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Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and a whole gene deletion in the other) with early growth impairment in infancy. Growth hormone deficiency was confirmed at 20 months of life. Recombinant growth hormone treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Background Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori, and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. Methods We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. Results Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 (P = 0.006) and rs1726866 (P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. Conclusion In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.

BackgroundTraditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes linkSDHBvariants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) andSDHDvariants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations forSDHDvariants. In the present study we zoom in on the genotype-phenotype associations ofSDHBgene variants, considering the impact of individual gene variants on disease risk and risk of malignancy.MethodsWe analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncatingSDHBvariants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis.ResultsCompared with missense variants, truncatingSDHBvariants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant.ConclusionSDHBtruncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.

The genetic cause of 46, XY Disorder of Sex Development(DSD) still cannot be determined in about half of the cases. GATA-4 haploinsufficiency is one of the rare causes of DSD in genetic males (46, XY). Twenty-two cases with 46, XY DSD due to GATA-4 haploinsufficiency (nine missense variant, two copy number variation) have been reported in the literature. In these cases, the phenotype may range from a mild undervirilization to complete female external genitalia. The haploinsufficiency may be caused by a sequence variant or copy number variation (8p23 deletion). The study aimed to present two unrelated patients with DSD due to GATA-4 variants and to review the phenotypic and genotypic characteristics of DSD cases related to GATA-4 deficiency.

Over the past decades, there has been a rapid increase in the incidence and prevalence of inflammatory bowel disease (IBD) in Asia. The natural history of IBD in Asian patients could be different from that in Western patients due to variations in disease phenotypes and genotypes as well as the healthcare environment between the 2 populations. To adequately cope with this disease, it is important to fully understand the potential differences in its natural history among different populations. In this review, we evaluated the differences in the clinical course of IBD between Asian and Western patients with regards to phenotypic progression, hospitalization, major surgery, risk of colorectal cancer, and mortality, mainly based on the results of population-based studies. The findings of our narrative review suggest that the clinical course of Asian patients with IBD, especially ulcerative colitis, is better than that of Western patients, as indicated by the lower rates of major surgery and hospitalization. In addition, similar to Western patients, the clinical course of Asian patients with IBD has been improving as evidenced by the decreasing rates of disease behavior progression (in Crohn’s disease), hospitalization, and major surgery.

Background Protection against Plasmodium falciparum is observed in a population deficient in glucose-6-phosphate dehydrogenase (G6PD), particularly in African and Mediterranean regions. However, such protection remains unknown among G6PD-deficient individuals in Southeast Asia. Methods In this study, we assessed the invasion and maturation of P falciparum K1 in a culture of erythrocytes isolated from Thai subjects carrying Viangchan (871G > A) and Mahidol (487G > A). Results We found that the parasites lost their ability to invade hemizygous and homozygous G6PD-deficient erythrocytes of Viangchan and Mahidol variants in the second and third cycles of intraerythrocytic development. It is interesting to note that P falciparum parasites selectively grew in erythrocytes from hemi- and homozygous genotypes with normal G6PD activity. Moreover, externalization of phosphatidylserine upon P falciparum infection was significantly increased only in Viangchan hemizygous variant cells. Conclusions This study is the first to show that blockage of invasion in long-term culture and potentially enhanced removal of parasitized erythrocytes were observed for the first time in erythrocytes from Viangchan and Mahidol G6PD-deficient individuals.

Background Chlamydia trachomatis is considered a public health problem due to the high prevalence in sexually active women and men. The distribution of genital Chlamydia genotypes among Mexican men is unknown. Objective To assess the prevalence of Chlamydia genotypes in men with infertile women as sexual partners. Methods A total of 659 urine samples were collected from men whose sexual partners were infertile women; the identifying Chlamydia infection was by means of a real-time nucleic acid amplification test (qPCR). OmpA gene PCR-RFLP and sequencing were used to confirm the genotypes of C. trachomatis. The association of genotypes with age, spermatic parameters and gynecological data of sexual partners was further analyzed. Results Forty-nine urine samples were positive infection (7.4%). The Chlamydia infection was significantly associated with teratozoospermia, azoospermia, hypospermia, and oligozoospermia. Five genotypes (F 51%; 12.2% to D; 12.2% to E; 6.1% to L2 and 4.1% Ia) were correctly identified. None genotypes identified in this comparative study were positively associated with changes in some of the spermatic values because all of them typically produce some considerable damage to these cells. Conclusions The F genotype was the most frequent genotype identified in infertile men from Mexico City and all genotypes play an important role in the seminal alteration of Mexican men whose female partners are infertile.

Hepatitis B virus [HBV], the best-described hepadnavirus, is distributed all around the world and may lead to chronic and acute liver disease, cirrhosis, and hepatocellular carcinoma. Despite the advancement in treatment against HBV, an errorprone reverse transcriptase, which is required for HBV replication as well as host immune pressure, leads to constant evolution and emergence of genotypes, subgenotypes and mutant viruses; so, HBV will remain as a major healthcare problem around the world. This review article mainly focuses on the HBV mutations which correlated to occult HBV infection, immune escape, vaccine failure and eventually liver cirrhosis and HCC. The current study indicated that preS/S region mutations are related to vaccine failure, immune escape, occult HBV infection and the occurrence of HCC. Whereas P region Mutations may lead to drug resistance to NA antivirals. PreC/C region mutations are associated with HBeAg negativity, immune escape, and persistent hepatitis. Moreover, X region Mutations play an important role in HCC development.

Introduction By providing timely actionable results for prompt management, point-of-care testing (POCT) kits have revolutionised medical care for various diseases, ranging from infectious diseases like malaria to genetic disorders, such as sickle cell disease (SCD). They are, however, underutilised in the diagnosis of SCD in developing countries, where the need is greatest. Objective The study was aimed at assessing the sensitivity of HemoTypeSC POCT among a cohort of children with SCD, previously diagnosed by Alkaline cellulose acetate hemoglobin electrophoresis (ACAE), with or without high-performance liquid chromatography (HPLC). Methods In this descriptive cross-sectional study, HemoTypeSC test was conducted on all participants and its sensitivity was determined by comparing results with those obtained using ACAE. Discordance was verified with HPLC. Results One hundred and forty-five children aged one to 19 years were studied. There were 84 males and 61 females (male: female ratio = 1.4: 1). The HemoTypeSC was able to correctly diagnose sickle cell anemia (SCA) and hemoglobin SC in all (100%) of the children tested. Conclusion The HemoTypeSC shows high sensitivity in detecting SCA and hemoglobin SC. Hence, it is useful for targeted screening of individuals suspected of having SCD, leading to rapid diagnosis of these hemoglobinopathies, even in resource-constrained settings.

