.

Increased oxidative stress and altered levels of nitric oxide and peroxynitrite in Tunisian patients with chronic obstructive pulmonary disease: correlation with disease severity and airflow obstruction.

This study was aimed to evaluate the oxidant-antioxidant imbalance in the pathogenesis of chronic obstructive pulmonary disease (COPD) in Tunisians. We assessed 16 parameters related to the oxidative status that include malondialdehyde (MDA), total protein carbonyls (PCs), and advanced oxidation protein products (AOPP). We also examined the activity of glutathione peroxydase (GSH-Px), catalase, and superoxide dismutase (SOD) in the plasma and erythrocytes. Levels of total thiols, reduced glutathione (GSH), total antioxidant status (TAS), hydrogen peroxide, ascorbic acid, iron, and protein sulfhydryls were determined using spectrophotometry. We also evaluated the level of nitric oxide (NO) and peroxynitrite in plasma from COPD patients and healthy controls. Estimation of DNA damage was determined using the comet assay. Pulmonary functional tests were performed by body plethysmography. Levels of MDA, PC, DNA damage, and AOPP were significantly increased while total thiols, GSH, and TAS were decreased in COPD patients. GSH-Px activity was higher in COPD patients while no difference was found for catalase and SOD. We also observed a lower level of NO and peroxynitrite in COPD patients. Decreased levels of peroxynitrite were found to correlate with disease progression, as well as with forced expiratory volume in 1 s/forced vital capacity among COPD patients. Multivariate analysis revealed that NO is associated with pathological pathways that help to predict patient outcome independently of the degree of airflow obstruction. These results indicate the presence of a systemic oxidative stress and highlight the importance of NO and peroxynitrite as major effectors in COPD development and airflow obstruction.

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.