CC Variant Research Articles

The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption - a stable iron isotope study in Taiwanese women.

Genome wide studies have associated TMPRSS6 rs855791 (2321 C>T) with iron status and hepcidin. It is unclear whether this polymorphism affects iron absorption. We administered standardized ricebased test meals containing 4 mg of labeled 57Fe or 58Fe as FeSO4 on alternate days in non-anemic Taiwanese women (n=79, 44 TT variant, 35 CC variant). Fractional iron absorption was measured by erythrocyte incorporation of the tracers 14 days after administration. Compared to the CC variant, iron and transferrin saturation were lower (P=0.001; P<0.001, respectively) and serum hepcidin/transferrin saturation and serum hepcidin/serum iron ratios were higher (P=0.042; P=0.088, respectively) in the TT variant. Serum hepcidin did not differ between the groups (P=0.862). Geometric mean (95% Confidence Interval [CI]) fractional iron absorption, corrected to a serum ferritin of 15 μg/L, was 26.6% (95% CI: 24.0-29.5) in the CC variant and 18.5% (95% CI: 16.2-21.1) in the TT variant (P=0.002). Overall, predictors of iron absorption were: serum ferritin (P<0.001); genetic variant (P=0.032); and hepcidin (P<0.001). In the models by variant, in the CC variant the model explained 67-71% of variability in absorption and serum ferritin was the only significant predictor (P<0.001); while in the TT variant, the model explained only 35-43% of variability, and hemoglobin (P=0.032), soluble transferrin receptor (P=0.004) and hepcidin (P<0.001) were significant predictors. Women with the TMPRSS6 rs855791 (2321 C>T) polymorphism show altered iron homeostasis which affects oral iron absorption and may increase their risk for iron deficiency. The trial was registered as clinicaltrials gov. Identifier: NCT03317873, and funded by the Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, (grant CMRPG8F0721) and ETH Zurich, Switzerland.

The influence of age, gender and the FKBP5 genotype on subjective health complaints in the Norwegian working population

ObjectiveIn the present study we examined the potential association between age, gender, the genetic variant FKBP5 rs9470080 and subjective health complaints. MethodsThe data were collected through a three-wave nationally representative survey of 1060 Norwegian employees drawn from the Norwegian Central Employee Register by Statistics Norway. The follow-up period was six months. Subjective health complaints were scored by eight items reflecting; headache, neck pain, mid- and low back pain, stomach cramps or intestinal discomfort, problems with sleep onset or maintenance and early morning awakening. Genotyping with regard to FKBP5 rs9470080, previously linked to cortisol sensitivity, was carried out using Taqman assay. ResultsThe baseline data showed that in women, levels of subjective health complaints were highest among those above 50 years of age. Moreover, in women the rs9470080 CC variant at baseline was associated with higher levels of subjective health complaints. However, the effect size was not large, and no relationships were demonstrated between age or genotype and subjective health complaints in men. Also, the study variables were not related to any changes in the levels of subjective health complaints during the follow-up period. ConclusionWe conclude that our biology such as age and sex, but also single genetic variants found in non-sex chromosomes, may be important in understanding the mechanisms underlying subjective health complaints in the general working population.

Association of -344C/T polymorphism in the aldosterone synthase (CYP11B2) gene with cardiac and cerebrovascular events in Chinese patients with hypertension.

ObjectiveSeveral recent studies have shown that the aldosterone synthase gene (CYP11B2) −344C/T polymorphism is related to cardiovascular diseases. However, whether the −344C allele influences the incidence of cardiovascular diseases in Chinese patients with hypertension is unclear.MethodsChinese patients with essential hypertension were genotyped for the −344C/T polymorphism in CYP11B2 (n = 755; CC, n = 112; CT, n = 361; TT, n = 282) and followed for 11 years for major adverse cardiovascular events (MACEs), including stroke, onset of coronary artery disease (CAD), and CAD-related death. Established cardiovascular risk factors were used to adjust the multivariate Cox analysis.ResultsAfter a mean follow-up period of 7.60 ± 1.12 years, a significantly higher incidence of MACEs was seen in patients with the CC genotype than in those with the CT and TT genotypes. The CC variant was significantly and independently predictive of MACEs (hazard ratio = 2.049), CAD (hazard ratio = 1.754), and stroke (hazard ratio = 2.588), but not CAD-related stroke or death.ConclusionThe CYP11B2 −344 CC genotype is a risk factor for CAD and stroke, independent of other established cardiovascular risk factors in Chinese patients with hypertension.

