Transmembrane Protein 187 (TMEM187) and Interleukin 1 Receptor Associated Kinase (IRAK1) gene polymorphism association with rheumatoid arthritis susceptibility in Egyptian patients.

Rheumatoid arthritis (RA) is a chronic auto-inflammatory disease of connective tissue with progressive joint damage and systemic disorders. RA is considered a multifactorial disease triggered by a genetic predisposition and environmental factors. Polymorphisms have been identified in the Xq28 locus as risk loci for RA. The aim of study was to assess the association between two polymorphisms in the Xq28 region containing Transmembrane Protein 187 (TMEM187) gene (rs13397) and interleukin1 receptor associated kinase (IRAK1) gene (rs1059703) with the disease susceptibility and activity in Egyptian RA patients. This study was conducted on 100 RA patients and 100 age and sex matched normal controls, together were recruited from the Rheumatology Department, Beni-Suef University Hospital. We detected TMEM187 (rs13397) and IRAK1 (rs1059703) gene polymorphisms using the real time PCR TaqMan allelic discrimination assays. We found that the frequency of the major genotypes (GG) of TMEM 187 gene was higher in RA group (54%) compared to controls (50%); while the minor genotypes (AA) was higher in the control group (22%) compared to the diseased one (18%), but such differences did not reach statistical significance (p=0.599). Regarding the IRAK1 gene, we revealed that the frequency of the major genotypes (AA) of the rs1059703 was slightly higher in RA group (48%) compared to controls (46%); while the minor genotypes (GG) was the same in both groups (26%). However, there was higher incidence of minor genotype in the TMEM187 and IRAK1 genes in males; with a statistical significance (p=0.004 and 0.015, respectively). We concluded that the major allele G of TMEM187(rs 13397) could be considered as a risk genetic allele for RA in Egyptian populations.

Influence of glutathione S transferase A1 gene polymorphism (-69C > T, rs3957356) on intravenous cyclophosphamide efficacy and side effects: a case-control study in Egyptian patients with lupus nephritis.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. Cyclophosphamide (CYC) is a cytotoxic drug of a narrow therapeutic window that is commonly used in lupus nephritis (LN) treatment. However, 30-40% of patients experience CYC resistance. CYC inactivation is mediated by the glutathione S transferases (GSTs) superfamily: GST class A (GSTA) has the greatest activity and contains 5 isoenzymes. Polymorphisms of genes involved in the drug metabolism could alter the drug pharmacokinetics and effectiveness. CYC pharmacokinetics and pharmacogenomics are extensively studied in malignancies; however, scarce data are available about this issue in the autoimmune rheumatic diseases. Prediction of the drug response helps the achievement of the highest benefit-to-risk ratio. The aim of this case-control study was to address the association between GSTA1 polymorphism (-69C > T, rs3957356), and the rate of response to and side effects of intravenous CYC in LN patients. METHODS: Ninety-four patients were included and divided into matched groups: resistant and responsive. Genotyping was performed using restriction fragment length polymorphism method after amplification. RESULTS: A significant association between the TT genotype, and CYC resistance and partial response was observed. Concerning the recessive model, none of the patients within the TT group achieved complete remission. CYC side effects were more common with the polymorphism under the genotype, recessive model, and allele distributions. When patients' pre- and post-treatment characteristics were compared, patients with the TT genotype did not show any significant improvement. CONCLUSION: LN patients with GSTA1 (-69C > T, rs3957356) TT genotype have the highest risk of CYC unresponsiveness and toxicity. Key-Points • LN patients with the wild genotype of GSTA1 have the greatest probability of achieving a complete renal response to IV CYC. • The homozygous GSTA1 (-69C > T, rs3957356) TT genotype is associated with the highest risk of LN unresponsiveness to IV CYC. • The homozygous GSTA1 (-69C > T, rs3957356) TT genotype is associated with the highest risk of CYC-related side effects.

Association Study of FOXO3a Single-Nucleotide Polymorphism and Bronchial Asthma in Egyptian Children.

Asthma is the most common chronic illness in children and is a leading cause of childhood hospitalization and school absenteeism. Asthma presents with different phenotypes depending on age, gender, genetic background, environmental exposures and epigenetic factors. Forkhead box O3 (FOXO3) is a transcription factor involved in the pathogenesis of a number of inflammatory and respiratory diseases. The study aims to investigate the association between the SNP rs13217795 in FOXO3 gene and pediatric onset asthma in the Egyptian population. Ninety asthmatics and 160 healthy controls were subjected to genotyping of FOXO3 SNP (rs13217795) using the PCR-RFLP method. The proportion of homozygous (CC) and heterozygous (CT) genotypes was lower in the asthmatic group compared to the control group but statistically insignificant; P > 0.05. On the other hand the proportion of the mutant homozygous (TT) genotype in asthmatic group was higher; 30 (33.3%) than the control group; 28(17.5%), the difference was significant in Recessive model of disease penetrance with Odds ratio OR (95% CI) of 2.4(1 - 5.49) and P=0.039. This association was more pronounced in male gender; OR and 95% CI of 5.3 (1.4- 19.3) and P=0.01. In conclusions, Egyptian children carrying the mutant (TT) genotype were at higher risk to develop asthma with a higher risk in male gender.

Role of Cannabinoid CB2 Receptor Gene (CNR2) Polymorphism in Children with Immune Thrombocytopenic Purpura in Beni-Suef Governorate in Egypt.

The cannabinoid system is involved in the immune regulation by modulation of Th cells type 1 and 2. It is composed of the CB2 receptor which is expressed at 10 to 100 folds greater levels on immune cells than the CB1 receptors. The CB2 is encoded by the cannabinoid CB receptor gene (CNR2) gene. This study aims to investigate the polymorphism in CNR2 gene variation rs 35761398 (Q63R) in Egyptian children with immune thrombocytopenic purpura and to investigate the relation between this gene polymorphism and either the susceptibility to or the chronicity of the disease. Forty children diagnosed as ITP were included in this study and 20 healthy children as normal control. CNR2 gene was investigated in those children by PCR RFLP technique (restriction fragment length polymorphism). CNR2 genotyping revealed that 45% of ITP patients had the QR heterotype, 50% had the RR homotype and 5% had QQ, the wild type with significantly higher frequency of homomutant genotype in comparison to controls. The relative odds ratio suggested a double risk for developing ITP in RR homotype (OR 2.152). A significant overpresentation of the RR genotype and of R allele was observed in the chronic patients (P=0.002 and 0.003, respectively). The associated risk to develop chronic ITP increased more than two folds for the RR homotype (OR=2.854). In conclusion, this study confirms the role of CNR2 Q63R polymorphism in the susceptibility to ITP in children and chronicity of the disease.