GATA3 rs3824662 gene polymorphism as possible risk factor for systemic lupus erythematosus.

BACKGROUND: There is no report about the association between GATA3 rs3824662 polymorphism and systemic lupus erythematosus (SLE). OBJECTIVE: To investigate the possible role of GATA3 rs3824662 polymorphism as a susceptibility risk factor for either adult SLE (aSLE) or pediatric SLE (pSLE) and to evaluate its role in the development of lupus nephritis (LN) in pSLE. METHODS: Typing of GATA3 rs3824662 polymorphism was done using real-time polymerase chain reaction for three groups; 104 pSLE patients, 140 aSLE patients and 436 age- and sex-matched healthy controls. RESULTS: Non-significant differences were found between SLE patients and healthy controls for the allele and genotype frequencies of GATA3 rs3824662 ( p > 0.05). In pSLE; the AC genotype was associated with LN ( p = 0.04); the A allele and AC genotype were associated with persistent proteinuria ( p = 0.036 and 0.01, respectively) and both the A allele and AA genotype were associated with higher chronicity index ( p = 0.031 and 0.04, respectively). In aSLE; the C allele was associated with cellular cast ( p = 0.03) and thrombocytopenia ( p = 0.01). Logistic regression analysis revealed significant association between the AC+AA genotypes and the prediction of LN and renal active disease in pSLE ( p = 0.04 and 0.01, respectively). CONCLUSION: GATA3 rs3824662 is not associated with susceptibility to SLE either in adult or in pediatric patients; however, in pSLE patients, the heterozygous AC genotype could be considered a risk factor for LN. At the same time, the AC and AA genotypes could be considered as predictors for LN and active renal disease. However, the small sample size is a limiting factor of the present study when interpreting the positive association.

C1q rs292001 polymorphism and C1q antibodies in juvenile lupus and their relation to lupus nephritis.

C1q deficiency is related strongly to systemic lupus erythematosus (SLE), but very few and inconsistent studies explored the single nucleotide polymorphisms of the C1q gene in relation to juvenile SLE (jSLE) and lupus nephritis (LN). The objective of this study was to analyse whether C1q rs 292001 polymorphism is associated with SLE and disease phenotype, especially nephritis, and to investigate the relation between this polymorphism and clinical data, treatment outcome, serum level of C1q protein and antibodies. Typing of C1q rs292001 polymorphism using restriction fragment length polymorphism and measuring serum levels of C1q protein and antibodies by enzyme-linked immunosorbent assay (ELISA) were performed for 130 children with SLE and 208 healthy controls. The A allele of C1q rs292001 was associated with jSLE and LN (P = 0·005 and 0·013, respectively) and the AA genotype was associated with jSLE (P = 0·036). Low serum levels of C1q protein were found in jSLE and LN (P < 0·001 and 0·009, respectively), and these levels were increased after treatment in patients with LN (P = 0·009) and active renal disease (P = 0·027). Higher titres of C1q antibodies were found in patients with LN (P = 0·015) and correlated negatively with C1q protein level (P < 0·001) and patient age (P = 0·04). The A allele and AA genotype of C1q rs292001 can be considered a susceptibility risk factor and the GG genotype could be considered protective for jSLE and LN in the studied cohort of Egyptian children. Decreased serum levels of C1q protein and increased titres of C1q antibodies may be involved in the pathogenesis of jSLE, especially LN.

Clinical Role of Human Leukocyte Antigen in Health and Disease.

Most of the genes in the major histocompatibility complex (MHC) region express high polymorphism that is fundamental for their function. The most important function of human leukocyte antigen (HLA) molecule is in the induction, regulation of immune responses and the selection of the T cell repertoire. A clinician's attention is normally drawn to a system only when it malfunctions. The HLA system is no exception in this regard, but in contrast to other systems, it also arouses interest when it functions well - too well, in fact. Population studies carried out over the last several decades have identified a long list of human diseases that are significantly more common among individuals that carry particular HLA alleles including inflammatory, autoimmune and malignant disorders. HLA-disease association is the name of this phenomenon, and the mechanism underlying is still a subject of hot debate. Social behaviours are affected by HLA genes and preference for HLA disparate mates may provide 'good genes' for an individual's offspring. Also, certain HLA genes may be associated with shorter life and others with longer lifespan, but the effects depend both on the genetic background and on the environmental conditions. The following is a general overview of the important functional aspects of HLA in health and diseases.

TIM-1 rs41297579 G>A (-1454) and TIM-4 rs7700944 gene polymorphisms as possible risk factor for rheumatoid arthritis: relation to activity and severity.