Effects Of Caffeine On Physiological Responses To Exercise And Time-trial Performance: Influence Of CYP1A2 Genotype.

PURPOSE: The aim of this study was to investigate the influence of CYP1A2 genotype (which influences the rate of caffeine metabolism) on the effects of caffeine on physiological responses to submaximal exercise and cycling time-trial performance. METHODS: Eighty six cyclists were screened for their CYP1A2 genotype before being separated into two groups (AA [wildtype] versus AC or CC variant). Seventeen participants from each group (age: 45 ± 9 yrs; height: 1.81 ± 0.07 m; body mass: 76.4 ± 9.9 kg; V̇O2max: 4.02 ± 0.46 L·min-1) were then matched for self-reported endurance ability before taking part in a randomised, double-blind, placebo controlled study. In Trial 1, participants completed incremental cycling tests to establish the V̇O2-power output relationship and V̇O2max. In trials 2 and 3 participants ingested a capsule containing 5 mg-kg-1 of caffeine or placebo one hour before completing a submaximal incremental cycling test (4-min stages) at 40, 55, 70, and 85% of VO2max, followed by a time trial (~ 30 mins). 95% confidence limits (CL95) were calculated for all estimates. RESULTS: Relative to placebo, caffeine led to a significant reduction in time to complete the time trial (caffeine: 29.21 ± 1.60 mins; placebo: 30.30 ± 1.96 mins); but there was no effect of genotype. During submaximal exercise, caffeine resulted in significant reductions in heart rate (mean difference: 2.4 b·min-1; CL95: 1.1 - 3.8 b·min-1), with effects dissipating as exercise intensity increased. Caffeine also led to submaximal exercise reductions in ratings of perceived exertion (mean difference: 0.5; CL95: 0.2 – 0.8) and significant increases in respiratory exchange ratio (mean difference: 0.013; CL95: 0.002 – 0.025), minute ventilation (mean difference: 3.4 L·min-1; CL95: 0.4 – 6.4 L·min-1), and blood lactate concentration (mean difference: 0.24 mmol·L-1; CL95: 0.11 – 0.37 mmol·L-1). However, the responses were not affected by genotype. CONCLUSION: Caffeine influences physiological responses to submaximal exercise and improves time-trial performance. However, those effects are not influenced by CYP1A2 genotype.

Интернет-зависимость у подростков: поиск генетических ассоциаций

Стремительность распространения интернет-зависимости у подростков связана с возникновением проблемной зависимости от неконтролируемого мобильного доступа в сеть. Это делает актуальным проблему поиска молекулярно-генетических и психологических маркеров высокого риска развития интернет-зависимости. Целью работы было изучение распространенности различных по степени выраженности вариантов интернет-зависимости у подростков и распределения у них полиморфных вариантов генов COMT и CHRNA4. Выявлено, что CC генотип rs1044396 CHRNA4 ассоциирован с интернет-зависимостью у подростков: его распространенность прогрессивно увеличивается с тяжестью интернет-зависимости. Аллельный вариант Т имеет «защитный» эффект от тяжелой и неконтролируемой зависимости. The rapidity of the emergence and spread of Internet addiction in adolescent populations, combined with the amount of consumed content, is associated with the emergence of a problematic dependence on uncontrolled mobile access to the network. This makes the problem of searching for molecular genetic and psychological markers of high risk of developing Internet addiction relevant. The aim of the work was to study the prevalence of Internet-dependent variants of different degrees of severity in adolescents and the distribution of polymorphic variants of the COMT and CHRNA4 genes. It was revealed that the CC variant rs1044396 CHRNA4 is associated with Internet addiction in adolescents: its prevalence progressively increases with the severity of Internet addiction. Whereas the allelic variant T has a “protective” effect against severe and uncontrolled dependence.

Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism

BackgroundPolymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment.MethodsgDNA from whole blood was extracted using a commercially available kit (Axygen) and quantified by spectrophotometry. Global gDNA methylation was determined by ELISA and rs1801133 polymorphism by PCR-RFLP. Statistical analysis of gDNA methylation profile and rs1801133 variants included Mann-Whitney, Kruskal-Wallis, Spearman point-biserial correlation tests (SPSS and Graphpad Prism packages; significant results for effect size higher than 0.4). Prognostic value of gDNA methylation and rs1801133 variants considered survival profiles at 25 weeks of POH treatment, having the date of protocol adhesion as starting count and death as the final event.ResultsMost rGBM patients showed global gDNA hypomethylation (median = 31.7%) and a significant, moderate and negative correlation between TT genotype and gDNA hypomethylation (median = 13.35%; rho = − 0.520; p = 0.003) compared to CC variant (median = 32.10%), which was not observed for CT variant (median = 33.34%; rho = − 0.289; p = 0.06). gDNA hypermethylated phenotype (median = 131.90%) exhibited significant, moderate and negative correlations between TT genotype (median = 112.02%) and gDNA hypermethylation levels when compared to CC (median = 132.45%; rho = − 0,450; p = 0.04) or CT (median = 137.80%; rho = − 0.518; p = 0.023) variants. TT variant of rs1801133 significantly decreased gDNA methylation levels for both patient groups, when compared to CC (d values: hypomethylated = 1.189; hypermethylated = 0.979) or CT (d values: hypomethylated = 0.597; hypermethylated = 1.167) variants. Positive prognostic for rGBM patients may be assigned to gDNA hypermethylation for survivors above 25 weeks of treatment (median = 88 weeks); and TT variant of rs1801133 regardless POH treatment length.ConclusionrGBM patients under POH-based therapy harboring hypermethylated phenotype and TT variant for rs1801133 had longer survival. Intranasal POH therapy mitigates detrimental effects of gDNA hypomethylation and improved survival of patients with rGBM harboring TT mutant variant for MTHFR rs1801133 polymorphism.Trial registrationCONEP -9681- 25,000.009267 / 2004. Registered 12th July, 2004.

Heterozygosity in LDLR rs2228671 and rs72658855 Gene is Associated with Increased Risk of Developing Coronary Artery Disease in India –A Case-Control Study

Coronary artery disease (CAD) is one of the most common causes of death worldwide. Risk factors of CAD include high LDL-C, low high-density lipoprotein (HDL), hypertension, lack of exercise, genetic factors, etc. Polymorphisms of the LDLR gene have been associated with CAD in previous studies. The LDLR-rs72658855 C>T genotyping was detected by using allele-specific PCR (ASPCR). The association of rs2228671 and rs72658855 with CAD in a south Indian cohort (200 CAD patients and 200 matched healthy controls was studied. Our findings showed that rs2228671 gene variability is associated with increased susceptibility to coronary artery disease in the codominant inheritance model for variant CC vs. CT OR 3.42(1.09-10.7), with P<0.034. A non-significant association was reported in the recessive inheritance model for the variant (CC+CT) vs. TT OR 0.56(0.16-1.95), at P<0.36. and in the dominant inheritance model for variant CC vs. (CT+TT) OR 2.8(1.07-7.34), at P<0.032 .In case of allelic comparison, it was indicated that the LDLR rs2228671-T allele was associated with an increased risk of developing CAD compared to C allele OR=2.4, with 95% CI (1.05-5.64) and P< 0.036 . Our findings showed that LDLR rs72658855 C>T gene variability was associated with an increased susceptibility to coronary artery disease in the codominant inheritance model for variant CC vs. CT OR 1.7(1.1-2.6), at P<0.015 and in the dominant inheritance model for variant CC vs. (CT+TT) OR 1.66(1.07-2.58), at P<0.0.02.. In case of allelic comparison, a non-significant association was reported in LDLR rs72658855-T and C allele. We concluded that the heterozygosity in LDLR-rs72658855 and rs2228671 and T allele in LDLR rs2228671 are strongly associated with increased susceptibility to coronary artery disease. These results must be validated by future well-designed studies with larger sample sizes and different populations.

