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.

A pilot study revealing host-associated genetic signatures for source attribution of sporadic Campylobacter jejuni infection in Egypt.

Campylobacter jejuni (C. jejuni), is considered among the most common bacterial causes of human bacterial gastroenteritis worldwide. The epidemiology and the transmission dynamics of campylobacteriosis in Egypt remain poorly defined due to the limited use of high-resolution typing methods. In this pilot study, we evaluated the discriminatory power of multiple typing 'gene-by-gene based' techniques to characterize C. jejuni obtained from different sources and estimate the relative contribution of different potential sources of C. jejuni infection in Egypt. Whole genome sequencing (WGS) was performed on 90 C. jejuni isolates recovered from clinical samples, retail chicken, and dairy products in Egypt from 2017 to 2018. Comparative genomic analysis was performed using conventional seven-locus multilocus sequence typing (MLST), ribosomal MLST (rMLST), core genome MLST (cgMLST), allelic variation in 15 host-segregating (HS) markers, and comparative genomic fingerprinting (CGF40). The probabilistic source attribution was performed via STRUCTURE software using MLST, CGF40, cgMLST and allelic variation in HS markers. Comparison of the discriminatory power of the aforementioned genotyping methods revealed cgMLST to be the most discriminative method, followed by HS markers. The source attribution analysis showed the role of retail chicken as a source of infection among clinical cases in Egypt when HS and cgMLST were used (64.2% and 52.3% of clinical isolates were assigned to this source, respectively). Interestingly, the cattle reservoir was also identified as a contributor to C. jejuni infection in Egypt; 35.8% and 47.7% of clinical isolates were assigned to this source by HS and cgMLST, respectively. Here, we provided evidence of the importance of using WGS typing methods to facilitate source tracking of C. jejuni. Our findings suggest the importance of non-poultry sources, together with the previously reported role of retail chicken in human campylobacteriosis in Egypt that can provide insights to inform national control measures.

A role for Rad5 in ribonucleoside monophosphate (rNMP) tolerance.

Ribonucleoside monophosphate (rNMP) incorporation in genomic DNA poses a significant threat to genomic integrity. In addition to repair, DNA damage tolerance mechanisms ensure replication progression upon encountering unrepaired lesions. One player in the tolerance mechanism is Rad5, which is an E3 ubiquitin ligase and helicase. Here, we report a new role for yeast Rad5 in tolerating rNMP incorporation, in the absence of the bona fide ribonucleotide excision repair pathway via RNase H2. This role of Rad5 is further highlighted after replication stress induced by hydroxyurea or by increasing rNMP genomic burden using a mutant DNA polymerase (Pol ε - Pol2-M644G). We further demonstrate the importance of the ATPase and ubiquitin ligase domains of Rad5 in rNMP tolerance. These findings suggest a similar role for the human Rad5 homologues helicase-like transcription factor (HLTF) and SNF2 Histone Linker PHD RING Helicase (SHPRH) in rNMP tolerance, which may impact the response of cancer cells to replication stress-inducing therapeutics.

Assessment of Interferon Gamma-Induced Protein 10 mRNA Release Assay for Detection of Latent Tuberculosis Infection in Egyptian Pediatric Household Contacts.

OBJECTIVES: Current diagnostic tests for tuberculosis (TB) in children living in low-endemic countries are limited by low specificity and the inability of the current tests to differentiate between active TB and latent TB infection (LTBI). This study aimed to evaluate the blood IP-10 mRNA expression level to detect LTBI in Egyptian pediatric household contacts (PHC). METHODS: TB-specific IP-10 and IFN-γ mRNA levels were assessed by real-time quantitative PCR (RT-qPCR) in 72 Egyptian PHC of active pulmonary TB cases. All study participants were also assessed by Tuberculin Skin Test (TST) and Quantiferon gold in tube (QFN-GIT) assay. RESULTS: IP-10 and IFN-γ mRNA expression levels were significantly higher in PHC with active TB or LTBI than TB negative (p < 0.0001). The level of IP-10 mRNA expression was significantly higher in PHC with active TB than LTBI (p = 0.0008). In contrast, there was no significant differences in the IFN-γ mRNA expression between PHC with active TB compared to LTBI (p = 0.49). The sensitivity and specificity of the IP-10 RT-qPCR were 94.2% and 95.2%, respectively, in PHC with active TB compared to 85.7% and 81.8% in PHC with LTBI. The negative and positive predictive values and accuracy of IP-10 RT-qPCR for distinguishing active TB from LTBI were 85.2%, 58.3%, and 72.6% respectively. CONCLUSION: Blood IP-10 mRNA expression level may be a potential diagnostic marker to help distinguish active TB from LTBI in PHC.

The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine.

In the era of precision medicine, analyzing the transcriptomic profile of patients is essential to tailor the appropriate therapy. In this study, we explored transcriptional differences between two invasive breast cancer subtypes; infiltrating ductal carcinoma (IDC) and lobular carcinoma (LC) using RNA-Seq data deposited in the TCGA-BRCA project. We revealed 3854 differentially expressed genes between normal ductal tissues and IDC. In addition, IDC to LC comparison resulted in 663 differentially expressed genes. We then focused on DNA repair genes because of their known effects on patients' response to therapy and resistance. We here report that 36 DNA repair genes are overexpressed in a significant number of both IDC and LC patients' samples. Despite the upregulation in a significant number of samples, we observed a noticeable variation in the expression levels of the repair genes across patients of the same cancer subtype. The same trend is valid for the expression of miRNAs, where remarkable variations between patients' samples of the same cancer subtype are also observed. These individual variations could lie behind the differential response of patients to treatment. The future of cancer diagnostics and therapy will inevitably depend on high-throughput genomic and transcriptomic data analysis. However, we propose that performing analysis on individual patients rather than a big set of patients' samples will be necessary to ensure that the best treatment is determined, and therapy resistance is reduced.