Introduction Thromboembolic events occur due to an imbalance in the hemostasis and some factors associated with this condition can be inherited. In order to evaluate the frequency of genotypes considered to be common hereditary risk factors for thrombophilia associated with venous thrombosis (g.1691G > A and g.20210G > A) and hyperhomocysteinemia (g.677C > T and g.1298A > C), samples from voluntary healthy blood donors at the Hospital de Clinicas de Porto Alegre were tested. Methods We examined 325 blood samples from blood donors collected from October 2017 to July 2018. Blood was collected on filter paper and the DNA was extracted for single nucleotide polymorphisms (SNPs) analysis using the qualitative real time polymerase chain reaction. Results The calculated frequencies of each genetic variant in heterozygosity were 4% for the FV gene (g.1691G > A), 4% for the F2 gene (g.20210G > A) and 42% and 39% for methylenetetrahydrofolate reductase (MTHFR), g.677C > T and g.1298A > C, respectively. Only the genetic variants of MTHFR were found in homozygosity, with frequencies of 14% and 6% (g.677C > T and g.1298A > C), respectively. Discussion Altogether, these results describe the frequencies of genetic variants associated with venous thrombosis and hyperhomocysteinemia in the analyzed group and are important to enhance our current knowledge about the genetic profiles of Brazilian blood donors.

Background Anti-TB drugs are most common cause of idiosyncratic hepatotoxicity worldwide. Reactive metabolite formed during drug metabolism has been involved in a clinical toxicity are described as ‘idiosyncratic’ drug induce liver injury (DILI). We have observed the distribution of glutathione S -transferase (GST) gene polymorphism & its association with drug-induced liver injury in patients taking anti-tubercular treatment. Methods A prospective observational study including 96 patients receiving anti-tubercular treatment. Blood sample was collected for LFT and gene extraction after ruling out other cause of liver injury. DNA extraction for GST gene was done follow by polymerase chain reaction to identify homozygous null mutation at GSTM1 and GSTT1 loci. Association of GSTM1 and GSTT1 gene with DILI was seen. Results Out of 96 tubercular patients under treatment, drug induced liver injury was found in 21 (21.9%) patients and 75 does not develop DILI, GST M1 gene null mutation was observed in 14 (66.7%), GST T1 gene null mutation was observed in 9 (42.9%), Both GST gene null mutation was observed in 8 (38.1%) in DILI group. Conclusion The GSTM1 gene null mutation and both GSTM1 and T1 gene null mutation were a risk factor for the development of DILI. But there is no significant association between GSTT1 gene null mutation and DILI in TB patients.

Both environmental factors, such as alcohol consumption and smoking, and genetic factors are strongly associated with the risk of developing chronic pancreatitis (CP). However, comprehensive understanding of their impacts on the progression of CP remains elusive.A prospective cohort study was performed on a large cohort of CP patients with known genetic backgrounds. The cumulative incidence of pancreatic insufficiency after the onset of CP was analyzed using Kaplan-Meier survival curves. Multivariate Cox proportional hazards regression analysis also was performed.A total of 798 patients were enrolled in the study and followed up for 10.5 years. Rare pathogenic genotypes in the SPINK1, PRSS1, CTRC, or CFTR genes were identified in 410 (51.4%) patients. The development of pancreatic insufficiency was significantly earlier in patients with a history of smoking and/or alcohol consumption in both the positive (P.001) and negative (P = .001) gene mutation groups. However, the development of pancreatic insufficiency did not differ significantly between patients with and without gene mutations despite alcohol and/or smoking status, with P values of .064 and .115, respectively. Multivariate Cox regression analysis showed that age at onset of CP (hazard ratio, [HR], 1.02; P.001) and alcohol consumption (HR, 1.86; P.001) were independent risk factors for the development of diabetes, while male sex (HR, 1.84; P = .022) and smoking (HR, 1.56; P = .028) were predictors of steatorrhea.Although rare pathogenic mutations in the 4 major susceptibility genes for CP were not correlated significantly with the development of pancreatic insufficiency, environmental factors (either alcohol consumption or smoking) significantly accelerated disease progression (ClinicalTrials.gov: NCT04574297).

OBJECTIVES Vascular endothelial growth factor is an endothelial-specific growth factor that promotes endothelial cell proliferation, differentiation, and survival; mediates endothelium-dependent vasodilatation; induces microvascular hyperpermeability; and participates in interstitial matrix remodeling. The aim of the present study was to investigate the association between +405 G/C polymorphism of vascular endothelial growth factor and the risk of liver rejection in liver transplant recipients. MATERIALS AND METHODS The present study included 124 patients with liver disease that led to liver transplant. There were 22 patients who experienced histologically proven acute liver rejection, and the other 102 patients showed no rejection. Both groups were matched for sex and age. The VEGF+405 G/C polymorphism was evaluated by the polymerase chain reaction-restriction fragment-length polymorphism method. RESULTS Our analyses showed no significant relationships between genotypes and alleles of +405 G/C and risk of acute liver transplant rejection. CONCLUSIONS Our report indicated that there was no association between the carrier states of +405 G/C gene polymorphism of vascular endothelial growth factor and acute rejection or nonrejection of liver transplant.

Background: Febrile Seizures (FS) are the most common seizures in children younger than 5 years. In the last decade, various coding and noncoding sequence variations of voltage-gated sodium channels SCN2A have been identified in patients with seizures, implying their genetic base. We aimed to evaluate the association between SCN2A c. G/A genetic polymorphism among Egyptian children with febrile seizure plus. Methods: The present cross-sectional study was carried out on 100 epileptic infants and children, attendants of the Neurology Unit, pediatric department, Menoufia University Hospitals (Group Ι). The patients were sub-classified into two groups, according to response to anti-epileptic treatment; Group Ι a (drug responder) and Group Ι b (drug-resistant). Evenly divided number of apparently healthy, age and gender-matched children were selected as controls (Group II). A complete history, throughout the systemic examination and radiological & metabolic assessment, whenever needed was provided, all participants were genotyped for SCN2A rs17183814 polymorphism by Restriction Fragment Length Polymorphism (PCR-RFLP). Results: Both of A allele and AA, GA genotypes of SCN2A c. 56 G/A were detected more in patients with febrile seizure plus comparison to the control group with a statistically significant difference at frequencies of 17% and 11% and 12% respectively; OR (CI95%): 10.04 (3.49-28.87) and p Conclusion: SCN2A rs17183814 (A) allele was specifically associated with developing febrile seizure plus and could modulate the patient's response to anti-epileptic medications.

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10−11), rs12454712 (BCL2; P = 2.7 × 10−8), and rs10506418 (FAM19A2; P = 1.9 × 10−8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

A 4-year-old boy presented with his mother to genetics in the 1980s, with a family history (FH) of macrocephaly and intellectual disability (ID). He remained undiagnosed until his mother developed multiple cancers and was diagnosed with Cowden syndrome (CS) in 2017, a rare, multisystem cancer predisposition syndrome. CS was then confirmed in multiple family members. Clinical examination revealed potentially novel features; gingival enlargement, dental abnormalities and joint hyperextensibility. These features could contribute to revised PTEN hamartoma tumour syndrome, National Comprehensive Cancer Network, minor diagnostic criteria. The paediatric CS phenotype is still emerging and features expressed in this family during childhood could potentially aid paediatric diagnosis. This case reminds clinicians to seek genetic input for PTEN testing when macrocephaly is identified alongside, a personal or FH of ID, early-onset tumours (especially breast, bowel or thyroid) or multiple tumours. Thus detailed FH is pivotal to earlier CS diagnosis and improved patient outcomes.

