Association of the CAG repeat polymorphism in mitochondrial polymerase gamma (POLG1) with male infertility: a case-control study in an Algerian population.

Polymorphisms in the have been speculated to be associated with male infertility. The main objective of our study was to CAG repeat polymorphism in POLG1 gene and male mitochondrial DNA polymerase gamma (POLG) assess the possible association of infertility in Algerian population. Genomic DNA from 89 infertile men and 84 controls was extracted using salting-out method. CAG repeat polymorphism was analyzed by the automated direct sequencing protocol. Statistical analysis was performed by Epi-info(r) (v6.0) software. A significant association with male infertility was found for CAG repeat polymorphism in heterozygous genotypes (10/≠10 vs 10/10: OR = 2.00 [0.99 - 4.05], p=0.03; "infertile vs control groups"; 10/≠10 vs 10/10: OR = 3.75[1.20-11.96], p=0.01 "oligoasthenoteratospermic group"). ALso, the results showed a significant association between the mordib allele (≠10) and male infertility (2.07 [01.07 - 04.02], p=0.01). Our results showed that POLG1 CAG repeat polymorphism might be a risk factor for male infertility in Algerian population. Investigations with larger sample sizes and representative population-based cases and matched controls are needed to validate our results.

First study of microdeletions in the Y chromosome of Algerian infertile men with idiopathic oligo- or azoospermia.

The human Y chromosome is essential for human sex determination and spermatogenesis. The long arm contains the azoospermia factor (AZF) region. Microdeletions in this region are responsible for male infertility. The objective of this study was to determine the frequency of Y microdeletions in Algerian infertile males with azoospermia and oligoasthenoteratozoospermia syndrome (OATS) and to compare the prevalence of these abnormalities with other countries and regions worldwide. A sample of 80 Algerian infertile males with a low sperm count (1-20 × 10(6) sperms/ml) as well as 20 fertile male controls was screened for Y chromosome microdeletions. 49 men were azoospermic and 31 men had OATS. Genomic DNA was isolated from blood and polymerase chain reaction was carried out with a set of 6 AZFa, AZFb and AZFc STS markers to detect the microdeletions as recommended by the European Academy of Andrology. Among the 80 infertile men screened for microdeletion, 1 subject was found to have microdeletions in the AZFc (sY254 and sY255) region. The deletion was found in azoospermic subjects (1/49, 2%). The overall AZF deletion frequency was low (1/80, 1.3%). AZF microdeletions were observed neither in the OATS group nor in the control group. The frequency of AZF microdeletions in infertile men from Algeria was comparable to those reported in the literature. We suggest analyzing 6 STS in the first step to detect Y microdeletions in our population.

Identification of Virulence Markers and Phylogenetic Groups' Association, and Antimicrobial Susceptibility of Uropathogenic Escherichia coli Isolates.

BACKGROUND: Urinary tract infections represent a world public health problem, which is caused mainly by Uropathogenic Escherichia coli. Although they are originally found in the intestinal microbiota in the majority of the cases, urinary tract infections can also be caused by intra-intestinal pathogenic E. coli. OBJECTIVE: The main objective of our research is to identify the virulence factors generally associated with different pathotypes across phylogenetic groups. METHODS: E. coli were isolated from patients with urinary tract infections. Antimicrobial susceptibility tests, virulence genes and phylogroups were prospected. The data analysis were performed using the chi-square and Fisher exact test. RESULTS: In total, 72.2% of isolates showed multidrug resistant. We have also depicted an important association between E. coli from inpatients with UTIs and pap and hlyA genes (p-0.041 and p-0.019 respectively). The predominant phylogenetic group in our isolates is B2 (45.4%) followed by D (12.4%). Our results showed that 9.3% of isolates have an unknown phylogroup which shows a significant association with astA gene (p-0.008). We have as well found a significant association between B2 and three virulence genes namely pap, hlyA and invE (p-0.002, p-0.001, p-0.025 respectively); B1 and pap, hlyA genes (p-0.049 and p-0.021 respectively); E and afa gene (p-0.024). CONCLUSION: Certain virulence factors have been shown to be potential targets for drug design and therapeutic pathways in order to deal with the antimicrobial resistance problem enhanced by antibiotic therapy.

Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort.

