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  1. Litvinova MM, Khafizov KF, Speranskaya AS, Matsvay AD, Asanov AY, Nikolskaya KA, et al.
    Sovrem Tekhnologii Med, 2023;15(2):60-70.
    PMID: 37389024 DOI: 10.17691/stm2023.15.2.06
    The aim of the study was to define the spectrum of genetic risk factors of chronic pancreatitis (CP) development in patients living in the European part of the Russian Federation.

    MATERIALS AND METHODS: The study group included 105 patients with CP, with the age of the disease onset under 40 years old (the average age of onset was 26.9 years). The control group consisted of 76 persons without clinical signs of pancreatitis. The diagnosis of chronic pancreatitis in patients was made on the basis of clinical manifestations and the results of laboratory and instrumental investigations. Genetic examination of patients was conducted using the next-generation sequencing (NGS) technology and included targeted sequencing of all exons and exon-intron boundaries of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes. The genotyping of the rs61734659 locus of the PRSS2 gene was also conducted.

    RESULTS: Genetic risk factors of the CP development were found in 61% of patients. Pathogenic and likely-pathogenic variants associated with the risk of CP development were identified in the following genes: CTRC (37.1% of patients), CFTR (18.1%), SPINK1 (8.6%), PRSS1 (8.6%), and CPA1 (6.7%). The frequent gene variants in Russian patients with CP were as follows: CTRC gene - c.180C>T (rs497078), c.760C>T (rs121909293), c.738_761del24 (rs746224507); cumulative odds ratio (OR) for all risk alleles was 1.848 (95% CI: 1.054-3.243); CFTR gene - c.3485G>T (rs1800120), c.1521_1523delCTT (p.Phe508del, rs113993960), and c.650A>G (rs121909046); OR=2.432 (95% CI: 1.066-5.553). In the SPINK1, PRSS1, and CPA1 genes, pathogenic variants were found only in the group of patients with CP. The frequent variants of the SPINK1 gene include c.101A>G (p.Asn34Ser, rs17107315) and c.194+2T>C (rs148954387); of the PRSS1 gene - c.86A>T (p.Asn29Ile, rs111033566); of the CPA1 gene - c.586-30C>T (rs782335525) and c.696+23_696+24delGG. The OR for the CP development for the c.180TT genotype (rs497078) CTRC according to the recessive model (TT vs. CT+CC) was 7.05 (95% CI: 0.86-263, p=0.011). In the CTRC gene, the variant c.493+49G>C (rs6679763) appeared to be benign, the c.493+51C>A (rs10803384) variant was frequently detected among both the diseased and healthy persons and did not demonstrate a protective effect. The protective factor c.571G>A (p.Gly191Arg, rs61734659) of the PRSS2 gene was detected only in the group of healthy individuals and confirmed its protective role. 12.4% of the patients with CP had risk factors in 2 or 3 genes.

    CONCLUSION: Sequencing of the coding regions of the PRSS1, SPINK1, CTRC, CFTR, and CPA1 genes allowed to identify genetic risk factors of the CP development in 61% of cases. Determining the genetic cause of CP helps to predict the disease course, perform preventive measures in the proband's relatives, and facilitate a personalized treatment of the patient in future.

    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics
  2. Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, et al.
    Nat Genet, 2013 Oct;45(10):1160-7.
    PMID: 23974870 DOI: 10.1038/ng.2745
    Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of ł0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.
    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics*
  3. Abdul Rahim FH, Thambiah CS, Samsudin IN, Mohamed Mokhtar N
    Malays J Pathol, 2020 Aug;42(2):297-300.
    PMID: 32860386
    INTRODUCTION: Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder as a result of CF transmembrane conductance regulator gene mutation. It has a wide range of disease severity in patients with the same genotype.

    CASE REPORT: A 5-year-old Malay boy with a history of recurrent pneumonia, presented with productive cough, fever and worsening tachypnoea. Physical examination revealed coarse crepitations, reduced breath sounds and clubbing. Biochemical investigations showed that he had respiratory type 2 failure as a result of bronchiectasis. Sweat conductivity done twice was raised supporting a diagnosis of CF. Other investigations such as bronchoscopy to look for congenital anomaly of the lung, infectious disease screening and tuberculosis, fungal and viral culture and sensitivity were negative. Further cascade screening revealed high sweat conductivity results in his siblings.