This study was aimed to evaluate the impact of both TIM-1 rs41297579 G>A (-1454) and TIM-4 rs7700944 polymorphisms on susceptibility to rheumatoid arthritis (RA) in a cohort of Egyptian population and to evaluate for the first time their relation to activity, severity, disease-related disability and erosion. TIM-1 rs41297579 G>A (-1454) and TIM-4 rs7700944 gene polymorphisms were typed by RFLP for 128 patients with RA and 125 healthy controls. The A allele, A-containing genotypes (GA and AA) of the TIM-4 and GA haplotype were present with significant higher frequency in patients with RA than healthy controls (Pc  < 0.001). These findings suggest that the A allele, A-containing genotypes (GA and AA) and GA haplotype may be a susceptibility risk factor for RA [OR = 5.83 (3.6-9.4), OR = 9.41 (5.0-17.6) and OR = 4.21 (1.07-19.2), respectively]. No associations were found between TIM genotypes and disease activity, severity or presence of erosion. However, the RA patients with GA genotype of TIM-4 have higher grade of rheumatoid factor (RF) positivity (P = 0.018), and have worse disease-related disability (P = 0.007) and worse pain (0.025). TIM-4 rs7700944 and not TIM-1 rs41297579 G>A (-1454) is associated with RA in the present cohort of Egyptian and may be a risk factor for development of RA in Egyptian. Both SNPs have no effect on disease activity, severity or erosion. However, TIM-4 GA genotype is associated with higher grade of RF positivity and worse disease-related disability and pain.

CAG repeat length in androgen receptor gene and male infertility in Egyptian patients.

The CAG repeat and its association with infertility has been debatable. Therefore, this study was planned to assess the distribution of CAG repeat expansion in Egyptian patients and to investigate its association with male infertility. Forty-five infertile men were eligible for the study in addition to 20 aged-matched fertile males as control. Semen analysis, scrotal sonography, assay of serum testosterone, follicle-stimulating hormone (FSH) and luteinising hormone (LH), and determination of the CAG repeat number within exon 1 of the androgen receptor (AR) gene were carried out. Statistically significant difference was found between infertile and control groups regarding sperm count, sperm motility, serum FSH level and CAG repeats (P < 0.05); statistically insignificant difference for the CAG repeats (P = 1.0) was found between oligozoospermic and asthenospermic groups; negative correlation was found between CAG repeat length and sperm count, and a positive correlation was found between CAG repeat length and serum FSH (P < 0.05). Our results validate the concept that long stretches of CAG repeat may be associated with lower AR function with derangement of sperm production, and this may contribute to male infertility in Egyptian men.

Association of tumour necrosis factor-alpha -308 G/A promoter polymorphism with susceptibility and disease profile of rheumatoid arthritis.

The objective was to analyze the possible involvement of tumour necrosis factor-alpha (TNF-α) -308 G/A promoter polymorphism in the susceptibility and/or the disease profile of rheumatoid arthritis (RA) in Egyptian patients. TNF-α-308 G/promoter polymorphism detection by amplification refractory mutation system (ARMS) technique was carried out for 122 RA patients and 120 healthy controls. TNF-α-308 G allele/GG homozygous genotype were higher in patients with rheumatoid arthritis than those in control group (P < 0.001, respectively). A statistically significant association was found between the frequency of the A allele and presence of erosion (OR = 3.42, P = 0.015). No associations were found between the distribution of TNF-α-308 G/A alleles/genotypes and age of patients, disease duration, absence of remission, presence of deformity, clinical manifestations of the disease and presence or absence of rheumatoid factor. The positivity of rheumatoid factor was associated with occurrence of erosion (OR = 25.0, P < 0.001). The results of this study demonstrate the association of the TNF-α-308 G allele and GG homozygous genotype with susceptibility to RA and the A allele with the presence of erosion in the Egyptian patients.

Association between HLA-E *0101 homozygosity and recurrent miscarriage in Egyptian women.

The objective was to investigate the frequency of human leucocyte antigen (HLA)-E alleles in Egyptian women with and without recurrent miscarriage (RM) to evaluate their role on the maintenance of pregnancy. A case-control study was adopted. HLA-E gene polymorphism typing was carried out by restriction fragment length polymorphism for 108 women with RM and 120 fertile female controls. The frequency of HLA-E *0101 allele was higher in patients with RM and HLA-E*0103 allele was higher in fertile controls, and the difference was statistically significant (P=0.003, P(c)=0.006). HLA-E*0101/0101 genotype was the most frequent genotype in patients (45.4%), followed by HLA-E*0101/0103 (44.4%) and finally HLA-E*0103/0103 genotype (10.2%). The difference in the frequency of HLA-E*0101/0101 homozygous genotype in patients with RM compared with that in the fertile controls was statistically significant (OR=2.02, 95% CI=1.13-3.62, P=0.011, P(c)=0.033). We found an increased frequency of homozygosity for HLA-E*0101 in Egyptian women with RM. HLA-E*0101 homozygosity may thus be a risk factor for RM.

Association of human leucocyte antigen Class I (HLA-A and HLA-B) with chronic hepatitis C virus infection in Egyptian patients.

