Genome-wide association study of psoriasis in an Egyptian population.

Psoriasis is a chronic inflammatory disorder of the skin, with genetic factors reportedly involved in the disease pathogenesis. Numerous studies reported psoriasis candidate genes. However, these tend to involve mostly in the European and Asian populations. Here, we report the first genome-wide association study (GWAS) in an Egyptian population, identifying susceptibility variants for psoriasis using a two-stage case-control design. In the first discovery stage, we carried out a genome-wide association analysis using the Infinium® Global Screening Array-24 v1.0, on 253 cases and 449 control samples of Egyptian descent. In the second replication stage, 26 single-nucleotide polymorphisms (SNPs) were selected for replication in additional 321 cases and 253 controls. In concordance with the findings from previous studies on other populations, we found a genome-wide significant association between the MHC locus and the disease at rs12199223 (Pcomb  = 6.57 × 10-18 ) and rs1265181 (Pcomb  = 1.03 × 10-10 ). Additionally, we identified a novel significant association with the disease at locus, 4q32.1 (rs12650590, Pcomb  = 4.49 × 10-08 ) in the vicinity of gene GUCY1A3, and multiple suggestive associations, for example rs10832027 (Pcomb  = 7.28 × 10-06 ) and rs3770019 (Pcomb  = 1.02 × 10-05 ). This proposes the existence of important interethnic genetic differences in psoriasis susceptibility. Further studies are necessary to elucidate the downstream pathways of the new candidate loci.

Association between CD226 polymorphism and soluble levels in rheumatoid arthritis: Relationship with clinical activity.

OBJECTIVE: To study the relation between CD226 rs763361 gene polymorphism and CD226 serum level and to evaluate their role in susceptibility and disease activity of RA in a cohort of Egyptian individuals. METHODS: The serum level of CD226 was measured using a suitable ELISA kit and the CD226 rs763361 gene polymorphism was typed by PCR-RFLP for 112 RA patients and 100 healthy controls. RESULTS: Significant association with RA was found with CD226 T allele (OR (95%CI) = 1.6 (1.04-2.4), P = 0.032), and higher CD226 serum level (P = 0.001). Higher CD226 levels were associated with higher ESR values (P = 0.035), positive CRP (0.048), increased number of tender joints (P = 0.045), and higher DAS score (P = 0.035). Serum CD226 is an independent risk factor for the prediction of RA (P = 0.001). No correlations were found between the serum level of CD226 and different CD226 genotypes and also between them and RA activity grades. CONCLUSION: The CD226 T allele may be susceptibility risk factors for the development of RA and the higher serum level of CD226 may be involved in the pathogenesis of RA in Egyptian patients. The serum level of CD226 and not CD226 genotypes could be considered as an independent risk factor for the prediction of RA within healthy individuals and also for RA disease activity.

Association of interleukin-17F (rs763780) single nucleotide polymorphism with multiple sclerosis and optic neuritis.

IL-17F single nucleotide polymorphism (SNP) can affect IL-17F expression and activity and this can lead to the increased susceptibility to several autoimmune diseases. The aim was to investigate the association of IL-17F (rs763780) SNP with the development of multiple sclerosis (MS) in a cohort of Egyptian patients and to evaluate the effect of this polymorphism on the disease course. IL-17F (rs763780) gene polymorphisms was typed by TaqMan genotyping assay for 231 Egyptians divided into 102 MS patients and 129 healthy controls with matched age and sex. The IL-17F rs763780 C containing genotypes (CT+CC) and C allele have statistically significant increased frequency in MS patients when compared with controls (p = 0.005 and 0.004 respectively) especially in females' patients (p = 0.005 and 0.006 respectively). The heterozygous CT genotype was associated with the presence of optic neuritis (p = 0.038). The multivariable regression analysis revealed significant associations between smoking, the higher frequency of attacks and the prediction of higher EDSS score (p = 0.032, 0.049 respectively). It can be concluded that the IL-17F rs763780 C containing genotypes (CT and CC) and C allele may be risk factors for the development of MS in the studied Egyptian cohort by a gender-dependent mechanism that contributes to tendency for predisposition in females and optic neuritis is more common in patients carrying the CT heterozygous genotype.