BACKGROUND: SIRT1 is a multifunctional protein, possibly essential in tumorigenesis pathways, which can act both as a tumor promoter and tumor suppressor depending on the oncogenes, specific to particular tumors. Pathogenesis of laryngeal cancer is multifactorial and the association of SIRT1 expression with the clinical characteristics and prognosis of LSCC has not been fully identified. OBJECTIVES: The study aimed to evaluate associations between single gene nucleotide polymorphisms (SNPs) of SIRT1 (rs3818292, rs3758391, and rs7895833), serum SIRT1 levels, and 5-year survival rate in patients with laryngeal squamous cell carcinoma (LSCC). METHODS: The study involved 302 patients with LSCC and 409 healthy control subjects. The genotyping of SNPs was performed using RT-PCR, and serum SIRT1 levels were determined by the ELISA method. RESULTS: Our study found significant differences in genotype distributions of SIRT1 rs3758391 polymorphisms between the study groups. SIRT1 rs3758391 T/T genotype was associated with the increased LSCC development odds (OR = 1.960 95% CI = 1.028–3.737; p= 0.041). Carriers of SIRT1 rs3758391 T/T genotype had statistically significantly increased odds of LSCC development into advanced stages under the codominant and recessive genetic models (OR = 2.387 95% CI = 1.091–5.222; p= 0.029 and OR = 2.287 95% CI = 1.070–4.888; p= 0.033, respectively). There were no statistically significant differences in serum SIRT1 levels between the LSCC and control groups. However, LSCC patients with SIRT1 rs3818292 AG genotype demonstrated a tendency to significantly lower SIRT1 serum levels than controls (p= 0.034). No statistically significant associations between SIRT1 (rs3818292, rs3758391, and rs7895833) SNPs and the 5-year survival rate of LSCC patients were found. CONCLUSION: The present study indicated a statistically significant association between the SIRT1 rs3758391 T/T genotype and increased LSCC development odds. LSCC patients with SIRT1 rs3818292 AG genotype showed a tendency to manifest with lower SIRT1 serum levels. No associations between SIRT1 SNPs and the 5-year survival rate of LSCC patients were detected.

Background Cystic fibrosis (CF) is a recessive condition caused by variants in each CF transmembrane conductance regulator (CFTR) allele. Clinically affected individuals without two identified causal variants typically have no further interrogation of CFTR beyond examination of coding regions, but the development of variant-specific CFTR-targeted treatments necessitates complete understanding of CFTR genotype. Methods Whole genome sequences were analyzed on 5,058 individuals with CF. We focused on the full CFTR gene sequence and identified disease-causing variants in three phases: screening for known and structural variants; discovery of novel loss-of-function variants; and investigation of remaining variants. Results All variants identified in the first two phases and coding region variants found in the third phase were interpreted according to CFTR2 or ACMG criteria (n = 371; 16 [4.3%] previously unreported). Full gene sequencing enabled delineation of 18 structural variants (large insertions or deletions), of which two were novel. Additional CFTR variants of uncertain effect were found in 76 F508del homozygotes and in 21 individuals with other combinations of CF-causing variants. Both causative variants were identified in 98.1% (n = 4,960) of subjects, an increase of 2.3 percentage points from the 95.8% (n = 4,847) who had a registry- or chart-reported disease-causing CFTR genotype. Of the remaining 98 individuals, 78 carried one variant that has been associated with CF (CF-causing [n = 70] or resulting in varying clinical consequences n = 8]). Conclusions Complete CFTR gene sequencing in 5,058 individuals with CF identified at least one DNA variant in 99.6% of the cohort that is targetable by current molecular or emerging gene-based therapeutic technologies.

Introduction Tobacco consumption and radon exposure are considered the first and second most common causes of lung cancer, respectively. The aim of this study was to analyze both whether selected genetic polymorphisms in loci that are in DNA repair pathways, are related to non-small-cell lung cancer (NSCLC) and whether they may modulate the association between residential radon exposure and lung cancer in both smokers and never smokers. Methods A multicentre, hospital-based, case–control study with 826 cases and 1201 controls was designed in a radon-prone area. Genotyping was determined in whole blood and residential radon exposure was measured in participants’ dwellings. Results Attending to tobacco exposure, the variant in the gene NBN (rs1805794) was associated with lung cancer in never smokers (OR 2.72; 95%1.44–5.2) and heavy smokers (OR 3.04; 95%CI 1.21–7.69). The polymorphism with the highest lung cancer association was OGG1 (rs125701), showing an OR of 8.04 (95%CI 1.64–58.29) for its homozygous variant genotype in heavy smokers. Attending to indoor radon exposure (>200 Bq/m3), rs1452584, for its homozygous variant genotype, showed the highest association (OR 3.04 (95%CI 1.15–8.48). Conclusion The genes analyzed seem to have no association with the fully adjusted model, but they might modulate lung cancer association when different categories of tobacco consumption are considered (i.e. heavy smokers). This association may similarly be elevated for those individuals having high indoor radon exposures, though at a minor extent.

BACKGROUND Attenuated familial adenomatous polyposis is characterised by low number (≤ 100) and delayed development of colorectal adenomas. Various definitions have been used, and genotype-phenotype correlations suggested. OBJECTIVE We aim to evaluate phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and assess familial variability. DESIGN This is a retrospective study. SETTINGS This study was conducted at a tertiary polyposis registry. PATIENTS Individuals with attenuated familial adenomatous polyposis were identified. Phenotypic group was defined as ≤ 100 adenomas at age 25 years and genotypic group was defined as a variant in the Adenomatous polyposis coli region associated with attenuated familial adenomatous polyposis. Pathology polyp count was used for patients who had undergone surgery and endoscopic polyp count for those with intact colon. MAIN OUTCOME MEASURES We evaluated phenotypic and genotypic correlation in patients with presumed attenuated familial adenomatous polyposis and familial variability. RESULTS A total of 69 patients were identified in the phenotypic group of which 54 (78%) had a pathogenic variant in the attenuated regions of the adenomatous polyposis coli gene. Forty-eight (70%) had intact colon (median age at last colonoscopy 43 [25-73] years; median endoscopic polyp count 20 [0-100]) and 21 (30%) had undergone colectomy (median age at surgery 45 [25-54] years; median pathology polyp count 43 [3-100]). Eighty-three patients were identified in the genotypic group of which 54 (65%) had attenuated phenotype. Inter- and intra- familial variability were observed. LIMITATIONS This study was limited by its retrospective nature and single-center experience. CONCLUSION Phenotype in familial adenomatous polyposis lies on a spectrum - being determined in part by genotype and age at adenoma count. Diagnosis of attenuated familial adenomatous polyposis should be based on phenotype; genotype is not a reliable indicator. Management should be personalized according to the phenotype of each individual. See Video Abstract at http://links.lww.com/DCR/B775.