Egypt has the highest prevalence of hepatitis C virus (HCV) in the world, ranging from 6% to 28% with an average of approximately 13.8% in the general population. It has been reported that human leucocyte antigen (HLA) alleles are associated with the outcome of HCV infection, but this associations showed ethnic and geographical differences. The objective of this study is to investigate the association between the frequencies of HLA Class I and chronic HCV infection in Egyptian patients and to find out whether there is a relation between certain HLA Class I antigens and HCV viral load, degree of fibrosis, activity and alanine aminotransferase (ALT) level. A case control study was conducted on 100 patients with chronic HCV infection and 150 healthy controls. HLA-A and HLA-B typing by complement-dependent micro-lympho-cytotoxicity assay was performed for both groups. HLA-A11 antigen was significantly increased in patients with chronic HCV infection versus controls (OR 3.98; 95% CI = 1.85-8.89; P = 0.001; and Pc = 0.021). HLA-B12, HLA-B13, HLA-B17 and HLA-B40 were higher in patients, and HLA-A32 and HLA-B14 were higher in controls, although the significance was lost after correction for multiple testing. HLA-A9 was significantly associated with low viral load (P = 0.008, Pc = 0.048). The results of this work implicate that HLA-A11 antigen may influence chronic HCV infection and may play a role in viral persistence. Different HLA Class I antigens are not associated with degree of liver fibrosis, grades of activity or level of ALT. However, HLA-A9 is associated with low HCV viral load in chronic HCV Egyptian patients.

Interferon-gamma +874 T/A and interleukin-10 -1082 A/G single nucleotide polymorphism in Egyptian children with tuberculosis.

The aim was to investigate the association of interferon-gamma (IFN-γ) +874 T/A and interleukin-10 (IL-10)-1082 A/G single nucleotide polymorphisms with tuberculous infection and post-BCG lymphadenitis in Egyptian children. IFN-γ +874 T/A and IL-10 -1082 A/G polymorphism detection by amplification refractory mutation system technique was carried out for 110 patients with TB, 40 patients with post-BCG lymphadenitis and 118 healthy controls. IFN-γ +874 A allele was higher in TB and post-BCG patients than those in healthy controls (Pc=0.006 and 0.002, respectively). IFN-γ +874 genotype AA was significantly higher in patients with TB than that in control (Pc=0.015), in extrapulmonary than patients with pulmonary TB (PTB) (Pc=0.009), and young children with TB below 5 years (Pc=0.024). No statistically significant differences were observed between patients with TB and controls for the frequency of IL-10(-1082) alleles or genotypes (P>0.05); however, a statistically significant difference in the frequency of IL-10 (-1082) GG genotype was found between patients with pulmonary and extrapulmonary TB (Pc=0.003). Low producer IFN-γ +874 A/A genotype is associated with post-BCG lymphadenitis and TB disease especially in younger children below 5 years. IL-10-1082 G/G genotype did not exhibit significant association except for increased GG frequency in PTB. Both cytokine polymorphisms have no relation to tuberculin reaction in patients with TB.

Anti-cyclic citrullinated peptide antibodies in patients with juvenile idiopathic arthritis.

The objectives were to determine the prevalence and clinical significance of anti-cyclic citrullinated peptide (anti-CCP) antibodies in patients with juvenile idiopathic arthritis (JIA). Anti-CCP antibodies were checked by ELISA in 68 children with JIA, 38 males and 30 females with mean age of 10.6 (+/-4.02) years and disease duration of 3.7 (+/-1.8) years. Thirty-eight (56%) patients had polyarticular disease, 20 (29%) patients had oligoarticular disease and 10 (15%) patients had systemic onset disease. All patients had their antinuclear antibodies (ANA), rheumatoid factor (RF) and ESR checked and x-rays performed to look for erosions. Results were compared to those of 20 healthy children, 14 children with juvenile systemic lupus erythematosus (JSLE) and 30 adults with rheumatoid arthritis (RA). Anti-CCP antibodies were positive in 14/68 (20.6%) patients with JIA, all had polyarticular-onset disease. All patients with positive anti-CCP antibodies had RF-positive polyarthritis. Anti-CCP antibodies were negative in all patients with oligoarticular-onset and systemic-onset disease including 2 patients with extended oligoarthritis. Anti-CCP antibodies were negative in healthy and JSLE controls but were positive in 20/30 (66.5%) adults with RA. Anti-CCP antibodies correlated significantly with joint erosions in patients with JIA (p = 0.004) but no significant relation was found between anti-CCP antibodies and ANA positivity or raised ESR. These data confirm that anti-CCP antibodies are less prevalent in JIA than adult RA but are detectable in a significant proportion of RF-positive patients with polyarticular-onset JIA. The current study showed significant relation between anti-CCP positivity and erosive joint disease in JIA.