IL33 rs1342326 gene variation is associated with allergic rhinitis at school age after infant bronchiolitis.

Interleukin (IL)-33, encoded by the IL33 gene, is associated with allergy and asthma. We evaluated IL33 rs1342326 polymorphism in relation to asthma, asthma medication and allergic rhinitis after infant bronchiolitis. IL33 rs1342326 polymorphism was studied in children, who were hospitalised for bronchiolitis at age younger than 6months and who were prospectively followed until 5-7years (N=141) and 11-13years (N=125) of ages. The presence of the wild AA vs variant AC or CC genotypes of the IL33 rs1342326 showed no significant associations with previous or current asthma at the mean ages of 6.4 or 11.7years. However, 22.5% of children with the variant genotype used inhaled corticosteroids at the 5-7years of visit (adjusted OR: 2.94, 95% CI: 1.04-8.33 vs those 8.9% with the wild genotype). The variant IL33 rs1342326 genotype was associated with allergic rhinitis at 6.4years (adjusted OR: 2.17, 95% CI: 1.01-4.76) and 11.7years (3.23, 1.18-9.09) of ages. The frequent use of asthma control medication in 6.4-year-old children with IL33 rs1342326 polymorphism suggests that this variation may increase susceptibility to severe asthma at preschool age. The IL33 rs1342326 variant genotype was associated with a 3-fold risk of allergic rhinitis at school age.

Is ADC(3) as Accurate as CC3 for Valence and Rydberg Transition Energies?

The search for new models rapidly delivering accurate excited-state energies and properties is one of the most active research lines of theoretical chemistry. Along with these developments, the performance of known methods is constantly reassessed on the basis of new benchmark values. In this Letter, we show that the third-order algebraic diagrammatic construction, ADC(3), does not yield transition energies of the same quality as the third-order coupled cluster method, CC3. This is demonstrated by extensive comparisons with several hundred high-quality vertical transition energies obtained with FCI, CCSDTQ, and CCSDT. Direct comparisons with experimental 0-0 energies of small- and medium-size molecules support the same conclusion, which holds for both valence and Rydberg transitions. Considering these results, we introduce a composite approach, ADC(2.5), which consists of averaging the ADC(2) and ADC(3) excitation energies. Although ADC(2.5) does not match the CC3 accuracy, it significantly improves the ADC(3) results, especially for vertical energies.

The role of serum E-selectin level and E-selectin gene S128R polymorphism on theenlargement of renal cyst in patients withpolycystic kidney disease: Geneticbackground of renal cyst growth .

To determine the role of E-selectin gene S128R polymorphism on the enlargement of renal cysts in patients with polycystic kidney disease (PKD). 76 PKD patients with no comorbidity were enrolled in the study. Serum E-selectin levels were analyzed by enzyme-linked immunoabsorbent assay (ELISA). E-selectin gene S128R (561 A>C, rs: 5361) polymorphism was examined by polymerase chain reaction restriction fragment length (PCR-RFLP). Magnetic resonance imaging was performed at baseline evaluation and at the end of the 1st year to determine cyst enlargement and total kidney volume (TKV). No significant difference was identified between AA genotype and AC or CC variants of E-selectin gene S128R polymorphism in terms of age, disease duration, baseline cyst volume, cyst volume at the 12th month, baseline dominant cyst volume, and dominant cyst volume at the 12th month. In contrast, a significant difference was determined between the groups with regard to the change of TKV (2.9±13.4 vs. 5.2±16.3 mm3; respectively, p = 0.01). In the correlation analysis, the serum E-selectin level was significantly correlated to glucose, alanine transaminase, creatinine, calcium, phosphorus, total protein, albumin, and end diastolic volume (p = 0.0001, p = 0.001, p = 0.03, p = 0.021, p = 0.023, p = 0.002, p = 0.003, and p = 0.047, respectively). Multivariate logistic regression analysis demonstrated a 1.32-fold higher risk of cyst enlargement in patients with CC polymorphism when compared to AA genotype (p = 0.052), but not between AA and AC genotypes or CC and AC genotypes. PKD patients with CC variants of the E-selectin gene S128R polymorphism are at greater risk of cyst enlargement. The results of the present study should be confirmed with further studies with large sample size and longer duration of follow-up.

