Genomic Variations in ATP7B Gene in Indian Patients with Wilson Disease.

OBJECTIVE: To report genotype data of the patients with Wilson disease (WD) hailing from across several parts of India to add to the available spectrum of causative variants in ATP7B gene (ATPase copper transporting beta polypeptide gene) and associated phenotypes in the Indian population. METHODS: The entire ATP7B gene was sequenced in 58 patients with WD and additional testing was also done by MLPA to look for intragenic deletions duplications and exome sequencing to rule out genetic variations with similar phenotypic overlap. RESULTS: Of all patients, 37 patients had a total of 33 distinct pathogenic variations, including 29 in the exonic regions and 4 at intronic splice sites. Of the variations identified, six were novel. The underlying genomic variations could be identified in nearly two-thirds of the patients by sequencing the entire gene. CONCLUSIONS: This study reports the genotype-phenotype data to add to the available spectrum of causative variants in ATP7B gene. The inability to detect a pathogenic variation in some patients and the existence of phenotypic variations in individuals with the same variation suggest that additional factors or genes may play a role in causation of the disease. Further, a marked genetic heterogeneity was found in the study patients, indicating ethnic diversity of the Indian population.

Evaluation of cytogenetic and molecular markers with MTX-mediated toxicity in pediatric acute lymphoblastic leukemia patients.

PURPOSE: Pediatric acute lymphoblastic leukemia (pALL) patients have better overall survival and methotrexate (MTX) is an effective drug used in their treatment. However, the treatment-related adverse effects (TRAEs) have a bigger impact on the therapy. In this study, we have evaluated the association of polymorphisms in genes encoding proteins engaged in MTX metabolism, and the cytogenetic aberrations with TRAEs. METHODS: A total of 115 patients between the age of 1 and 18 years (average: 6.6) under maintenance therapy were selected for the study. SLC19A1 (c.80G > A), MTHFR (c.677C > T; c.1298A > C), and TYMS (c.*450_*455del) genotypes were determined using PCR techniques and Sanger sequencing. Cytogenetic and SNP findings were analyzed for any association with the reported toxicities using odds ratio, chi-square test, multifactor dimensionality reduction (MDR) analysis for synergistic effect and, multinomial logistic regression analysis for the likelihood of adverse events. RESULTS: Among the evaluated genetic variations, SLC19A1 (c.80G > A) was significantly associated with TRAEs (OR = 5.71, p = 0.002). Multinomial logistic regression analysis (chi-sq = 16.64, p < 0.001) and MDR analysis (chi-sq = 10.51 p < 0.001) confirmed the finding. On the other hand, no significant association was observed between adverse events and any specific cytogenetic aberration. CONCLUSION: SLC19A1 facilitates the import of cyclic dinucleotides and reduced folates, evaluating genotypes in this gene can help in better management of patients on methotrexate treatment. Assessing a broader gene panel can help in finding more associated markers and delivering personalized medicine to the patients.

Association of HLA-A, -B, DRB, and DQB Alleles with Persistent HPV-16 Infection in Women from Tamil Nadu, India.

Women with persistent human papillomavirus (HPV) infections have a high risk of developing cervical cancer (CaCx). HPV-16 alone accounts for more than 60% of CaCx worldwide. Most of the HPV infections are transient and only a subset of women develop persistent HPV-16 infection. Many studies have shown associations of different human leukocyte antigen (HLA) alleles with HPV-mediated CaCx, but there are only a few studies globally that relate to persistent HPV-16 infection. Furthermore, such studies from India are sparse. Hence, we investigated the association of HLA-A, B, DRB, and DQB alleles with persistent HPV-16 infection and HPV-16-positive CaCx in south India (Tamil Nadu). HPV-16 persistent infection was observed in 7% of normal women. A total of 50 women with HPV-16-positive CaCx, 21 women with HPV-16 persistent infection, and 74 HPV-16-negative normal women were recruited for this study. Low-resolution typing of HLA-A, B, DRB, and DQB alleles was performed. HLA-B*44 and DRB1*07 showed a significant association with persistent HPV-16 infection (odds ratio, p-value = 26.3, 0.03 and 4.7, 0.01, respectively). HLA-B*27 and DRB1*12 were significantly associated with both HPV-16+ CaCx and persistent HPV-16 infection (23.8, 0.03; 52.9, 0.01; 9.8, 0.0009; and 13.8, 0.009; respectively). HLA-B*15 showed a negative association with HPV-16-positive CaCx (0.1, 0.01), whereas DRB1*04 exhibited protection to both HPV-16-positive CaCx and persistent HPV-16 infection (0.3, 0.0001 and 0.1, 0.0002, respectively). Thus, we show HLA allelic association with HPV-16 infection in Tamil Nadu. Larger studies on high-resolution HLA typing coupled with HPV-16 genome diversity will offer further insights into host/pathogen genome coevolution.