Objective To investigate the association of genic region polymorphisms of FAS and FASL in Indian patients with oral cancer. Study design The study included 960 consenting control participants and patients with oral cancer. Genotyping was performed using Polymerase Chain Reaction -Restriction Fragment Length Polymorphism (PCR-RFLP). Cancer risk, 5-year survival, and hazards ratio (HRs), with respect to risk and clinical factors, were estimated using Fisher's exact test, Kaplan-Meier analysis, and Cox proportional hazards models. Results FASL IVS2nt-124 ‘AG’ increased risk in males with buccal mucosa cancer (BMC) but decreased risk in females. FAS 21196 ‘CT’ decreased risk of tongue cancer (TC) and BMC in females. The survival of the patients also differed between sexes in TC and BMC. FAS 21196 ‘CT’ increased HR by 23-fold in females with BMC when adjusted for age, stage, grade, LVS, PNI, tobacco use, and alcohol. ‘TT’ genotype increased the HR in females with BMC when adjusted for age, stage, grade, lymphovascular spread (LVS), perineural invasion (PNI), and perinodal spread (PNS). Our bioinformatic study revealed the presence of CTCF binding regions and CpG islands near FAS and FASL. Conclusions These single nucleotide polymorphisms (SNPs) altered the risk and survival of BMC and TC patients differentially that varied with clinical and risk factors.

Aim This study aimed to identify genotype enterotoxigenic antimicrobial-resistant Staphylococcus aureus species, mainly methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) among commensal rodents. Methods and results A total of 280 samples were collected from nasal and mouth swabs, heart blood, intestinal content and lung tissues of 56 commensal rodents trapped from North Sinai, Egypt. Antimicrobial susceptibility testing was performed to bacteriologically identified S. aureus isolates against 15 antimicrobial agents by disc diffusion method. Detection was conducted for identifying coagulase gene (coA), antimicrobial-resistant genes (mecA and vanA/B), enterotoxigenic and virulence determinant genes (hlg, seb, sed and see) among the MRSA and VRSA isolates. Results Staphylococcus aureus species were isolated from 24 (42.86%) out of 56 rodents. Phenotypic examination revealed that all the isolates were multidrug-resistant, whereas two isolates were multiple antibiotic resistant (MAR). Out of 33 examined isolates, 33 (100%) were resistant to oxacillin and amoxicillin, 31 (93.93%) to cefoxitin and 12 (36.36%) to vancomycin. PCR assay revealed that 24 isolates revealed (100%) positivity to coA gene, 17 (70.83%) to mecA gene and 12 (50%) to vanA/B genes. Enterotoxin genes and haemolysin genes were detected among MRSA and VRSA isolates. There was a strong positive correlation between the tested antimicrobial-resistant genes and virulence genes (p > 0.05). Conclusions This study demonstrated the occurrence of MRSA and VRSA strains among commensal rodents in North Sinai, Egypt. The detection of enterotoxigenic and virulence genes of the isolated MRSA and VRSA strains indicated the health hazards of food contamination and zoonotic infections. Significance and impacts of the study. This study emphasizes the role of commensal rodents in maintaining and disseminating multidrug-resistant MRSA and VRSA strains to the environment, animals and human beings.

The Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the causal agent of Kaposi sarcoma (KS), but is also pathogenetically related to several lymphoproliferative disorders, including primary effusion lymphoma (PEL)/extra-cavitary (EC)-PEL, KSHV-associated multicentric Castleman disease (MCD), KSHV-positive diffuse large cell lymphoma (DLBCL) and germinotropic lymphoproliferative disorder (GLPD). These different KSHV-associated diseases may co-occur and can have overlapping features. KSHV, similar to the Epstein-Barr virus (EBV), is a lymphotropic gamma herpesvirus which is preferentially present in abnormal lymphoid proliferations occurring in immune compromised individuals. Notably, both KSHV and EBV can infect and transform the same B cell, which is frequently seen in the KSHV-positive, EBV-positive PEL/EC-PELs. The mechanisms by which KSHV leads to lymphoproliferative disorders is thought to be related to the expression of a few transforming viral genes that can affect cellular proliferation and survival. There are critical differences between KSHV-MCD and PEL/EC-PEL, the two most common KSHV-associated lymphoid proliferations, including the viral associations, the patterns of viral gene expression and the cellular differentiation stage reflected by the phenotype and genotype of the infected abnormal B cells. Advances in treatment have improved outcomes, but mortality rates remain high. Our deepening understanding KSHV biology, the clinical features of KSHV-associated diseases, and newer clinical interventions should lead to improved and increasingly targeted therapeutic interventions.

BACKGROUND: Somatic variations in rearranged during transfection (RET) proto-oncogene acts to influence Thyroid cancer (TC) in a low penetrance manner, but their effects tend to vary between different populations. OBJECTIVE: This case-control study was aimed to evaluate effect of RET G691S, S904S and L769L single nucleotide polymorphisms (SNPs) on the risk for differentiated thyroid carcinoma (DTC). METHODS: A total of 180 patients and 220 controls were genotyped by Polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP). Di-Deoxy Sanger sequencing was performed on 100 samples with variations and 20 wild samples for each amplified exon. In addition, In Silico tools were used to evaluate structural and functional impact of individual SNPs in disease progression. RESULTS: In RET G691S/L769L/S904S SNPs, frequency of variant genotypes in DTC cases was 61.1%, 54.4% and 76.6% as compared to 45.9%, 43.6% and 89.09% in controls respectively (P⩽ 0.05). In Silico analysis revealed that different protein formed due to G691S substitution decreases the stability of 3D structure of protein. The RET G691S and L769L SNP followed “Dominant” but RET S904S SNP confirmed an “Additive” mode of inheritance. CONCLUSION: RET G691S/L769L/S904S SNPs are significantly associated with DTC with G691S SNP declining the stability of final protein product.

Background: FimH adhesin is proposed to enhance Escherichia coli kidney infection by acting with PapGII adhesin, but genetic epidemiology study and animal study have not been widely conducted to confirm this hypothesis. Methods: We compared the prevalence of adhesin gene and their coexistent pattern between upper and lower urinary tract infection (UTI) strains. fimH mutant (EC114FM), papGII mutant (EC114PM) and fimH/papGII double mutant (EC114DM) were constructed from a pylonephritogenic strain (EC114). We compared among these strains for the infection ability in bladders and kidneys of female BALB/c mice challenged transurethrally with these bacteria and assessed 1, 3, and 7 days after inoculation. Results: Strains carrying fimH-only genotype were significantly more prevalent in lower UTI (P

Contains fulltext : 248942.pdf (Publisher’s version ) (Open Access) The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals.