In a majority of individuals with disorders/differences of sex development (DSD) a genetic etiology is often elusive. However, new genes causing DSD are routinely reported and using the unbiased genomic approaches, such as whole exome sequencing (WES) should result in an increased diagnostic yield. Here, we performed WES on a large cohort of 125 individuals all of Algerian origin, who presented with a wide range of DSD phenotypes. The study excluded individuals with congenital adrenal hypoplasia (CAH) or chromosomal DSD. Parental consanguinity was reported in 36% of individuals. The genetic etiology was established in 49.6% (62/125) individuals of the total cohort, which includes 42.2% (35/83) of 46, XY non-syndromic DSD and 69.2% (27/39) of 46, XY syndromic DSD. No pathogenic variants were identified in the 46, XX DSD cases (0/3). Variants in the AR, HSD17B3, NR5A1 and SRD5A2 genes were the most common causes of DSD. Other variants were identified in genes associated with congenital hypogonadotropic hypogonadism (CHH), including the CHD7 and PROKR2. Previously unreported pathogenic/likely pathogenic variants (n = 30) involving 25 different genes were identified in 22.4% of the cohort. Remarkably 11.5% of the 46, XY DSD group carried variants classified as pathogenic/likely pathogenic variant in more than one gene known to cause DSD. The data indicates that variants in PLXNA3, a candidate CHH gene, is unlikely to be involved in CHH. The data also suggest that NR2F2 variants may cause 46, XY DSD.

SRY and NR5A1 gene mutation in Algerian children and adolescents with DSD and testicular dysgenesis.

BACKGROUND: In humans, sex determination and differentiation is genetically controlled. Disorders of sex development (DSD) result in anomalies of the development of the external and internal genitalia. Variants in transcription factors such as SRY, NR5A1 and SOX9, can cause changes in gonadal development often associated with ambiguity of the external genitalia. OBJECTIVES: This study has been conducted to determine the frequency, types and associated genetic alterations in patients with DSD in the Algerian population. METHODS: Thirty patients were included. Based on their clinical presentation, thirteen patients presented with ambiguous external genitalia, thirteen patients presented with hypospadias and four patients presented with bilateral undescended testes. Karyotype analysis was performed on peripheral blood lymphocytes using standard R-banding. DNA was isolated from blood leukocytes for PCR reaction and mutational analysis of SRY and NR5A1 was done by direct sequencing. RESULTS: Most patients with ambiguous genitalia had a 46,XY karyotype. One patient had a deletion of SRY, otherwise no point mutations in SRY or NR5A1 genes were identified. However, a single NR5A1 polymorphism (p.Gly146Ala) in patient with 46,XX DSD has been detected. CONCLUSIONS: The absence of mutations in these genes suggests that there are others genes playing an important role in sex development and differentiation.

Analysis of EGFR Mutation Status in Algerian Patients with Non-Small Cell Lung Cancer.

BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR) mutation status is used as a predictive biomarker for the tyrosine kinase inhibitors therapy in non-small cell lung cancer (NSCLC). The incidence of EGFR mutations appears to vary according to ethnic and geographical backgrounds. This retrospective study aimed to investigate the EGFR mutation status in Algerian NSCLC patients and its association with clinicopathological features. METHODS: We examined the presence of EGFR mutations (Exons 19-21) in 58 unselected  NSCLC samples using PCR followed by direct sequencing. RESULTS: The present study included 53 (91.4%) men and 5 (8.6%) women, with a median age of 59 (ranging from 44 to 94 years old). EGFR mutations were detected in 23 patients, with an overall rate of 39.6%. There were 21 (91.3%) cases with the exon-21 L585R single mutation and two (8.7%) with dual mutations of exon-19 deletions and L585R. EGFR mutations were more frequently found in patients with confirmed adenocarcinoma (14/27, 51.8%) than in non-adenomatous NCSCL subtypes (3/14, 21.4%; p=0.03). Furthermore, early stages of the disease were significantly associated with a higher rate of EGFR mutations (14/27, 51.8%) compared with those at  advanced stage (5/21, 23.8%; p=0.02). There were no significant differences in EGFR mutation frequency by age, gender, or smoking status. CONCLUSION: We found that Algerian NSCLC patients exhibited a high rate of EGFR mutations, which was quite similar to that in Asians population rather than Caucasian patients. Thus, TKI-based treatments may be more beneficial for Algerian patients with NSCLC. Further studies using a large number of patients are required to confirm our preliminary findings.

Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37.

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

Epidemiology and survival analyses of 333 adult glioma patients from Eastern Algeria (2008-2016).

BACKGROUND: Gliomas are a relatively rare group of tumors with a poor prognosis. We aimed to describe and analyze the clinical characteristics and survival of patients with glioma tumors of Eastern Algeria. METHODS: A retrospective study was conducted at the University Hospital of Constantine. Medical records of patients enrolled between January 2008 and October 2016 were consulted. Demographic characteristics, clinical data, treatment strategy and dates of last follow-up or death were collected. Chi-square test was used for checking associations, Kaplan-Meier methodology for estimating the survival, and the cox model for identifying prognosis factors. RESULTS: A total of 333 patients composed our cohort. The mean age was 48.07 years, and men were 1.87 times more frequent than women. High grade tumors were mainly observed among adults and old adults and in supra-tentorial locations. More than half of the patients had a large resection and a curative protocol of oncological treatment (50.7% and 57%, respectively). The mean overall survival was 45.4 months, the median was 21.7 months, and survival rates at 1-, 2-, and 5-years were: 62.8%, 48.5% and 32.9% respectively. Age, histology, grade of malignancy and oncological treatment were the major prognosis factors. CONCLUSION: Our sample was relatively young with a higher survival compared to others.

