Nasser A. Elhawary

Molecular Updating of β-Thalassemia Mutations in the Upper Egyptian Population

We have updated the dataset of the molecular spectrum of the β-thalassemia (β-thal) in Upper Egypt. Buccal swabs were analyzed from 94 unrelated patients with β-thal major (β-TM) using reverse dot-blot and multiplex amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). The most frequent mutation was IVS-I-110 (G>A) (57%). The IVS-I-110, IVS-I-6 (T>C) and IVS-I-1 (G>A) mutations accounted for 87% of the β-thal anomalies. The codon 39 (C>T) and frameshift codon (FSC) 6 (–A) (GAG>–GG) mutations were only detected in Al-Minya and Qina, respectively. We did not observe the IVS-II-745 (C>G) or –101 (C>T) mutations. Forty-three percent of Upper Egyptians were homozygotes. Our efforts were an important step to complete the mutation map of β-thal in Egypt restricted to Cairo and the Nile Delta regions. This study will help to develop preventative programs for Upper Egyptians. It addressed the genetic drift of the β-thal gene mutations in Africa, Asia, and Europe.

The MTHFR 677T Allele May Influence the Severity and Biochemical Risk Factors of Alzheimer's Disease in an Egyptian Population

Objective. We evaluated whether the methylenetetrahydrofolate reductase (MTHFR) 677C>T marker influences the risk and severity of Alzheimers disease (AD) and whether AD is associated with homocysteine, vitamin B12, and cholesterol levels in Egypt. Methods. Forty-three Alzheimers cases and 32 non-AD controls were genotyped for the 677C>T polymorphism. Clinical characteristics and levels of homocysteine, vitamin B12, and cholesterol were assessed. Results. No significant differences in the frequencies of the MTHFR alleles or genotypes between AD cases and controls (P = 0.14) were identified. The 677T mutant allele was significantly overrepresented in AD cases compared to controls (OR = 2.22; P = 0.03). The 677T/T frequency was three times higher in AD patients than in controls, which could increase plasma homocysteine levels. Severe cases of AD were the most frequent in patients with the T/T genotype (11.6%). The effect of the MTHFR polymorphism on the risk of AD may be independent of homocysteine, vitamin B12, or even cholesterol levels. Conclusions. The MTHFR 677C>T polymorphism—especially the presence of one copy of the T allele—appears to confer a potential risk for the development of AD. The T/T genotype may contribute to hypercysteinemia as a sensitive marker.

The impact of common tumor necrosis factor haplotypes on the development of asthma in children: an Egyptian model.

Conflicting results have arisen among different ethnic populations with regard to the ability of tumor necrosis factor (TNF) to control the development of bronchial asthma. We examined common TNF polymorphisms (TNFA -1031C>T, TNFA -308G>A, and TNFB +252A>G) to develop a model of the associations between these genetic markers and the development of the disease in Egypt. Amplified DNA from buccal mucosa was genotyped for 240 children using polymerase chain reaction-restriction fragment length polymorphism. Skin prick test, total serum immunoglobulin E levels, and assessment of pulmonary functions were investigated. The onset age for one-third of the asthma patients in our study was between 7 and 10 years. The TNFA -1031C>T and TNFA -308G>A polymorphisms were strongly associated with the risk of asthma (p = 0.007, and p = 0.000, respectively), but the TNFB +252A>G polymorphism was not (p = 0.6). We detected a significant linkage between the +252A>G and -1031C>T, and another between the +252A>G and the -308G>A (p < 0.0001 for both). The -1031C>T and -308G>A polymorphisms were not linked (p = 0.14). The -308A/A genotype was absent, and the -308A allele was expressed only in patients with -308G/A heterozygosity (13%). All but the +252G/A genotype were also strongly associated with the severity of disease. Environmental factors, as genetic variations, clearly influence susceptibility, the onset, progression, and severity of bronchial asthma. More information is needed to develop genetic models of susceptibility for different ethnic populations.

TNF-238 polymorphism may predict bronchopulmonary dysplasia among preterm infants in the Egyptian population†

Bronchopulmonary dysplasia (BPD) remains as a major and increasing burden in Egypt.

Association between ANKK1 (rs1800497) and LTA (rs909253) Genetic Variants and Risk of Schizophrenia.

Limited research has assessed associations between schizophrenia and genetic variants of the ankyrin repeat and kinase domain containing 1 (ANKK1) and lymphotoxin-alpha (LTA) genes among individuals of Middle Eastern ancestry. Here we present the first association study investigating the ANKK1 rs1800497 (T>C) and LTA rs909253 (A>G) single-nucleotide polymorphisms in an Egyptian population. Among 120 patients with DSM-IV and PANSS (Positive and Negative Syndrome Scale) assessments of schizophrenia and 100 healthy controls, we determined the genotypes for the polymorphisms using endonuclease digestion of amplified genomic DNA. Results confirmed previous findings from different ethnic populations, in that the rs1800497 and rs909253 polymorphisms were both associated with risk of schizophrenia. Differences between the genotypes of cases and controls were strongly significant (P = 0.0005 for rs1800497 and P = 0.001 for rs909253). The relative risk to schizophrenia was 1.2 (P = 0.01) for the C allele and 0.8 (P = 0.04) for the G allele. The CC, GG, and combined CC/AA genotypes were all more frequent in cases than in controls. These results support an association between ANKK1 and LTA genetic markers and vulnerability to schizophrenia and show the potential influence of just one copy of the mutant C or G allele in the Egyptian population.