Background Alpha-1 antitrypsin deficiency (AATD) is an autosomal co-dominant condition that predisposes to emphysema, cirrhosis, panniculitis, and vasculitis. Under-recognition has prompted efforts to enhance early detection and testing of at-risk individuals. Direct-to-consumer (DTC) genetic testing represents an additional method of detection. Research Question The study addressed three questions: 1) Does a DTC testing service identify previously undetected individuals with AATD? 2) What was the time interval between initial AATD-related symptoms and initial diagnosis of AATD in such individuals? and 3) What was the behavioral impact of learning about a new diagnosis of AATD through a DTC test? Study Design and Methods In this cross-sectional study, 195,014 individuals responded to a survey within the 23andMe, Inc. research platform. Results Among 195,014 study participants, the allele frequency for either the PI*S and PI*Z AATD variants was 21.6% (6.5% for PI*Z and 15.1% for PI*S); 0.63% were PI*ZZ, half of whom reported having a physician confirm the diagnosis. Approximately 27% of those with physician-diagnosed AATD reported first becoming aware of AATD through the DTC test. Among those newly-aware participants, the diagnostic delay interval was 22.3 years. Participants frequently shared their DTC test results with healthcare providers (HCPs) and the reported impact of learning a diagnosis of AATD was high. For example, 51.1% of PI*ZZ individuals shared their DTC result with an HCP. The odds ratio for PI*ZZ smokers to report smoking reduction as a result of receiving the DTC result was 1.7 [CI 1.4, 2.2] compared to those without a Z allele and for reduced alcohol consumption was 4.0 [CI 2.6, 5.9]. Interpretation In this largest available report on DTC testing for AATD, this test, in combination with clinical follow-up, can help to identify previously undiagnosed AATD patients. Moreover, receipt of the DTC AATD report was associated with positive behavior change, especially among those with risk variants.

Background The introduction of primary HPV screening has doubled the number of colposcopy referrals because of the direct referral of HPV-positive women with a borderline or mild dyskaryosis (BMD) cytology (ASC-US/LSIL) triage test. Further risk-stratification is warranted to improve the efficiency of HPV-based screening. Methods This study evaluated the discriminative power of FAM19A4/miR124-2 methylation, HPV16/18 genotyping and HPV16/18/31/33/45 genotyping in HPV-positive women with BMD (n = 294) in two Dutch screening trials. Absolute CIN3+ risks and colposcopy referrals within one screening round were calculated. Results Methylation analysis discriminated well, yielding a CIN3+ risk of 33.1% after a positive result and a CIN3+ risk of 9.8% after a negative result. HPV16/18 and HPV16/18/31/33/45 genotyping resulted in a 27.6% and 24.6% CIN3+ risk after a positive result, and a 13.2% and 9.1% CIN3+ risk after a negative result. Colposcopy referral percentages were 41.2%, 43.2%, and 66.3% for FAM19A4/miR124-2 methylation, HPV16/18 and HPV16/18/31/33/45 genotyping, respectively. The CIN3+ risk after a negative result could be lowered to 2.8% by combining methylation and extended genotyping, at the expense of a higher referral percentage of 75.5%. Conclusion The use of FAM19A4/miR124-2 methylation and/or HPV genotyping in HPV-positive women with BMD can lead to a substantial reduction in the number of direct colposcopy referrals.

Prader–Willi syndrome (PWS) is a rare genetic syndrome, caused by the loss of expression of the paternal chromosome 15q11-q13 region. Over the past years, many cases of patients with characteristics similar to PWS, but without a typical genetic aberration of the 15q11-q13 region, have been described. These patients are often labelled as Prader–Willi-like (PWL). PWL is an as-yet poorly defined syndrome, potentially affecting a significant number of children and adults. In the current clinical practice, patients labelled as PWL are mostly left without treatment options. Considering the similarities with PWS, children with PWL might benefit from the same care and treatment as children with PWS. This review gives more insight into the pheno- and genotype of PWL and includes 86 papers, containing 368 cases of patients with a PWL phenotype. We describe mutations and aberrations for consideration when suspicion of PWS remains after negative testing. The most common genetic diagnoses were Temple syndrome (formerly known as maternal uniparental disomy 14), Schaaf–Yang syndrome (truncating mutation in the MAGEL2 gene), 1p36 deletion, 2p deletion, 6q deletion, 6q duplication, 15q deletion, 15q duplication, 19p deletion, fragile X syndrome, and Xq duplication. We found that the most prevalent symptoms in the entire group were developmental delay/intellectual disability (76%), speech problems (64%), overweight/obesity (57%), hypotonia (56%), and psychobehavioral problems (53%). In addition, we propose a diagnostic approach to patients with a PWL phenotype for (pediatric) endocrinologists. PWL comprises a complex and diverse group of patients, which calls for multidisciplinary care with an individualized approach.

Objective To retrospectively investigate the relationship between apolipoprotein E (APOE) gene polymorphism and in-stent restenosis (ISR) after stenting at the beginning of the vertebral artery. Methods The study included 155 patients who successfully underwent stenting at the beginning of the vertebral artery and had postoperative digital subtraction angiography or computed tomography angiography. Based on the follow-up results, they were divided into the restenosis (ISR) group and non-restenosis (non-ISR) group. The clinical information and APOE genotypes of both groups were analyzed. A binary logistic regression model was used to analyze independent risk factors for ISR. Results After 1 year of follow-up, 49 (31.6%) patients had ISR and 106 (68.4%) did not. Binary logistic regression analysis showed that serum low-density lipoprotein cholesterol (LDL-C), serum lipoprotein-related phospholipase A2 (Lp-PLA2), and E3/E4 genotype were independent risk factors for ISR after stenting at the beginning of the vertebral artery. In addition, the LDL-C level of patients with the E3/E4 genotype was higher compared to the E3/E3 genotype group (P Conclusions APOE gene polymorphism is associated with ISR, and the E3/E4 genotype is an independent risk factor for ISR after stenting at the beginning of the vertebral artery. Further genetic studies can identify risk genotypes to facilitate the early prediction and identification of high-risk patients with ISR.

Background Citrullinated proteins formed by peptidyl arginine deiminases (PADIs) deimination of arginine residues in proteins are of particular interest in arthritis pathogenesis. Polymorphisms on the PADI-4 gene lead to the malfunctioning of PADIs leading to the onset of arthritis. Objective The present study was conducted to determine the polymorphisms on the PADI-4 gene and their association with rheumatoid arthritis (RA) as well as Osteoarthritis (OA). Methodology To achieve the above-mentioned objective a case-control study was conducted. Blood samples were collected from RA, OA, and control subjects. DNA was extracted from each blood sample by modified organic method and was quantified as well as qualified by DNA gel electrophoresis and Nanodrop. Patients were tested for rs874881, rs11203366, rs11203367, rs2240336, rs2240337, rs2240339, rs1748033 and rs2240340 polymorphic sites by amplifying targeted regions through PCR with site-specific primers. Genotyping was performed by Restriction Fragment Length Polymorphism and direct sequencing method. Mutations were identified by analyzing sequences on BioEdit software. Allelic, genetic, and multiple site analysis were performed by SHEsis and PLINK software. Change in the amino acid sequence was identified by MEGA 6.0 software. Results Polymorphisms were identified on all targeted polymorphic sites except rs2240337 in both RA and OA individuals. In addition, two novel mutations were also identified in exon 4 identified i-e SCV000804840: c.218T > C and SCV000807675: c.241G > T. All the SNPs except rs11203366 were found to be significantly associated with RA at an allelic level whereas all SNP’s have been significant risk factors in the onset of OA. At genotypic level rs874881, rs11203366, rs2240339, SCV000804840 and SCV000807675 were significantly associated to RA development whereas rs874881, rs11203366, rs11203367, rs2240339, SCV000804840 and SCV000807675 were genetic risk factors in OA onset. Haplotype analysis indicated that GACCACGCC and GACCACGCT were highly significant in disease development. Polymorphisms identified altered the functioning of PADIs by altering their amino acid sequence. Conclusion In conclusion, it was found that PADI-4 gene polymorphism was not only involved in the onset of RA but was also found to be a significant risk factor in OA onset.