Association of TERT, OGG1, and CHRNA5 Polymorphisms and the Predisposition to Lung Cancer in Eastern Algeria.

Lung cancer remains the most common cancer in the world. The genetic polymorphisms (rs2853669 in TERT, rs1052133 in OGG1, and rs16969968 in CHRNA5 genes) were shown to be strongly associated with the risk of lung cancer. Our study's aim is to elucidate whether these polymorphisms predispose Eastern Algerian population to non-small-cell lung cancer (NSCLC). To date, no study has considered this association in the Algerian population. This study included 211 healthy individuals and 144 NSCLC cases. Genotyping was performed using TaqMan probes and Sanger sequencing, and the data were analyzed using multivariate logistic regression adjusted for covariates. The minor allele frequencies (MAFs) of TERT rs2853669, CHRNA5 rs16969968, and OGG1 rs1052133 polymorphisms in controls were C: 20%, A: 31%, and G: 29%, respectively. Of the three polymorphisms, none shows a significant association, but stratified analysis rs16969968 showed that persons carrying the AA genotype are significantly associated with adenocarcinoma risk (pAdj = 0.03, ORAdj = 2.55). Smokers with an AA allele have a larger risk of lung cancer than smokers with GG or GA genotype (pAdj = 0.03, ORAdj = 3.91), which is not the case of nonsmokers. Our study suggests that CHRNA5 rs16969968 polymorphism is associated with a significant increase of lung adenocarcinoma risk and with a nicotinic addiction.

Angiotensin-converting enzyme insertion/deletion gene polymorphisms and the risk of glioma in an Algerian population.

INTRODUCTION: Just recently, it has been established that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is linked to the pathogenesis and to the evolution of human cancers. Therefore, the present study was concerned with the investigation of an eventual association between glioma and I/D polymorphism of the ACE gene. METHODS: The expression of ACE gene was detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis in 36 Algerian patients with glioma and 195 healthy controls. RESULTS: In glioma cases, allelic frequencies and genotypes distribution of the ACE I/D polymorphism were different from controls cases. ACE DD genotype were highly presented in glioma cases (63.9%) than controls (33.8%) and conferred 3.64-fold risk for predisposition in glioma cases (vs ID genotype, p<0.001). Recessive model (ACE II + ID genotypes vs DD) was associated with a 72% reduced risk of glioma (OR = 0.28, 95% CI: 0.13-0.60, p <0.001). Per copy D allele frequency was found higher in glioma cases (79.2%) than in controls (63.3 %), OR = 2.20, 95% CI: 1.20 - 4.03, p = 0.009. CONCLUSION: The obtained data showed that the presence of the D allele might be a risk factor for the development of glioma. Further studies considering different ethnic groups with large samples are required to confirm this finding.

Foetal haemoglobin in normal healthy adults: relationship with polymorphic sequences cis to the beta globin gene.

We evaluated the effects of polymorphic markers within the beta globin gene cluster on HbF expression in two groups. These groups were randomly selected from a survey of HbF distribution in a large population study of unrelated healthy Algerian adults (n=827). The first group contained individuals with normal HbF levels (0.1-0.5%) and the second group contained individuals with raised HbF levels (0.8-2.3%). Of the various polymorphic markers analysed, only the -309 G gamma A-->G, the -158 G gamma C-->T, the G gamma IVS2 TC (TG)(9) AG (TG)(2) (CG)(2) and the -540 beta (AT)(9) T(5) sequence configurations were significantly associated with increased HbF levels. More than 84% of the subjects with elevated HbF levels carried one or several of these four marker configurations, suggesting that the beta globin gene cluster exerts a significant effect on HbF expression in healthy individuals.

Influence of methylenetetrahydrofolate reductase C677T gene polymorphisms in Algerian infertile men with azoospermia or severe oligozoospermia.

AIMS: The C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene has been suggested to represent a risk factor for male infertility. To confirm this association, the distribution of the single-nucleotide polymorphism C677T was investigated in idiopathic infertile Algerian patients with nonobstructive azoospermia (NOA) or severe oligoasthenoteratozoospermia (OAT). A case-control study was carried out, including 74 idiopathic infertile Algerian patients with NOA (n=46) or severe OAT (n=28) and 84 fertile men as controls. Polymorphism C677T was studied by polymerase chain reaction-restriction fragment length polymorphism, and the results were statistically analyzed. RESULTS: The frequency of genotypes MTHFR 677CC, 677CT, and 677TT in idiopathic infertile men with NOA was 43.48%, 41.30%, and 15.22%; 39.29%, 50%, and 10.71% regarding the severe oligozoospermic men; and 42.86%, 45.24%, and 11.90% in the control group. CONCLUSIONS: The data suggest that the C677T MTHFR polymorphism is not a risk factor for idiopathic male subfertility in an Algerian population.