Genome-wide association study for systemic lupus erythematosus in an egyptian population.

Systemic lupus erythematosus (SLE) susceptibility has a strong genetic component. Genome-wide association studies (GWAS) across trans-ancestral populations show both common and distinct genetic variants of susceptibility across European and Asian ancestries, while many other ethnic populations remain underexplored. We conducted the first SLE GWAS on Egyptians-an admixed North African/Middle Eastern population-using 537 patients and 883 controls. To identify novel susceptibility loci and replicate previously known loci, we performed imputation-based association analysis with 6,382,276 SNPs while accounting for individual admixture. We validated the association analysis using adaptive permutation tests (n = 109). We identified a novel genome-wide significant locus near IRS1/miR-5702 (Pcorrected = 1.98 × 10-8) and eight novel suggestive loci (Pcorrected < 1.0 × 10-5). We also replicated (Pperm < 0.01) 97 previously known loci with at least one associated nearby SNP, with ITGAM, DEF6-PPARD and IRF5 the top three replicated loci. SNPs correlated (r 2 > 0.8) with lead SNPs from four suggestive loci (ARMC9, DIAPH3, IFLDT1, and ENTPD3) were associated with differential gene expression (3.5 × 10-95 < p < 1.0 × 10-2) across diverse tissues. These loci are involved in cellular proliferation and invasion-pathways prominent in lupus and nephritis. Our study highlights the utility of GWAS in an admixed Egyptian population for delineating new genetic associations and for understanding SLE pathogenesis.

HLA-class II alleles in Egyptian patients with hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is linked to environmental, dietary, and life style factors. Its incidence and distribution vary widely among ethnic groups, sex, and geographic regions. HBV and HCV Infection, liver cirrhosis, male gender, and old age are important risk factors of HCC. Variability in outcome following exposure, and the clustering of HCC within families raise the possibility that genetic factors are also involved in susceptibility to HCC. The Major Histocompatibility Complex (MHC) plays a key role in anti-virus and tumor defense. HLA polymorphism is implicated in conferring genetic susceptibility to a large number of immune-mediated diseases, including some cancers. The association between HLA class II antigen and HCC in different ethnic populations that has been reported is controversial. Therefore, the aim of this work was to study the association between HLA class II-DRB1 and DQB1 polymorphism and HCC in Egyptian patients and to investigate their role as risk factors for the development of HCC. METHODS: HLA-class II (DRB1 and DQB1) typing was done by SSP for 100 subjects; 50 patients suffering from HCC (45 males and 5 females) with age range 40-64 years (51.16 years (y) +/- 6.16); and 50 normal healthy control subjects. RESULTS: 1. A significantly increased frequency of DRB1*04, and DQB1 *02 in HCC patients versus control group (p = 0.016, and 0.032, respectively) was found; 2. A significantly decreased frequency of DQB1*06 (p = 0.032) was found; 3. A significantly increased frequency of DRB1*07 (odds ratio (OR) = 4.929) was found; and 4. A significantly decreased frequency of DRB1*15 (OR = 0.316) was seen. In conclusion, while some alleles are significantly associated with HCC (DRB1*04, DQB1*02) and others are not associated (DQB1*06); therefore, it can be concluded that the DRB1*04 and DQB1*02 alleles might be risk factors for the occurrence of HCC (OR = 4.373 and 3.807, respectively), and DQB1*06 may be a protective allele (OR = 0.259).

HLA-DQB1* alleles and genetic susceptibility to type 1 diabetes mellitus.