TCF7-L2 rs7903146 polymorphism in metabolic syndrome with and without acute coronary syndrome.

To determine the frequency and association of single nucleotide polymorphism of transcription cell factor7-like2 rs7903146 (C>T) in metabolic syndrome patients with and without acute coronary syndrome. The cross-sectional comparative study was conducted at the University of Health Sciences, Lahore, Pakistan, from July to December 2017. Patients of metabolic syndrome with and without acute coronary syndrome were selected from Sheikh Zayed Hospital, Lahore, and the Punjab Institute of Cardiology, Lahore. Healthy subjects were enrolled to act as controls. A fasting blood sample of 8ml was taken for deoxyribonucleic acid extraction and estimation of biochemical parameters. Single nucleotide polymorphism of transcription cell factor7-like2 rs7903146 C>T was determined using restriction fragment length polymorphism. SPSS 22 was used for data analysis. Of the 500 subjects, 200(40%) were group A patients without acute coronary syndrome, 100(20%) were in group B with acute coronary syndrome and 200(40%) were group C controls. Overall, 385(77%) were males and 115(23%) were females. The frequency of CC variant in group A was 35(17.5%) and in group C 22(11%), while CT was 32(16%) and 65(32.5%), and TT was 133(66.5%) and 113(56.5%), respectively. There was significant association of TT genotype with increased risk of metabolic syndrome (p=0.031), and CC genotype had no association (p=0.121). There was no significant difference of genotype frequency between groups A and B (p=0.246), but TT variant was significantly higher in group A compared to group B (p=0.009). TT genotype of transcription cell factor7-like2 rs7903146 C>T was found to be associated with increased risk of metabolic syndrome in patients without acute coronary syndrome compared to those with acute coronary syndrome and healthy controls.

Remanufacture of rotary tables for heavy duty machine tools

In this paper, the authors present some of the theoretical and experimental research conducted on the occasion of rotary tables remanufacturing for CNC machine tools belonging to Boring and Milling Machines family. They give the constructive solutions applied on CNC machines and the specific systems of guiding, locking and driving. The authors present also the modifications required when passing from CC variant to CNC variant in terms of locking - indexing systems and hydraulic suspension systems. The paper presents different achievements but insists particularly on the remanufacture of the rotary table with useful area 1700x2000 mm with longitudinal travel of 1000 mm (MRD 1700x2000/1000).

Genetic Effects of Vascular Endothelial Growth Factor A (VEGF-A) and Its Association with Disease Progression in Breast Cancer Population of Saudi Arabia.

Aim:Previous studies have shown that vascular endothelial growth factor (VEGFA) gene variants were associated with breast cancer risk. The goal of the current study was to evaluate the genetic effects of the vascular endothelial growth factor (VEGF) on the risk of breast cancer and its association with disease progression. Methodology:This case control study was conducted on 110 Breast cancer cases and 110 gender matched healthy controls. Vascular endothelial growth factor A (VEGF-A) 1 (-460T>C) genotyping was performed using Amplification refractory mutation system PCR method. The vascular endothelial growth factor A (VEGF-A) (-460T>C) genotypes were collated with different clinicopathological features of breast cancer patients. Results:A significant difference was observed between the genotype distribution of VEGF-A (-460T>C) among breast cancer cases and gender matched healthy controls (p=0.006). The frequencies of all three genotypes CC,CT,TT reported in the breast cancer patients and sex matched healthy controls were 4.54%, 46.36% ,49.20% and 7.27%, 64.54%, 28.18% respectively. The increased susceptibility to breast cancer disease was found to be associated with VEGF (-460T>C) CC vs TT variant in codominant inheritance model OR 2.78 (0.83-9.26) RR 1.68(1.01 to 2.81) P=0.04. A significant association was reported with VEGF (-460T>C) (CC+CT vs. TT) variant in recessive inheritance model, (OR=2.45 (95% CI= (1.40-4.29), P=0.003. Our findings indicated that VEGF (-460T>C) TT genotype is associated with an increased susceptibility to breast cancer disease. Our result indicates a potential dominant effect of VEGF (-460T>C) TT genotype on susceptibility to the breast cancer disease. Conclusion:VEGF (-460T>C) TT genotype significantly increased the risk of breast cancer. VEGF-A (-460T>C) genetic ariability was significantly associated with distant metastasis of the disease. It may be a useful as predisposing genetic marker for breast cancer .Further studies with larger sample sizes are necessary to confirm our findings.

