Association Of CC Genotype Research Articles

Farnesyl Diphosphate Synthase Gene Associated with Loss of Bone Mass Density and Alendronate Treatment Failure in Patients with Primary Osteoporosis.

Aminobisphosphonates (NBPs) are the first-choice medication for osteoporosis (OP); NBP treatment aims at increasing bone mineral density (BMD) by inhibiting the activity of farnesyl diphosphate synthase (FDPS) enzyme in osteoclasts. Despite its efficacy, inadequate response to the drug and side effects have been reported. The A allele of the rs2297480 (A > C) SNP, found in the regulatory region of the FDPS gene, is associated with reduced gene transcription. This study evaluates the FDPS variant rs2297480 (A > C) association with OP patients' response to alendronate sodium treatment. A total of 304 OP patients and 112 controls were enrolled; patients treated with alendronate sodium for two years were classified, according to BMD variations at specific regions (lumbar spine (L1-L4), femoral neck (FN) and total hip (TH), as responders (OP-R) (n = 20) and non-responders (OP-NR) (n = 40). We observed an association of CC genotype with treatment failure (p = 0.045), followed by a BMD decrease in the regions L1-L4 (CC = -2.21% ± 2.56; p = 0.026) and TH (CC = -2.06% ± 1.84; p = 0.015) after two years of alendronate sodium treatment. Relative expression of the FDPS gene was also evaluated in OP-R and OP-NR patients. Higher expression of the FDPS gene was also observed in OP-NR group (FC = 1.84 ± 0.77; p = 0.006) when compared to OP-R. In conclusion, the influence observed of FDPS expression and the rs2897480 variant on alendronate treatment highlights the importance of a genetic approach to improve the efficacy of treatment for primary osteoporosis.

Association of Single Nucleotide Polymorphisms in Nucleotide-Binding Domain Leucine-Rich Repeat Protein 1 with Clostridioides difficile Colonization or Infection.

Nucleotide-binding domain leucine-rich repeat protein (NLRP) is critical in the inflammasome-activation pathway, which is important for host survival and the clearance of Clostridioides difficile. Therefore, the influence of NLRP1 polymorphisms on C. difficile colonization (CdC) or infection (CDI) was analyzed. A prospective cohort study consisted of hospitalized adults was conducted from January 2011 to January 2013. Single nucleotide polymorphisms (SNPs) of NLRP1, including rs12150220, rs2670660, rs6502867, rs878329, rs8182352, rs3744717, and rs11078571, were incorporating in analyses. The episodes of CdC and CDI were the primary and secondary outcome, respectively. Of the total of 509 eligible patients, 376 (73.9%) had neither CdC nor CDI, 104 (21.8%) had CdC without developing CDI, and 29 (4.3%) developed CDI during the study period. Through multivariate analyses, comorbid diabetes mellitus (adjusted odds ratio [AOR] 1.59, P=0.04) and CC genotype in NLRP1 rs3744717 (AOR 1.70, P=0.02) were recognized as the risk factor of CdC. After adjusting the independent predictors of CDI, in terms of comorbid diabetes mellitus (AOR 3.18, P=0.005) and prior exposure to ceftazidime/ceftriaxone (AOR 2.87, P=0.04) or proton pump inhibitors (AOR 3.86, P=0.001), patients with CC+GC genotype in NLRP1, rs878329 (AOR 2.39, P=0.03) remained a higher risk of CDI. For hospitalized adults, the association of CC genotype in NLRP1 rs3744717 and CdC as well as the CC+GC genotype in NLRP1 rs878329 and CDI was respectively evidenced. We believed the prompt identification of patients having specific genotype in NLRP1 would prevent and improve the quality of care in CDI.

187P BUB1 (2530C>T) polymorphism and expression affects chemotherapy response and predicts poor prognosis in advanced epithelial ovarian cancer