Common bacterial causes of bovine respiratory disease (BRD) include Histophilus somni, Mannheimia haemolytica, and Pasteurella multocida. Within M. haemolytica, two major genotypes are commonly found in cattle (1 and 2); however, genotype 2 strains are isolated from diseased lungs much more frequently than genotype 1 strains. Outer membrane proteins (OMPs) of H. somni, P. multocida, and genotype 2 M. haemolytica may be important factors for acquired host immunity. The predicted OMP differences between genotypes 1 and 2 M. haemolytica have been previously identified. In this study, we expanded the focus to include bovine-isolated strain genomes representing all three species and the two M. haemolytica genotypes. Reported here are the core genomes unique to each of them, core genomes shared between some or all combinations of the three species and two M. haemolytica genotypes, and predicted OMPs within these core genomes. The OMPs identified in this study are potential candidates for further studies and the development of interventions against BRD.

Background Interleukin (IL)-17A has a dual role in tumor immunity, promotes anti-tumor responses and facilitates angiogenesis by interacting with IL-17 receptor A (IL-17RA). Although IL-17A has been associated with the pathogenesis of papillary thyroid carcinoma (PTC), the nucleotide variability at the IL17A and IL17RA genes is still poorly characterized. Aim To assess the contribution of the IL17A (-197 G >A, rs2275913) and IL17RA (-947 A >G, rs4819554) single nucleotide polymorphisms (SNP) on the development and progression of PTC and on IL-17 plasma levels. Methods We studied 188 PTC patients and 170 healthy controls. SNPs were identified using PCR-amplified DNA and restriction fragment length polymorphism (RFLP) techniques. Plasma levels of IL-17A was evaluated in 83 PTC patients using ELISA. Statistical analyses were performed to evaluate the associations between SNPs and clinicohistopathological features of PTC and IL-17A levels. Results No significant difference was observed regarding the allele and genotype distributions of both SNPs between PTC patients and controls. The IL17A GA was associated with poor biochemical and structural incomplete response to therapy, whereas no influence over the IL-17A expression was observed. The IL17RA AG was significantly associated with small-sized tumors, initial tumor stage at diagnosis and better response to therapy. Conclusions The IL17A SNP may predict an aggressive manifestation of PTC, whereas the IL17RA SNP was associated with a more favorable clinical outcome.

The aim of this study was to investigate the association between CYP2C19 gene polymorphisms and the risk of cardiovascular events in the early stage and subsequent period after percutaneous coronary intervention (PCI) among patients who received clopidogrel. Between October 2015 and January 2017, CYP2C19 genotyped patients who were treated with clopidogrel after PCI were enrolled in this study. Included patients were categorized as non-loss-of-function metabolizers, intermediate metabolizers, and poor metabolizers based on CYP2C19 genotype. The primary outcome was a composite of any-cause mortality, nonfatal myocardial infarction, nonfatal ischemic stroke, and stent thrombosis occurring during exposure to clopidogrel. The rates of clinical outcome events were compared between CYP2C19 phenotypes. Landmark analyses were processed at 90 days and 1 year post-PCI. Of 1341 patients, 161 (12.0%) had 2 copies of loss-of-function (LOF) alleles, 621(46.3%) had one LOF allele, and 559 (41.7%) had no LOF allele. At the 3-month follow-up, the primary outcome events were more frequent in carriers of 2 LOF alleles (5.6%) than in noncarriers (1.8%) [adjusted hazard ratio (HR) 2.944, 95% confidence interval, 1.184-7.321, P = 0.020). A similar finding was observed among in patients with acute coronary syndrome indications at the index PCI (adjusted HR 3.046, 95% confidence interval, 1.237-7.501, P = 0.015). These differences did not persist within the subsequent 9 months of follow-up, among either all comers or subjects with acute coronary syndrome. In conclusion, these data demonstrate a higher risk for ischemic events in patients with 2 CYP2C19 LOF alleles who are prescribed clopidogrel, seen at 3 months after PCI, that is not sustained for 12 months.

Background ABCB4-gene mutations are responsible for several cholestatic diseases with a heterogeneous clinical spectrum. Aims To analyse phenotype/genotype relationships in ABCB4-mutations. Methods Retrospective characterization of adult patients with ABCB4-variations diagnosed between 2015 and 2020. Genotype-phenotype correlations were analysed and compared with previously reported data. Results Twenty patients from 12 families were included. Thirteen patients presented recurrent elevated liver tests, eight fulfilled Low-Phospholipid-Associated-Cholelithiasis syndrome criteria, five had Intrahepatic Cholestasis of Pregnancy and three patients developed Drug-Induced-Liver-Injury. ABCB4 screening identified eight different mutations. Five patients were homozygotes to the variant c.504T > C. Ten patients had one mutation in heterozygote-state and five patients had two mutations in compound- heterozygosity . Portal fibrosis occurred in two patients. One of these patients presented progressive fibrosis and progression of cholestasis despite ursodeoxycholic-acid treatment, this patient also harbours a ABCB11 polymorphism. Conclusion Although, phenotype-genotype relationships have not been clearly defined, an early diagnosis of ABCB4-variants may have an important role in management decisions and patient outcomes. To our knowledge, we describe a not previously reported deletion (c.1181delT) in ABCB4. The c.504T > C polymorphism, although a silent mutation at the protein level, seems to be associated to different cholestatic diseases. The role of other genes variants, namely ABCB11, as co-factor for progression, needs to be clarified.

Метою цього дослідження була оцінка зв’язку носійства алелі ε4 гена аполіпопротеїну E (АРОЕ) зі станом когнітивних функцій і атрофічними змінами головного мозку у пацієнтів із фібриляцією передсердь. Усього обстежений 61 пацієнт (середній вік — 64,8 ± 8,2 року) з когнітивними порушеннями різного ступеня вираженості при фібриляції передсердь. Проведено аналіз і наведено результати дослідження впливу генотипу АРОЕ4 на стан когнітивних функцій і вираженість церебральної атрофії за даними комп’ютерної томографії. Встановлено, що носійство навіть однієї алелі ε4 впливало на тяжкість когнітивних розладів, рівень холестерину і ліпопротеїдів дуже низької щільності в плазмі крові. При аналізі морфометричних характеристик встановлено, що у 70,5 % пацієнтів із фібриляцією передсердь і вивченим генотипом АРОЕ когнітивні розлади розвивалися на тлі атрофічного процесу головного мозку. Встановлено кореляційні зв’язки між рівнем когнітивних функцій і морфометричних маркерів підкіркової атрофії в групах пацієнтів з АРОЕ4, що підтверджує провідну роль останньої у розвитку і прогресуванні когнітивного дефіциту. Проведене дослідження дозволяє розглядати АРОЕ4 як фактор ризику когнітивних порушень у пацієнтів із фібриляцією передсердь.фібриляція передсердь; когнітивні порушення; аполіпопротеїн E (АРОЕ)