Common Tag STSs in the AZF Region Associated with Azoospermia and Severe Oligospermia in Infertile Egyptian Men~!2009-12-21~!2010-04-13~!2010-06-18~!

Screening of Yq has become one of the most frequently performed postnatal molecular genetic tests in Egypt. Our purpose was to determine the tag sequence-tagged sites (STSs) in the AZF -region of Yq associated with azoospermia and severe oligospermia in infertile Egyptian men. We analyzed blood samples from 49 infertile men (28 with azoospermia and 21 with severe oligospermia) using multiplex PCR for six common AZFa, AZFb, and AZFc STS markers,, as recommended by the European Academy of Andrology. Twenty-four (37%) microdeletions with five separate deletions were identified. We found 66.7% of the deletions in the AZFb locus, 20.8% in the AZFa locus, and 12.5% in the AZFc locus. Some common haplotypes (7 of 10) were identified in our sample population. Haplotypes H3 (corresponding to sY127) and H4 (corresponding to sY134) were the most common. We suggest that screening with a minimum of three STSs-sY86, sY127, and sY134-would provide the highest level of clinical sensitivity in genetic testing among infertile Egyptian men. Moreover, separate microdeletions were localized in infertile Y-chromosome patients.

Combined Genetic Biomarkers Confer Susceptibility to Risk of Urothelial Bladder Carcinoma in a Saudi Population

We evaluated the associations between seven single nucleotide polymorphisms and susceptibility to urothelial bladder carcinoma (UBC) in a Saudi population. Genomic DNA was taken from buccal cells of 52 patients with UBC and 104 controls for genotyping of GSTT1, GSTM1, rs4646903, rs1048943, TP53 rs1042522, rs1801133, and rs1801394 using PCR and TaqMan® assays. The rs1801133 and rs1801394 variants showed strong associations with UBC (OR = 2.3, P = 0.0002; OR = 2.6, P = 0.0001, resp.). Homozygosity of Pro72 conferred a significant double risk in cases compared with controls (30.8% versus 15.4%), but the homozygote Arg/Arg had no effect on risk. Genotypic combinations of GSTM1/GSTT1, rs4646903/rs1048943, and rs1801133/rs1801394 exhibited significant linkage with the disease (χ2 = 10.3, P = 0.006; χ2 = 13.9, P = 0.003; and χ2 = 20.4, P = 0.0004, resp.). The GSTM1 and rs1042522Arg and rs1801394G variant alleles were more frequent in current smokers with UBC (52.4%, 52.5%, and 64.3%, resp.) than were the corresponding wild-types. Despite some variants having only a slight effect on UBC risk, the interaction effect of combined genetic biomarkers—or even the presence of one copy of a variant allele—is potentially much greater. Perhaps more studies regarding next-generation genetic sequencing and its utility can add to the risk of UBC.

Azoospermia factor microdeletions: common tag STSs in infertile men with azoospermia and sever oligospermia from Egypt

Background Screening of Yq has become one of the most frequently performed postnatal molecular genetic tests in Egypt. A survey sponsored by WHO estimated the prevalence of infertility among Egyptian couples to be 12% (4.3% for primary infertility and 7.7% for secondary infertility) [1]. The 10-Mb AZF region on the q-arm of the Y chromosome is frequently deleted in men with unexplained spermatogenic failure. Microdeletions are linked to AZF loci in 20-30% of patients with non-obstructive azoospermia and in 3-7% of patients with severe idiopathic oligospermia [2]. AZF microdeletions are associated with varied testicular histology, ranging from Sertoli-Cell-Only (SCO) syndrome to hypospermatogenesis to maturation arrest. We aim to determine the tag sequence-tagged sites (STSs) in the AZF-region of Yq associated with azoospermia and severe oligospermia in infertile Egyptian men. Materials and methods We analyzed buccal cells from 98 infertile Egyptian men with average ages 22-45 years (56 with azoospermia plus 42 with severe oligospermia) using multiplex PCR for six common AZFa, AZFb, and AZFc STS markers. Results Forty-eight (37%) microdeletions with five separate deletions were identified. We found 66.7% of the deletions in the AZFb locus, 20.8% in the AZFa locus, and 12.5% in the AZFc locus. Some common haplotypes (7 of 10) were identified in our sample population. Haplotypes H3 (sY127) and H4 (sY134) were the most common. Separate microdeletions were interestingly localized in infertile Y-chromosome patients. Conclusions We conclude that a minimum of three tags; STSs-sY86, sY127 and sY134 can be used to screen infertile Egyptian men for Yq microdeletions before assisted reproduction is initiated as a treatment.