Ovarian cancer (OC) is a frequent gynecological cancer with a complex pathophysiology and high mortality. This study determines roles of 2530C>T SNP in BUB1, a key component of spindle assembly checkpoint (SAC), and its expression in advanced OC pathology & treatment outcome. 77 advanced epithelial OC patients were recruited, who received postoperative adjuvant [I.V. doses of 175mg/m2 paclitaxel+ carboplatin AUC 5-6mg.min/mL] or neoadjuvant chemotherapy with interval debulking surgery. Their demographics, clinical parameters, toxicity and survival were recorded. BUB1(2530C>T) SNP was detected by the PCR-RFLP followed by sequencing. BUB1 expression, BUB1mRNA and miRNA-495 were assessed using IHC & qRT-PCR. Stages III (82·02%) and IV (17·98%) OC patients were mostly 41-60 (60%) years old. 37%, 40%, 23%% were categorized as responders (Rs), partial responders (PRs) and non-responders (NRs) with significantly different (p<0.05) survival outcomes. The polymorphic homozygous genotypes (CC) and (TT) of 2530C>T were most prevalent in NRs & PRs respectively showing significant association in chemotherapy response (p=0.021). The allele frequencies were found to be C= 0.2215, and T= 0.7784. The standard regimen was well tolerated but no significant relationship was observed between SNP and toxicities. The survival outcome was nearly significant (p= 0.06) showing association of CC genotype with higher risk (HR=9.938, 95%CI= 1.19-82.9) when compared to CT (HR=0.885, 95%CI= 0.109-7.19) and TT (HR=0.409, 95%CI= 0.049-2.209). 97.6% of biopsy samples showed low to moderate BUB1 IHC expression and did not have significant association with clinical response (p=0.32). BUB1 mRNA and miR-495 analysis revealed a Ct mean of 37.42 and 27.614 respectively. There was a negative correlation between BUB1mRNA and miR-495 levels (r= -0.551, p=0.16). The homozygous polymorphic phenotypes of 2530C>T are significantly associated with chemotherapy response and poor survival outcomes but not related to chemo-induced toxicity. The very low expression of BUB1 may be attributed to regulation by miR-495. The negative expression also suggests a deficient SAC response in the advanced tumour.

Association of angiotensinogen and angiotensin II receptor type I polymorphisms with biomarkers of carbohydrate and lipid metabolism in Dagestan residents with type 2 diabetes and hypertension

Aim. To study the associations of angiotensinogen (AGT) (s4762(С521Т), rs699(Т704C)) and angiotensin II receptor type I (AGTR1) (rs5186(A1166C)) genetic polymorphisms with serum levels of insulin, glucagon, C-peptide, leptin, as well as with dyslipidemia and glycemic levels in Dagestan residents with combination of type 2 diabetes (T2D) and hypertension (HTN), as well as with isolated T2D/HTN.Material and methods. We examined 16 patients with isolated T2D, 59 patients with T2D+HTN and 51 patients with isolated HTN from Dagestan. Genetic polymorphisms of the AGT and AGTR1 genes were studied. The levels of insulin, glucagon, C-peptide, and leptin were studied by enzyme-linked immunosorbent assay (ELISA), while lipid and carbohydrate metabolism — by biochemical methods.Results. In patients with T2D, the association of CC genotype of AGT gene rs4762(С521Т) polymorphism with a leptin decrease was determined, while its CT genotype was associated with an increase in serum level of triglycerides. The TC genotype of AGT gene rs699(Т704C) polymorphism was associated with an increase in leptin, triglyceride and glucose levels. The AA genotype of AGTR1 gene rs5186(A1166C) polymorphism was associated with an increase in insulin and glucose levels, as well as a decrease in leptin level. In patients with a combination of T2D and HTN, CC and CT genotypes of AGT gene rs4762(С521Т) polymorphism was associated with a decrease in glucagon level. The TT genotype of AGT gene rs699(Т704C) polymorphism was associated with an increase in insulin, triglyceride, glucose and body mass index (BMI) levels. In isolated HTN, the CC and CT genotypes of AGT gene rs4762(С521Т) polymorphism were associated ith a decrease in glucagon level. The TT genotype of AGT gene rs699(Т704C) polymorphism was associated with increased levels of insulin, low density lipoproteins, and BMI.Conclusion. Associations of AGT (s4762(С521Т), rs699(Т704C)) and AGTR1 (rs5186(A1166C)) genetic polymorphisms with carbohydrate and lipid metabolism changes are an important pathogenetic link of T2D and HTN, which allows developing an individual prognosis of these diseases in Dagestan residents.