TSHR rs2288496 associated with thyroid hormone and predict the occurrence of lymph node metastasis of papillary thyroid cancer.

This study aimed to evaluate the association of potential functional tagging single nucleotide polymorphisms (tagSNPs) in BRAF and TSHR with papillary thyroid cancer (PTC). Two tagSNPs (rs6464149 and rs7810757) in BRAF and six tagSNPs (rs17630128, rs2075179, rs7144481, rs2371462, rs2268477, and rs2288496) in TSHR were genotyped in 300 cases of PTC and 252 healthy controls. There was no difference in the genotype frequencies of BRAF and TSHR between PTC patients and control subjects, suggesting no contribution of BRAF or TSHR polymorphisms to the susceptibility to PTC. We observed that a tagSNP located in the 3' untranslated region of TSHR, rs2288496, could affect the incidence of lymph node metastasis (LNM). The variant TC and TC + CC genotypes conferred an increased risk of LNM (for TC vs. TT: odds ratio (OR) = 2.01, 95% confidence interval (CI): 1.07-3.77; P= 0.030; for TC + CC vs. TT: OR = 1.87, 95% CI: 1.04-3.39, P= 0.038). Moreover, subjects carrying variant genotypes had higher TSH levels and lower thyroxine (T4) and Anti-TG levels compared with those in subjects carrying common genotypes. Our findings showed that PTC patients carrying the TSHR rs2288496 TC and CC variants were associated with higher TSH level and lower T4 and Anti-TG levels and were prone to developing LNM. To confirm these results, additional studies and functional experiments, especially in other ethnic populations, are needed.

Analysis of Safety Issues of Using Statins in Patients with Diabetes and Hypothyroidism

The widespread use of statins in clinical practice necessitates a systematic approach to the risk and safety assessment. The aim of the study was to analyze information about adverse reactions to statins and their specific causes in patients with hypercholesterolemia accompanied by diabetes and hypothyroidism. The paper compares statin products (simvastatin, atorvastatin, pravastatin, rosuvastatin, and fluvastatin) in terms of the frequency of the most significant adverse reactions—statin-induced myopathy, liver damage, secondary hyperglycemia. It dis­cusses specific causes of adverse reactions to statins in patients with hypothyroidism and dia­betes. It was demonstrated that the use of statins in patients with compensated hypothyroid­ism, who have CC and TC allelic variants of the SLCO1B1*5 gene ( c.521T&gt;C ), is associated with a higher risk of developing statin-induced myopathies. The adjustment of statin doses, especially in patients with hypothyroidism and diabetes, should be made based on the results of pharmaco­genetic testing for SLCO1B1*5 ( c.521T&gt;C ) allelic variants. The results of dynamic clinical and laboratory control of the hepatic transaminase level, as well as the levels of glucose, glycated hemoglobin, and thyroid-stimulating hormone should be the key factors to be taken into account when adjusting treatment plans in this group of patients. The paper analyses polymorphisms of genes which are associated with resistance to statin therapy in patients with diabetes. Thus, the use of statins for primary prevention and treatment of cardiovascular diseases in patients with hypercholesterolemia accompanied by diabetes and/or hypothyroidism, requires a comprehen­sive assessment of the risk/benefit ratio.

Incidence of MicroR-4513C/T Gene Variability in Coronary Artery Disease - A Case-Control Study.

