A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East.

Background: Nephropathic Cystinosis, the most common cause of renal Fanconi syndrome, is a lysosomal transport disorder with an autosomal recessive inheritance pattern. A large number of mutations in CTNS have been identified as causative to date. A 57 kb deletion encompassing parts of CTNS is most commonly identified in Caucasians but this allele has not been identified in individuals of Eastern Mediterranean, Middle Eastern, Persian, or Arab origin to date. Methods and Results: Implementing whole exome sequencing (WES) in a consanguineous Iranian family, we identified this large deletion affecting CTNS in a patient initially presenting with hypokalemic metabolic alkalosis symptoms and considerable proteinuria. Conclusion: We show WES is a cost and time efficient genetic diagnostics modality to identify the underlying molecular pathology in Cystinosis individuals and provide a summary of all previously reported CTNS alleles in the Middle east population. Our work also highlights the importance to consider the 57-kb deletion as underlying genetic cause in non-European populations, including the Middle East. Limited diagnostic modalities for Cystinosis in developing countries could account for the lack of previously reported cases in these populations carrying this allele. Further, our findings emphasize the utility of WES to define genetic causes in clinically poorly defined phenotypes and demonstrate the requirement of Copy number variation (CNV) analysis of WES data.

Analysis of cytotoxic T-lymphocyte-associated antigen-4 and MMP-9 genes' methylation and their expression profiles with risk of non-alcoholic fatty liver disease.

OBJECTIVE: To investigate the effect of promoter methylation of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene and matrix metalloproteinases (MMPs) on the risk of non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: CTLA-4 and MMP-9 promoter methylation were investigated using a methylation-specific polymerase chain reaction (MS-PCR) in blood samples taken from 80 NAFLD individuals and 95 healthy controls. The expression levels of CTLA-4 and MMP-9 were also assessed in 10 blood and 9 liver tissues mRNA samples from NAFLD patients. These cases were compared to the blood (n = 10) samples of healthy controls with real-time quantitative reverse transcriptase PCR. RESULTS: No significant relationship was found for methylation of CTLA-4 and MMP-9 between cases and controls. The relative expression of CTLA-4 and MMP-9 mRNA in NAFLD was not significantly different compared to healthy control samples. CONCLUSION: For the first time, our outcomes indicate that the methylation status of CTLA-4 and MMP-9 genes has no significant function on the process of NAFLD.

Interleukin-12 gene polymorphism and cervical cancer risk.

AIM: : To investigate the effect of interleukin-12 p40 gene (IL-12ß) 3'-untranslated region polymorphism on the risk of cervical cancer. METHODS: DNA was isolated from peripheral blood of 200 patients with cervical cancer and 200 healthy controls. Polymerase chain reaction restriction fragment length polymorphism was used for the detection of IL-12ß (1188A/C) gene polymorphism. RESULTS: It was observed that genotypes AC [odds ratio (OR) = 1.80, 95% confidence interval (CI) = 1.17-2.78] and AC + CC (OR = 1.71, 95% CI = 1.11-2.63, P = 0.01) increase the risk of cervical cancer. The strength of the risk in passive smokers with AC and AC + CC genotypes was increased to more than 2.8 times in comparison with a nonsmoker with AA genotype (OR = 2.94, 95% CI = 1.56-5.55, P < 0.001; OR = 2.83, 95% CI = 1.52-5.31, P < 0.001, respectively). CONCLUSION: This is the first study to provide an evidence for the association of IL-12ß (1188A/C) gene polymorphism with the risk of cervical cancer.

Association of interleukin-18 gene promoter polymorphism on the risk of cervix carcinogenesis in north Indian population.

Cervical cancer is one of the most common neoplastic diseases affecting women, with a combined worldwide incidence of almost half a million new cases. Considering the fact that IL-18 plays an important role in the interactions among T cells, NK cells, and macrophages and induces IFN-gamma production, efforts should be made to understand the clinical impact of IL-18 cytokine in patients with solid malignancies, as not much study has been conducted in cervix carcinoma. In this study, we have observed in GC genotype statistically significant marginal increased risk of developing of cervical cancer (OR 1.8, 95% CI 1.17-2.76, p = 0.006). Similarly, when the GC with CC genotypes were combined results were once more statistically significant with borderline risk of developing cervix cancer (OR 1.6,95% CI 1.09-2.50, p = 0.01). Likewise, we found statistically significant increased risk between cases and controls in GC genotype and passive smokers with risk of cervical cancer (OR 4.3, 95%CI 2.13-8.99, p = 0.00001). Our investigation suggests that IL-18 gene -137 in different genotypes, as also in passive smokers, may increase risk of cervix carcinogenesis in north Indian women.

Association of genetic polymorphism of the DNA base excision repair gene (APE-1 Asp/148 Glu) and HPV type (16/18) with the risk of cervix cancer in north Indian population.

Cervical cancer is one of the most common neoplastic diseases affecting women, with a combined world wide incidence of almost half a million new cases. Reduced DNA repair capacity (DRC) can render a high risk of developing many types of cancer; including cervical cancer. Polymorphisms in DNA repair genes may contribute the genetic instability and carcinogenesis. Smoking experience and use of oral contraceptives have been confirmed to be risk factors for cervical cancer. The purpose of the present study was, therefore to investigate APE-1 genotypes (Asp/Asp, Asp/Glu, Glu/Glu) with different histological subtypes in cases compared with controls. It has been observed that Asp/Glu with Glu/Glu genotypes that combined we observed statistically significant with protective effect for developing of cervix cancer (OR-0.51, 95% CI 0.31-0.83, p-0.006). The combined Asp/Glu with Glu/Glu genotypes who were using oral contraceptives were shown to be statistically significant with reduced risk of cervical cancer (OR-0.22 95% CI- 0.11-0.47, p-0.0002). It has been suggested that significantly correlation between HPV 16 and users of oral contraceptives in certain APE-1 genotypes with reduced risk in developing cervix cancer. In conclusion we observed statistical significant association with reduced risk of cervix cancer in APE-1 with different genotypes, though, on the other hand, in association between HPV type 18 and those having SCC, highly increased risk of cervical cancer was observed.

Impact of polymorphism in IL-1RA gene on the risk of cervical cancer.

INTRODUCTION: Cervical cancer, the second most common malignancy in women worldwide, is almost invariably associated with infection by human papillomavirus (HPV). However, although many women are infected with high-risk types of HPV, only a subset of infected women will ever develop cervical cancer. Therefore, host genetic factor may play a role in cervical carcinogenesis. Several studies suggested that immunological components play a key role in the development of cervical cancer. Polymorphism in the IL-1RA gene was associated with various malignant diseases. Data are lacking for cervical cancer. MATERIALS AND METHODS: In a case-control study we analyzed the polymorphism of IL-1RA in 150 women with cervical cancer and 209 healthy controls. Genomic DNA fragments were amplified by PCR. RESULTS: There was a strong significantly protective association between heterozygous AB genotype and HPV 18 (OR = 0.11, 95% CI = 0.04-0.30, p = 0.0000000). Similarly this result was demonstrated, in combined AB + BB genotypes of IL-1RA with HPV 18 (OR = 0.12, 95% CI= 0.05-0.30, p = 0.0000000) and HPV type 16 + 18 (OR = 0.18,95% CI = 0.08-0.38, p = 0.000005). We found high protective significant association between heterozygous genotype AB with adenocarcinoma (OR = 0.19, 95% CI = 0.09-0.40, p = 0.0000002) as well. CONCLUSION: These findings therefore suggest that the IL1-RA polymorphism is associated with cervical cancer.