    DISCUSSION: Although CF prevalence is low in Malaysia, it is nevertheless an important diagnosis to be recognised as it is associated with increased morbidity.

    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics*
  4. Zilfalil BA, Sarina S, Liza-Sharmini AT, Oldfield NJ, Stenhouse SA
    Singapore Med J, 2006 Feb;47(2):129-33.
    PMID: 16435054
    Cystic fibrosis (CF) is one of the common genetic disorders in the western world. It has been reported to be very rare in Asian populations. According to the Cystic Fibrosis Genetic Analysis Consortium, more than 1,000 mutations of the CF gene have been identified. The CF gene, named the cystic fibrosis transmembrane conductance regulator (CFTR), is located on chromosome 7 and composed of 27 exons. This study aims to detect possible CFTR gene mutations in Malays.
    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics*
  5. Mohd Mokhtar H, Giribabu N, Kassim N, Muniandy S, Salleh N
    J Steroid Biochem Mol Biol, 2014 Oct;144 Pt B:361-72.
    PMID: 25125390 DOI: 10.1016/j.jsbmb.2014.08.007
    Estrogen is known to stimulate uterine fluid and Cl(-) secretion via CFTR. This study investigated testosterone effect on these changes in a rat model.
    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics
  6. Nathan AM, Thong MK, deBruyne J, Ariffin H
    J Paediatr Child Health, 2011 Aug;47(8):573-5.
    PMID: 21843195 DOI: 10.1111/j.1440-1754.2011.02149.x
    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics*
  7. Ismail N, Myint K, Khaing SL, Giribabu N, Salleh N
    Mol Biol Rep, 2023 Aug;50(8):6729-6737.
    PMID: 37382776 DOI: 10.1007/s11033-023-08555-6
    BACKGROUND: Unexplained infertility could arise from a defect in the cervix. However, the contribution of abnormal cervical fluid microenvironment to this problem still needs to be identified. Therefore, this study identifies the changes in the cervical fluid microenvironment, i.e., pH, electrolytes and osmolarity as well as expression of ion transporters in the cervix including ENaC, CFTR and AQP in fertile women and in women suffering from primary unexplained infertility.

    METHODS: Fertile women and women with unexplained infertility but having regular 28-day menstrual cycles were chosen in this study, Day-22 serum progesterone levels were determined. In the meantime, serum FSH and LH levels were determined on day 2 while, cervical flushing was performed at day 14 to analyse changes in the cervical fluid pH, osmolarity, Na+ and Cl- levels. Meanwhile, cells retrieved from cervical fluid were subjected to mRNA expression and protein distribution analysis for CFTR, AQP and ENaC by qPCR and immunofluorescence, respectively.

    RESULTS: No significant changes in serum progesterone, FSH and LH levels were observed between the two groups. However, cervical fluid pH, osmolarity, Na+ and Cl- levels were significantly lower in primary unexplained infertile group when compared to fertile group. Expression of CFTR and AQP (AQP 1, AQP 2, AQP 5 and AQP 7) in endocervical cells was lower and expression of β-ENaC was higher in primary unexplained infertile women (p 

    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics
  8. Palaniappan SK, Than NN, Thein AW, van Mourik I
    Cochrane Database Syst Rev, 2020 03 30;3:CD012056.
    PMID: 32227478 DOI: 10.1002/14651858.CD012056.pub3
    BACKGROUND: Cystic fibrosis is an autosomal recessive inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in abnormal regulation of salt and water movement across the membranes. In the liver this leads to focal biliary fibrosis resulting in progressive portal hypertension and end-stage liver disease in some individuals. This can be asymptomatic, but may lead to splenomegaly and hypersplenism, development of varices and variceal bleeding, and ascites; it has negative impact on overall nutritional status and respiratory function in this population. Prognosis is poor once significant portal hypertension is established. The role and outcome of various interventions for managing advanced liver disease (non-malignant end stage disease) in people with cystic fibrosis is currently unidentified. This is an updated version of a previously published review.

    OBJECTIVES: To review and assess the efficacy of currently available treatment options for preventing and managing advanced liver disease in children and adults with cystic fibrosis.

    SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 November 2019. We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 01 January 2020.

    SELECTION CRITERIA: Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal hypertension or variceal bleeding (or both).

    DATA COLLECTION AND ANALYSIS: Authors independently examined titles and abstracts to identify potentially relevant trials, but none were eligible for inclusion in this review.