Genetic variants in pre-microRNA genes or the 3'UTR of miRNA target genes could influence miRNA-mediated regulation of gene expression and thus contribute to the susceptibility and prognosis of human diseases. Several studies have investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes .Therefore the aim of study was to investigate the potential association of miR-4513 rs2168518 C>T gene variability with the risk of developing CAD and its association with different cardiometabolic phenotypes in an Indian cohort to stratify CAD burden in the general population. The study was conducted on 100 clinically confirmed CAD patients and 100 healthy individuals. Genotyping of MicroR-4513 rs2168518C>T gene variability was performed using Amplification refractory mutation system PCR method. A significant difference was observed in the genotype distribution among CAD cases and healthy controls. The frequencies of three genotypes CC, CT, TT in CAD patient and healthy controls were 5%, 77%, 18%, and 28%, 45% and 27% respectively. A multivariate analysis showed that miR- 4513 rs2168518 polymorphism is associated with an increased susceptibility to CAD in codominant inheritance model for variant CC vs. CT OR 9.58 CI (3.45-26.57), RR 2.3(1.75-3.02), P=0.001. Results also indicate a potential dominant effect of miR-4513 rs2168518 C/T polymorphism on susceptibility of CAD in dominant inheritance model for variant CC vs. (CT+TT) OR 7.38 (2.71-20.07), RR 1.96 (1.56-2.46), P=0.001. In allelic comparison, T allele weakly increased risk of CAD compared to C allele (OR=1.50, 95% CI (1.09-2.26) RR 1.15 (0.94-1.39) P=0.044. It is concluded that CT genotype and T allele of microR-4513 rs2168518 is strongly associated with increased susceptibility to CAD. Furthers studies with larger sample sizes are necessary to confirm this result.

Association between polymorphisms in PRNCR1 and risk of colorectal cancer in the Saudi population.

LncRNA Prostate cancer non-coding RNA (PRNCR1) is downregulated in many types of cancer. The current case-control study was performed on 144 patients with colorectal cancer and 130 matching controls. Genotyping was performed using TaqMan assays for four Single Nucleotide Polymorphisms (SNPs) in PRNCR1. RNAsnp Web Server was used to detect variations in the secondary structure for each SNP. The genotyping analysis for SNP rs1456315 showed increased association with colorectal cancer with the homozygous CC variant allele (OR: 2.09; χ2 = 4.95; CI: 1.08–4.02; p = 0.02), the minor allele frequency, and additive genotype, respectively (OR: 1.55; χ2 = 6.24; CI: 1.09–2.19; p = 0.01) & (OR: 1.64; χ2 = 4.04; CI: 1.01–2.67; p = 0.04). A risk association was also observed among younger age patients (≤57) and in female patients as well as in patients with tumors of the colon. For the other SNPs tested (rs16901946, rs13252298, rs1016343), no significant association was observed. The secondary structure of the rs1456315 mutant is different from that of the wild-type. Our findings suggest that the upregulation of PRNCR1 and its variants is associated with increased risk of colorectal cancer in Saudi patients, indicating that PRNCR1 might be a unique and valuable signature for predicting the risk of colorectal cancer in a Saudi population.

Co-exposure to polycyclic aromatic hydrocarbons and metals, four common polymorphisms in microRNA genes, and their gene-environment interactions: Influences on oxidative damage levels in Chinese coke oven workers

BackgroundHuman are often simultaneously exposed to polycyclic aromatic hydrocarbons (PAHs) and metals, yet relatively little is known regarding their co-exposure effects on oxidative damage. Genetic factors and the gene-environment interactions can also determine the severity of oxidative damage. Four polymorphisms in microRNA (miRNA) genes (rs11614913, rs2292832, rs2910164, and rs3746444) have been well-studied to be associated with oxidative damage-related diseases. ObjectiveTo investigate the influences of PAH-metal co-exposure, four polymorphisms, and their interactions on oxidative damage levels. MethodsWe conducted a cross-sectional study in 1385 coke oven workers. We quantified exposure levels of PAHs and metals by urinary monohydroxy-PAHs, plasma benzo[a]pyrene-7,8-diol-9,10-epoxide-albumin adducts, and urinary metals, respectively, and measured oxidative damage levels by 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine. We also genotyped four polymorphisms. ResultsIn multiple-pollutant models, 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were associated with multiple PAH exposure biomarkers, as well as with multiple metals (ptrend < 0.05). Metabolites of phenanthrene and pyrene interacted synergistically with lead and zinc to influence 8-iso-prostaglandin-F2α (βinteraction > 7.75%, false discovery rate-adjusted pinteraction ≤ 2.25 × 10−5). Significantly higher 8-hydroxydeoxyguanosine was observed in carriers of rs11614913 CC variant homozygote than TC carriers (p = 0.037). Associations of the number of rs11614913 C allele with increased 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were significant (βstd > 0, ptrend < 0.05) and more pronounced in workers with lower metals [p for modifying effect (pME) < 0.040]. Positive associations of some PAHs and metals with 8-iso-prostaglandin-F2α and 8-hydroxydeoxyguanosine were weaker in carriers of rs11614913 CC genotype or C allele (pME < 0.05). ConclusionPAH-metal co-exposure, rs11614913, and their interactions may affect oxidative damage levels in Chinese population in a complex manner that are worthy of further investigation.

