ABSTRACT
Long QT Syndrome (LQTS), a disorder of the cardiac repolarization process with prolongation of the QT interval (QTc ≥0.46 seconds), is an ion-channelopathy. Mutations in either KCNQ1 or KCNE1 genes are susceptible to LQTS. Hence, screening of KCNQ1 and KCNE1 genes is taken up to evaluate the genetic correlation of these genes in Long QT patients of Indian origin. A total of 33 Long QT Syndrome patients and 100 healthy subjects were enrolled for the present study. PCR-SSCP protocol was utilised for screening of KCNQ1 and KCNE1 genes followed by In-silico and statistical analysis. The clinical profile of the Long QT syndrome patients in our study revealed a higher percentage of females with the mean age also being higher in females when compared to males. The two variations (S546S and IVS13+36A>G) in KCNQ1 and the S38G polymorphism in KCNE1 gene were identified and their association with Long QT syndrome is being reported for the first time in Indian population. S546S is located in the KCNQ1 C terminus close to this domain and IVS13+36A>G is located in the intronic region in close proximity to the coding region for C-terminal domain; these may therefore affect the functional protein through non-assembly. S38G leads to a substitution of serine to glycine at 38th amino acid position (S38G) in the transmembrane domain of KCNE1. Our study reports compound heterozygosity/genetic compound ofS546S and IVS13+36A>G of KCNQ1 gene. Haplotype frequencies and linkage disequilibrium analysis revealed a significant association between the three biomarkers. Compound heterozygosity of the polymorphisms influence downstream signalling and KCNQ1- KCNE1 interactions.
ABSTRACT
Aim: The filariasis infection is initiated by mosquito derived third stage larva (L3), which establishes itself in different immunocompetent niches by adopting different evasion and immunomodulatory mechanisms. Immunological and clinical outcomes can vary considerably at the individual and population levels during lymphatic filariasis infection. The protein product coded by the interleukin-10 (IL-10) gene has broad immunomodulatory function in filarial load and patency of the disease. The potential influence of altered IL-10 expression encoded by IL-10 promoter single nucleotide polymorphisms (SNPs) and IL-10RA signaling pathway, in pathogenesis and clinical outcome of filarial infection was established in the present study Study Design: Genetic association based on case-control study. Place and Duration of Study: Lymphatic filariasis cases referred to National Filariasis Control Program (NFCP), Siddipet, Medak, Andhra Pradesh, India between Feb 2006 to Dec 2009. Methodology: A total of 100 non-endemic, 50 endemic and 118 lymphatic filariasis patients were included in the present study based on clinical and diagnostic criteria. Genetic polymorphisms in the IL-10 promoter region (-1082G/A, -819C/T and -592 A/C) and IL-10 RA coding region S138G were screened following PCR-RFLP and ARMS-PCR technique respectively. Results: Patients with familial aggregation of lymphedema exhibited significant association with IL-10 -1082 ‘A’ allele (A vs G OR 2.68, CI - 1.12-6.37, P=0.02) coding for lower IL-10 levels. Similarly the G variant of IL-10RA S138G SNP revealed a significant association with lymphatic filariasis in the endemic population studied (GG vs AA OR 2.50 CI-1.22-5.13, P= 0.021). The Haplotype analysis also revealed the low signaling ATA is significantly associated with the disease in this cohort (P=0.03). The Multifactor Dimensionality Reduction Analysis (MDR) for IL-10 and IL-10RA SNPs interaction revealed the three locus model as the best model wherein the epistatic interactions of variant G allele of IL-10RA S138G, the A allele of the -1082G/A and the T allele of the -819C/T SNPs in IL-10 were found to be a possible risk genotype for filarial infection. (TA = 0.5230, CV-10/10, P=0.001). Conclusion: IL-10 promoter haplotypes and IL-10 RA S138G polymorphisms are the possible genetic determinants of susceptibility to lymphatic filariasis. Further functional studies are warranted to validate these results.
ABSTRACT
Chronic pancreatitis [CP] is the progressive and irreversible destruction of the pancreas characterized by the permanent loss of endocrine and exocrine function. Trypsin, the most important digestive enzyme plays a central role in the regulation of all other digestive enzymes. Chymotrypsin, an endopeptidase hydrolyzes peptides at amino acids with aromatic side chains. Alpha-1-antitrypsin is a principal antiprotease which protects the mucosal tissue from the proteolytic effects of trypsin and chymotrypsin by the formation of molar complexes. The present study is aimed at examining the role of proteases [trypsin and chymotrypsin] and anti-protease [alpha1-anti-trypsin] in the etiopathogenesis of chronic pancreatitis. A total of 90 CP patients and 110 age and sex matched controls were considered for the study. Serum trypsin, chymotrypsin and alpha1-anti-trypsin levels were determined prospectively in CP patients and compared to healthy controls as described previously. The mean activity of trypsin were found to be increased in CP patients [X +/- SD = 0.82 +/- 0.838] in comparison to normal control group [X +/- SD = 0.55 +/- 0.328], [P = 0.001]. Chymotrypsin activity were also found to be elevated in CP patients [X +/- SD = 0.63 +/- 0.278] in comparison to control group [X +/- SD = 0.39 +/- 0.295], [P = 0.0001]. The mean alpha-1-anti-trypsin activity were found to be lowered in CP patients [X +/- SD = 0.42 +/- 0.494] in comparison to control group [X +/- SD = 0.67 +/- 0.465], with the variation being significant [P = 0.0003]. The findings suggest an imbalance in the synthesis and degradation of proteolytic enzymes and antiprotease indicating an altered aggressive and defensive role in the pathogenesis of chronic pancreatitis
ABSTRACT
Uterine leiomyomas/fibroids are the most common pelvic tumors of the female genital tract. The initiators remaining unknown, estrogens and progesterone are considered as promoters of fibroid growth. Fibroids are monoclonal tumors showing 40-50% karyotypically detectable chromosomal abnormalities. Cytogenetic aberrations involving chromosomes 6, 7, 12 and 14 constitute the major chromosome abnormalities seen in leiomyomata. This has led to the discovery that disruptions or dysregulations of HMGIC and HMGIY genes contribute to the development of these tumors. Genes such as RAD51L1 act as translocation partners to HMGIC and lead to disruption of gene structure leading to the pathogenesis of uterine fibroids. The mechanism underlying this disease is yet to be identified. The occurrence of PCOLCE amid a cluster of at least eight Alu sequences is potentially relevant to the possible involvement of PCOLCE in the 7q22 rearrangements that occur in many leiomyomata. PCOLCE is implicated in cell growth processes. Involvement of Alu sequences in rearrangements can lead to the disruption of this gene and, hence, loss of control for gene expression leading to uncontrolled cell growth. This can also lead to the formation of fibroids. Though, cytogenetics provides a broad perspective on uterine fibroid formation, further molecular analysis is required to understand the etiopathogenesis of uterine fibroids