Objective. The objective of this study was to determine the correlation between single-nucleotide polymorphism in filaggrin gene and expression of filaggrin mRNA in buccal epithelium and the phenotype of bronchial asthma with atopic dermatitis in medical history of children. Methods. Filaggrin genotyping (rs11204981) was carried out in group of patients with bronchial asthma and control group using real-time polymerase chain reaction (PCR). The level of mRNA expression was assessed by reverse transcription and subsequent real-time PCR. Results. We have found that 5 % of patients in the study group and 2 % in the control group had a minor allele (AA), 27 and 36 %, respectively, — heterozygous allele (GA), 67 and 61 % — major allele (GG). Variants with the AA genotype of the FLG rs11204981 were found 2.4 times more often in patients from the study group than in controls. Heterozygous variant had significantly higher expression in filaggrin in buccal epithelium. Conclusions. We believe that polymorphism in filaggrin gene (rs11204981) can serve as an important prognostic marker for the phenotype of bronchial asthma and atopic dermatitis, and that high levels of expression in the heterozygous state may indicate the protective role of this genotype in the development of allergy.

Мета цього дослідження — визначення зв’язку однонуклеотидних поліморфізмів в генах mTOR (mammalian target of rapamycin; мішень рапаміцину у ссавців) і ATG5 (autophagy related gene 5; ген автофагії 5) та розвитку алергічного фенотипу у дітей. Генотипування mTOR (rs11121704) та ATG5 (rs510432) проводили в групі хворих з атопічними захворюваннями і контрольній групі за допомогою полімеразної ланцюгової реакції у реальному часі. Виявлено, що у 50 (54,9 %) пацієнтів і 43 (49,4 %) здорових дітей наявна мажорна алель (ТТ) поліморфізму rs11121704; 36 (39,6 %) і 32 (36,8 %) відповідно мали гетерозиготну алель (ТС); у 5 (5,5 %) і 12 (13,8 %) виявлено мінорну алель (СС). Варіанти з генотипом СС rs11121704 у гені mTOR визначалися у 2,5 раза частіше у контрольній групі, ніж серед хворих. Алельні варіанти в гені ATG5 розподілилися так: 51 (52 %) пацієнт та 43 (44,3 %) здорових дитини мали гетерозиготну алель (СТ), 29 (29,6 %) і 21 (21,6 %) відповідно мав мінорну алель (ТТ), у 18 (18,4 %) та 33 (34 %) була мажорна алель (СС). ТТ-генотип асоціюється з підвищеним ризиком ранньої маніфестації бронхіальної астми (до 3 років життя). Вважаємо, що поліморфізми в генах mTOR (rs11121704) та ATG5 (rs510432) можуть служити корисними прогностичними маркерами для оцінки ризику виникнення бронхіальної астми та іншої алергічної патології у дітей.

BACKGROUND: Dysregulated apoptosis is a hallmark of cancer development and progression. TRAIL and its receptors (R1 and R2) are key players in the extrinsic apoptotic pathway. Genetic alteration or blockade of TRAIL-R1 may alter its apoptotic function, and subsequently provide growth advantage to neoplastic cells. OBJECTIVE: to investigate the possible association between -C626G, -A683C and -A1322G single nucleotide polymorphisms (SNPs) of TRAIL-R1 gene and the susceptibility to B-NHL in a cohort of Egyptians. METHODS: Genotypic analysis was performed for 100 newly diagnosed B-NHL patients and 150 age and gender matched healthy controls. RESULTS: The polymorphic alleles of -C626G and -A1322G conferred almost twofold increased risk of B-NHL (OR = 1.76; 95%CI = 1.01–3.22 and OR = 1.89; 95%CI = 1.01–3.75 respectively). There was no statistical difference in the distribution of TRAIL-R1-A683C alleles/genotypes between B-NHL patients and controls. B-NHL risk increased when -C626G and -A1322G polymorphic genotypes were co-inherited (OR = 3.57; 95%CI = 1.29–9.84). The risk conferred by -C626G SNP increased for DLBCL (OR = 3.39, 95% CI: 1.61–7.16). CONCLUSION: TRAIL-R1–C626G and -A1322G polymorphisms could be considered as molecular risk factors for B-NHL especially DLBCL. The data provided by the current study constitute an initial millstone towards developing a large-scale dataset for genetic variations that could contribute to lymphomagenesis in Egyptian population.

Occult Hepatitis B Infection (OBI) is a critical risk factor for triggering post-transfusion hepatitis (PTH), cirrhosis, hepatocellular carcinoma, and hepatitis B virus (HBV) reactivation, which β-thalassemia major (BTM) patients are at risk of it due to multiple blood transfusions. This study was aimed at determining the prevalence of OBI among BTM patients from Khuzestan Province, Iran. In this cross-sectional study, 90 thalassemia patients, who have received blood 36 to 552 times, participated referred to the Shafa hospital of Ahvaz city from January 2018 to April 2019. ELISA for determining serological markers (HBsAg, anti-HBc, anti-HBs, and anti-HCV) and real-time PCR for detecting HBV-DNA were performed; Nested PCR was conducted for DNA sequencing and determining the genotype of OBI case. Phylogenetic and statistical analyses were done by R package. Of 90 subjects enrolled in this study; 95.5% (86/90) were HBsAg negative, and the frequency of OBI among them was 1.16% (1/86). The anti-HBs, anti-HBc, and anti-HCV were detected in 80.00%, 7.78%, and 12.2% of patients, respectively. HBV-DNA was assessed at four HBsAg-positive subjects as well, and all of them were negative. The phylogenetic analysis showed that the detected HBV DNA in the OBI case belongs to the genotype D. This research, for the first time, demonstrated that OBI is present among β-thalassemia patients in Iran. Also, further studies are necessary to determine the actual prevalence of OBI among BTM patients in Iran to decisions concerning OBI screening, especially in transfusion centers.

We highlight the need to include an analysis of the B-1 B cell subset to complement the characterization of the cell-mediated immune response to the Mycobacterium tuberculosis Beijing lineage. The literature describes the B-1 cell repertoire’s involvement in the cell-mediated response within granulomas, which is different from the classic antibody response B cells are generally associated with. Specifically, the B-1 B cell subset migrates from other compartments along with other cells to the infection site. We provide details to complement the reported results from Cerezo-Cortes et al.