    MAIN RESULTS: A comprehensive search of the literature did not identify any published eligible randomised controlled trials.

    AUTHORS' CONCLUSIONS: In order to develop the best source of evidence, there is a need to undertake randomised controlled trials of interventions for preventing and managing advanced liver disease in adults and children with cystic fibrosis.

    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics
  9. Chinigarzadeh A, Karim K, Muniandy S, Salleh N
    J Biochem Mol Toxicol, 2017 Apr;31(4).
    PMID: 27891704 DOI: 10.1002/jbt.21878
    We hypothesized that genistein could affect the chloride (Cl(-) ) and bicarbonate (HCO3(-) ) secretory mechanisms in uterus. Ovariectomized female rats were given estradiol or estradiol plus progesterone with 25, 50, or 100 mg/kg/day genistein. Following completion of the treatment, uterine fluid Cl(-) and HCO3(-) concentrations were determined by in vivo uterine perfusion. Uteri were subjected for molecular biological analysis (Western blot, qPCR, and immunohistochemistry) to detect levels of expression of Cystic Fibrosis transmembrane regulator (CFTR), Cl(-) /HCO3(-) exchanger (SLC26a6), Na(+) /HCO3(-) cotransporter (SLC4a4), and estrogen receptor (ER)-α and β. Coadministration of genistein resulted in decrease in Cl(-) and HCO3(-) concentrations and expression of CFTR, SLC26a6, SLC4a4, and ER-α and ER-β in the uteri of estradiol-treated rats. In estradiol plus progesterone-treated rats, a significant increase in the above parameters were observed following high-dose genistein treatment except for the SLC24a4 level. In conclusion, genistein-induced changes in the uterus could affect the reproductive processes that might result in infertility.
    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics
  10. Gholami K, Muniandy S, Salleh N
    J Biomed Biotechnol, 2012;2012:596084.
    PMID: 23226939 DOI: 10.1155/2012/596084
    Under progesterone (P) dominance, fluid loss assists uterine closure which is associated with pH reduction. We hypothesize that P inhibits uterine fluid secretion and HCO3⁻ transport.
    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics*
  11. Shahzad H, Giribabu N, Karim K, Kassim NM, Muniandy S, Salleh N
    PLoS One, 2017;12(3):e0172765.
    PMID: 28253299 DOI: 10.1371/journal.pone.0172765
    Dysregulation of uterine fluid environment could impair successful reproduction and this could be due to the effect of environmental estrogens. Therefore, in this study, effect of quercetin, an environmental estrogen on uterine fluid and electrolytes concentrations were investigated under sex-steroid influence. Ovariectomised adult female Sprague-Dawley rats were given 10, 50 or 100mg/kg/day quercetin subcutaneously with 17-β estradiol (E) for seven days or three days E, then three days E plus progesterone (P) (E+P) treatment. Uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations were determined by in-vivo perfusion. Following sacrifice, uteri were harvested and levels of the proteins of interest were identified by Western blotting and Realtime PCR. Distribution of these proteins in the uterus was observed by immunofluorescence. Levels of uterine cAMP were measured by enzyme-linked immunoassay (EIA). Administration of quercetin at increasing doses increased uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations, but to the levels lesser than that of E. In concordant, levels of CFTR, SLC4A4, ENaC (α, β and γ), Na+/K+-ATPase, GPα/β, AC and cAMP in the uterus increased following increased in the doses of quercetin. Co-administration of quercetin with E caused uterine fluid secretion rate, Na+, Cl- and HCO3- concentrations to decrease. In concordant, uterine CFTR, SLC26A6, SLC4A4, ENaC (α, β and γ), Na+/K+-ATPase, GPα/β, AC and cAMP decreased. Greatest effects were observed following co-administration of 10mg/kg/day quercetin with E. Co-administration of quercetin with E+P caused uterine fluid Na+ and HCO3- concentrations to increase but no changes in fluid secretion rate and Cl- concentration were observed. Co-administration of high dose quercetin (100 mg/kg/day) with E+P caused uterine CFTR, SLC26A6, AC, GPα/β and ENaC (α, β and γ) to increase. Quercetin-induced changes in the uterine fluid secretion rate and electrolytes concentrations could potentially affect the uterine reproductive functions under female sex-steroid influence.
    Matched MeSH terms: Cystic Fibrosis Transmembrane Conductance Regulator/genetics
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