Role of VEGF165b/VEGFTOTAL ratio in gestational diabetes mellitus.

Proper vascular function is important for well-being of mother and growing fetus. VEGFTOTAL, and VEGF165b levels and its vascular endothelial complications in gestational diabetes mellitus (GDM) together with the association of inflammation and advanced glycation end products (AGEs) are less studied. VEGF165b/VEGFTOTAL (VEGF RATIO) in GDM pregnant women was investigated in this study. Plasma VEGFTOTAL was lower in GDM (17.68 ± 1.30 pg/mL) compared to non-GDM (25.69 ± 1.40 pg/mL). VEGF165b, ICAM-1, and AGEs were higher in GDM (9.9 ± 1.4 pg/mL, 201.04 ± 7.85 µg/mL, and 10.40 ± 0.98 µg/mL, respectively) and lower in non-GDM (6.47 ± 0.70 pg/mL, 174.1 ± 7.11 µg/mL, and 4.71 ± 0.39 µg/mL, respectively). Compared to non GDM (0.25 ± 0.02), VEGF RATIO was higher in GDM (0.45 ± 0.04) and correlated with -ICAM-1 (r = 0.375, p < .001) and AGEs (r = 0.199, p < .05). Tertile stratification of VEGF RATIO implied that frequency of GDM increases with increasing tertiles of VEGF RATIO (p for trend <.001). Association of VEGF RATIO with GDM was significant even after adjusting for AGEs (OR = 1.279, CI = 1.118-1.462, p < .0010) but it lost its significance when adjusted for ICAM-1 (OR = 1.006, CI = 0.995-1.017, p = .308). VEGF RATIO plays an important role in GDM in association with vascular inflammation.

A meta-analysis of association of Human Leukocyte Antigens A, B, C, DR and DQ with Human Papillomavirus 16 infection.

Human Papillomavirus (HPV) induced cervical cancer (CaCx) is a major health problem in women from both developing and developed regions of the world. This virus accounts for >95% of the CaCx cases with a preponderance of HPV type -16 (65%). Paradoxically HPV-16 is prevalent even in the cervix of healthier women and anti HPV-16 T-cell response is considered critical for the viral clearance. Studies on HLA association with HPV-16 infection and cervical cancer have yielded varied HLA associations in different epidemiological settings. To validate these associations, we performed a meta-analysis of HLA-A, B, C, DR and DQ association with HPV-16 infection. Of the 1409 studies retrieved, 26 qualified for meta-analysis based on stringent inclusion and exclusion criteria. HLA-B*47, B*57, DRB1*10, DRB1*15 and DQB1*0303 were significantly associated with HPV-16 infection (OR = 3.4, 1.8, 1.5, 1.1 and 1.5 respectively). HLA-B*49, B*39, A28 (serotype), C*04 and DRB1*13 were negatively associated with HPV-16 (OR = 0.5, 0.6, 0.7, 0.7, and 0.7 respectively). Certain HLA alleles such as B*07, DRB1*15, DRB1*11 and DRB1*07 showed weakly positive associations. A comprehensive analysis coupling HPV-16 antigenic diversity and the HLA variation in various global populations shall provide further insights into the immunogenetic predisposition to HPV-16 and shall help identify host-parasite co-evolution.