Targeted Sequencing Analysis of the Leptin Receptor Gene Identifies Variants Associated with Obstructive Sleep Apnoea in Chinese Han Population

PurposeObstructive sleep apnea (OSA) is a common sleep disorder that is influenced by various environmental and genetic factors. The potential associations of leptin and leptin receptor (LEPR) polymorphisms with OSA have been studied in different populations; however, the results remain inconclusive. The aim of this study was to examine the association between LEPR gene polymorphisms and OSA risk.MethodsA total of 322 samples were used, including 226 OSA subjects and 96 controls. Targeted sequencing of the entire LEPR gene was performed in all subjects. Polysomnography was used to diagnose obstructive sleep apnea. The associations between variants and OSA were determined by multivariate regression analyses.ResultsFour single-nucleotide polymorphisms of LEPR were identified in all subjects. The genotype frequency of locus rs3790435 was significantly different between the OSA and control groups. Specifically, the variant genotype rs3790435 CC in LEPR was associated with a lower risk of OSA (OR 0.462, 95% CI 0.250–0.854, p = 0.014) in a recessive model after controlling for potential confounders. After BMI stratification, obese patients with this variant genotype were found to have a lower risk of developing OSA. Moreover, subjects with the rs3790435 CC genotype were found to have a statistically lower apnea–hypopnea index (AHI) and higher nadir oxygen saturation than the TT/CC genotypes without differences in plasma leptin levels.ConclusionsOur study identified a novel variant of LEPR in patients with OSA, and specifically found an association between rs3790435 polymorphisms and OSA risk in Chinese Han subjects.

SNPs Within the MTOR Gene Are Associated With an Increased Risk of Developing De Novo Diabetes Mellitus Following the Administration of Everolimus in Liver Transplant Recipients

BackgroundThe impact of immunosuppressive drugs in patients following liver transplantation (LT) is very individual. Despite the multiple beneficial effects of the mammalian target of rapamycin (mTOR) inhibitor everolimus (EVR) in LT recipients, some patients do not benefit from EVR administration. We investigated whether the presence of common single-nucleotide polymorphisms (SNPs) in the mTOR gene are predictive for adverse events following the introduction of EVR after LT. Materials and MethodsThe feasibility and efficacy of EVR in 127 liver transplant recipients who were converted to EVR-based immunosuppression was documented retrospectively. Blood samples of these patients were analyzed for the occurrence of 4 SNPs in the mTOR promoter region (mTOR3099/rs2295079 C>G, mTOR3162/rs2295080 A>C) and the mTOR 3′ untranslated regio (mTOR8167/rs12139042 C>T, mTOR8600/rs2536 A>G); the specific allele variants were also associated with the incidence of adverse events (AEs). ResultsOf all patients, 21 (16.5%) did not tolerate the medication and had to discontinue. Of those patients who continued, 37% developed signs of reduced tolerance within the first 6 months, resolving after 12 months. When the cohort was divided according to genotype and allele frequency, patients with the mTOR3162/rs2295080 CC variant had a significantly higher risk (odds ratio = 5.89; 95% confidence interval = 1.48–23.40; P = .012) of developing new-onset diabetes mellitus following EVR treatment than AA or AC genotype carriers. ConclusionOur results suggest that the SNP mTOR3162/rs2295080 CC genotype is associated with the development of new-onset diabetes mellitus following EVR treatment.