Background Although population studies have implicated emotional burden in asthma severity, the underlying genetic risk factors are not completely understood. We aimed to evaluate the genetic influence of a functional single-nucleotide polymorphism (SNP) in the stress-related μ-opioid receptor gene (OPRM1; A118G SNP, rs1799971) on asthma severity. Methods We initially assessed disease severity in asthmatic outpatients carrying A118G. Using an ovalbumin-induced experimental asthma rodent model harboring the functionally equivalent SNP, we investigated the mechanism by which this SNP influences the allergic immune response. Results Among 292 outpatients, 168 underwent airway hyperresponsiveness (AHR) to methacholine testing. Compared with patients carrying the AA and AG genotypes, those carrying the GG genotype exhibited enhanced AHR. The stress levels were presumed to be moderate among patients and were comparable among genotypes. Compared with Oprm1 AA mice, GG mice demonstrated aggravated asthma-related features and increased pulmonary interleukin-4+CD4+ effector and effector memory T cells under everyday life stress conditions. Intraperitoneal naloxone methiodide injection reduced effector CD4+ T cell elevation associated with increased eosinophil numbers in bronchoalveolar lavage fluid of GG mice to the levels in AA mice, suggesting that elevated Th2 cell generation in the bronchial lymph node (BLN) of GG mice induces enhanced eosinophilic inflammation. Conclusions Without forced stress exposure, patients with asthma carrying the OPRM1 GG genotype exhibit enhanced AHR, attributable to enhanced Th2 cell differentiation in the regional lymph node. Further research is necessary to elucidate the role of the OPRM1 A118G genotype in the Th2 cell differentiation pathway in the BLN.

Background People with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation. Methods People ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV1 (ppFEV1) and ethnicity. Results 5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV1. In each age group, ppFEV1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort. Conclusions People with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine important in initiation of allergic inflammation. Single nucleotide polymorphisms (SNPs) in TSLP are associated with asthma, yet studies have shown inconsistent associations between circulating TSLP and asthma. Studies that integrate the combined effects of TSLP genotype, TSLP mRNA, circulating TSLP levels, and asthma outcome are lacking. OBJECTIVE: To recruit a novel cohort based on asthma-relevant TSLP SNPs and determine their impact on TSLP mRNA expression and TSLP circulating protein levels, and their individual and combined effects on asthma. METHODS: We developed an algorithm to prioritize TSLP SNPs and recruited 51 carriers and non-carriers based on TSLP genotypes. We quantified TSLP mRNA in nasal epithelial cells and circulating TSLP levels in plasma. We determined associations of defined TSLP risk genotypes and/or TSLP mRNA and protein levels with asthma. RESULTS: TSLP mRNA expression, but not circulating TSLP, was significantly increased in asthmatics compared to non-asthmatics (P=0.007; OR=1.44). Notably, 90% of children with the defined TSLP risk genotypes and high nasal TSLP mRNA expression (top tertile) had asthma compared to 40% of subjects without risk genotypes and with low TSLP expression (bottom tertile) (P=0.024). No association between circulating TSLP and asthma was observed. CONCLUSION: Collectively, these data suggest childhood asthma is modified by the combined effects of TSLP genotype and TSLP expression in the nasal epithelium. The increased asthma risk likely manifests when genetic variation enables eQTL in the TSLP locus to elevate TSLP. It is important to consider both biomarkers when factoring asthma risk. CLINICAL IMPLICATIONS: TSLP genotype and nasal mRNA expression may be useful biomarkers to aid asthma prediction and/or identify individuals who would benefit from therapy targeting this pathway.

Fanconi anemia (FA) is a cancer-prone inherited bone marrow failure syndrome caused by biallelic pathogenic variants in one of22 genes in the FA/BRCA DNA repair pathway. A major concern is whether the risk of cancer is increased in individuals with a single pathogenic FA gene variant.We evaluated the risk of cancer in the relatives of patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome cohort. We genotyped all available relatives and determined the rates, types of cancer and the age of patients at cancer diagnosis. We calculated the observed-to-expected (O/E) cancer ratios using data from the Surveillance, Epidemiology, and End Results Program adjusted for age, sex, and birth cohort.The risk of cancer was not increased among all FA relatives and FA heterozygotes (O/E ratios of 0.78 and 0.79, respectively). In particular, the risk of cancer was not increased among FANCA or FANCC heterozygotes (O/E ratios of 0.92 and 0.71, respectively). Relatives did not have typical FA cancers, and age at cancer diagnosis was not younger than expected.Understanding the risk of cancer in individuals with single pathogenic FA variants is critical for counseling and management. We did not find increased risk of cancer in these individuals. These findings do not extend to the known cancer predisposition autosomal dominant FA genes, namely BRCA1, BRCA2, PALB2, BRIP1, and RAD51C.

Inactivating germline variants in the CDH1 tumor suppressor gene cause the hereditary diffuse gastric cancer syndrome. Total gastrectomy is recommended for prevention, although it is associated with adverse outcomes and chronic health risks. Gastric cancer surveillance is an alternative to surgery; however, upper gastrointestinal endoscopy is limited by poor sensitivity. Cancer surveillance requires accurate detection of early carcinoma and patient-specific disease penetrance estimates. Current clinical care should incorporate up-to-date information on variable disease penetrance, which does not seem to correlate with CDH1 genotype. Affected patients and families warrant a balanced presentation of options for cancer surveillance and prophylaxis.

The goal of this review is to provide an overview of evaluating patients with adenomatous polyposis of the colon, including elements such as generating a differential diagnosis, referral considerations for genetic testing, genetic testing options, and expected outcomes from genetic testing in these individuals. In more recent years, adenomatous colonic polyposis has evolved beyond the more robustly characterized familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), now encompassing more newly described genes and associated syndromes. Technological innovation, from whole exome sequencing to multigene panel testing, has dramatically increased the amount of genotypic and phenotypic data amassed in adenomatous polyposis cohorts, which has contributed greatly to informing diagnosis and clinical management of affected individuals and their families.

Inflammation is the natural immunological response of an organism against any harmful, foreign or destructive effect to heal and repair damaged tissue. The nod-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is one of the main components of the inflammatory mechanism and is associated with many inflammatory diseases, but it is also closely related to metabolic abnormalities, such as type 2 diabetes mellitus (T2DM), insulin resistance and obesity. NLRP3 activates inflammation and causes interleukin-1β release, exogenous and endogenous danger signals, as well as insulin resistance. In this direction, we focus on the gene structure of NLRP3 in diabetes and accordingly, we aim to determine the relationship between eight gene variations in the NLRP3 gene and T2DM. We investigated the rs10802501, rs10733113, rs10754558, rs10925026, rs10925027, rs35829419, rs4612666 and rs4925659 single-nucleotide polymorphisms of NLRP3 gene using the Sequenom MassARRAY system in 100 T2DM patients and 100 control individuals. There were no significant differences between T2DM risk and the genotype frequencies of rs10802501, rs10733113, rs35829419 and rs10925026 variants (p0.05). However, significant genotype frequencies were determined for rs10925027 (p = 0.0013) and rs4925659 (p0.001). For the risk allele G of the rs10754558 variant, significant differences were found in the heterozygous and dominant model (p = 0.036, p = 0.033). The genotype distribution of the rs4612666 variant was significant only in the heterozygous model (p = 0.047). In this hospital-based case-control study, rs10925027, rs4925659 and rs10754558 variants were found to be closely related to T2DM risk. The rs10925027 CC genotype, rs4925659 GG genotype, rs10754558 GG and GC+GG genotypes of the NLRP3 were determined as important risk factors for the T2DM.

The aim of this study was to characterize the evolution of gonorrhea in the general population by correlating epidemiological, genotypic, and antimicrobial resistance data of Neisseria gonorrhoeae ...