AIM: To determine human leukocyte antigen (HLA)-DQB1 allele association with susceptibility to type 1 diabetes (T1D) and to clinical and laboratory findings. METHODS: This study was conducted on 85 unrelated Egyptian children with T1D recruited consecutively from the Pediatric Diabetes Endocrinology outpatients Clinic; Mansoura University Children's Hospital, Egypt. Patient mean follow up period was 2.5 years. Patients were subdivided according to level of HbA1c (optimal/suboptimal control < 8.5% and poor control ≥ 8.5%). The control group consisted of 113 unrelated age- and sex-matched healthy subjects without T1D or other autoimmune diseases. Genomic DNA extraction was done for all subjects using a DNA isolation kit. HLA-Class II-DQB1 allele typing was carried out with a polymerase chain reaction-sequence-specific oligonucleotide probe using a INNO-LiPA HLA-DQB1 update kit. RESULTS: Significant differences were detected between Egyptian patients with T1D and control groups in the frequencies of DQB1*02 [44.4% vs 18.6%, corrected P value (Pc) < 0.001] and DQB1*03 (41.2% vs 24.4%, Pc < 0.001). Significant differences were also observed between control groups and T1D patients in the frequencies of DQB1*05 (14.6% vs 7.2%, P = 0.029) and DQB1*06 (34.1% vs 7.2%, P < 0.001). However, after correction for multiple comparisons, the significance was retained for HLA-DQB1*06 (Pc < 0.001) but lost for HLA-DQB1*05. HLA-DQB1*0201, *0202, *030201 were positively associated with T1D (Pc = 0.014, Pc < 0.001, and Pc < 0.001 respectively), while HLA-DQB1*060101 was negatively associated (Pc < 0.001) with the condition. Although the HLA-DQB1 alleles 030101 and 050101 were significantly higher in controls (P = 0.016, P = 0.025 respectively), both of them lost statistical significance after correction of P value. The frequency of the HLA-DQB1 genotypes 02/02, 02/03, and 03/03 was higher in T1D patients, and the frequency of the genotypes 03/06, 05/06, and 06/06 was higher in controls, these differences being statistically significant before correction. After correction, the genotypes 02/02, 02/03 in T1D, and the genotypes 03/06, 06/06 in controls were still significant (Pc = 0.01, Pc < 0.001, Pc < 0.001, and Pc = 0.04, respectively). Non-significant associations were found between the frequency HLA-DQB1 alleles and genotypes in T1D in relation to the grade of diabetic control, Microalbuminuria, age, gender, age of presentation, weight, height, frequency of diabetic ketoacidosis (P = 0.42), serum cholesterol, and fasting and post-prandial level of C-peptide (P = 0.83, P = 0.9, respectively). CONCLUSION: The Current work suggests that HLA-DQB1 alleles *030201, *0202, *0201, and genotypes 02/03, 02/02 may be susceptibility risk factors for development of T1D in Egyptian children, while the HLA-DQB1*060101 allele, and 03/06, 06/06 genotypes may be protective factors. HLA-DQB1 alleles and genotypes do not contribute to microalbuminuria or grade of diabetic control.

Vascular endothelial growth factor, p53, and the H-ras oncogene in Egyptian patients with bladder cancer.

AIM: To evaluate the relationship between vascular endothelial growth factor (VEGF), p53, and the H-ras oncogene and different clinicopathological parameters in Egyptian patients with Schistosoma-associated transitional cell carcinoma of the bladder. METHODS: The study included 50 patients with transitional cell carcinoma for whom radical cystectomy and urinary diversions were carried out. VEGF and p53 protein expressions were evaluated with an immunohistochemical staining method, and H-ras oncogene mutations were analyzed with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: High grade tumors revealed higher p53 immunostaining than low grade tumors (P = 0.016). p53 and VEGF protein expressions, as well as H-ras oncogene mutations, had an insignificant impact on patient outcomes (P = 0.962, P = 0.791, and P = 967, respectively). Cancer extension to regional lymph nodes was associated with poor outcomes (P = 0.008). CONCLUSION: VEGF, p53 and the H-ras oncogene have no relation to patient survival and outcome in Schistosoma-associated transitional cell carcinoma.