Research of prevalence of polymorphism of the TLR 9 type gene in patients with infectious mononucleosis, caused by Epstein-Barr virus

There was studied the prevalence of -1486 T/C polymorphism of TLR-9 gene in 52 patients with infectious mononucleosis (IM), caused by Epstein-Barr virus. Three main genotypes of - 1486 T/C of TLR-9 gene: TT, TC, CC were identified based on obtained results. The study of the frequency of appearance of separate genotypes in patients with IM revealed the dominance of CC and TT genotypes compared with the control group. The study of the distribution frequency of -1486 T/C-polymorphism of TLR-9 gene for different genotypes demonstrated the specificity of CC genotype changes in patients with IM and the absence of such changes for TT and TC genotypes.Aim of research. The study of the frequency of - 1486 T/C polymorphism of TLR-9 gene in patients with IM, caused by Epstein-Barr virus.Materials and methods. The study for determining -1486 T / C polymorphism of TLR-9 gene was realized in 52 patients with IM. Among them women - 31 (59,6 %), men - 21 (40,4 %) in the age diapason from 18 to 34 years. The control group for studying the prevalence of - 1486 T/Cpolymorphism of TLR-9 gene consisted of 40 healthy donors. The mean age 24,2 ± 2,4 years, from 18 to 44 years.For revealing DNA of EBV by the method of the reverse transcription of PCR with hybridization-fluorescent detection of amplification products, sets of reagents Amplisens (Russia) were used. The polymorphic zone - 1486 T / C, rs187084 of TLR9 gene was used by PCR amplification in real time by determining the length of restrictive fragments of PCR using Ncol restrictive fragment and oligonucleotide primers.Results. The analysis of results of - 1486 T/C polymorphism of TLR-9 gene allowed to identify three main genotypes - TT, TC, CC. The study of the frequency of separate genotypes detection allowed to establish the prevalence of CC and TT genotypes compared with the heterozygotic TC genotype. The study of the distribution frequency of -1486 T/C-polymorphism of TLR-9 gene for different genotypes demonstrated the specificity of CC genotype changes in patients with IM and the absence of such changes for TT and TC genotypes.Our research established the correlation between - 1486 TLR-9 C/Cpolymorphism with IM that proves the important role of mediated TLR signalization in the pathogenesis of EBV infection. The study of genes polymorphism among receptors that take part in recognizing a virus is necessary for determining the genetic background, connected with the infection risk, disease course and possible IM results. It allows to reveal risk groups among patients and to carry out the timely therapy.Conclusions: 1. It was proved, that - 1486 T/C polymorphism of TLR-9 gene is detected reliably more often in patients with IM than in the control group.2. The distribution of -1486 Т / С polymorphism of TLR-9 allowed to reveal the association of CC genotype with manifest forms of IM

Interleukin-18 gene polymorphism and risk of CVD in older patients with type 2 diabetes mellitus

ObjectiveInterleukin-18 (IL-18), a proinflammatory cytokine, plays a key role in the acute and chronic inflammatory processes. It is associated with risk of developing cardiovascular disease (CVD). The aim of this study was to evaluate association between G(-137)C polymorphism (rs187238) in the IL-18 gene and risk of diabetes and CVD in type 2 diabetes patients. MethodsWe examined 1548 T2DM patients and 590 controls. All subjects were genotyped for the G(-137)C promoter region polymorphism by polymerase chain reaction (PCR-SSP). ResultsGenotype distribution of the G(-137)C polymorphism showed no significant difference between T2DM patients and controls (p=0.115). An association with CVD was analyzed in two age groups: ⩾65 and <65years. In patients younger than 65years there was a tendency to association of CC genotype with CAD (OR 1.87, 95% CI 1.0–3, p=0.051). In contrast, in subjects aged 65 or older, the C allele and CC genotype showed the significant association with the presence of CVD, with the OR 1.99, p=0.001 and OR 5.31, p=0.006, respectively. The C allele carriers showed the higher prevalence of CVD compared to non-carriers (61% vs. 39%, p<0.0001). ConclusionOlder T2DM patients carrying the C allele of IL-18 G(-137)C polymorphism have a significantly increased risk of CVD.

Effect of G(-174)C polymorphism in interleukin-6 gene on cardiovascular disease in type 2 diabetes patients

Interleukin-6 (IL-6) is an important pro-inflammatory cytokine of relevance to cardiovascular diseases. The aim of this case-control study was to evaluate the association between the G(-174)C functional polymorphism in the IL-6 gene and risk of cardiovascular disease (CVD) in type 2 diabetes patients. We examined 1090 patients with T2DM and 612 controls. All subjects were genotyped for the G(-174)C polymorphism by polymerase chain reaction (PCR) and restriction analysis. There were no significant differences in the distribution of genotypes and alleles between T2DM patients and healthy controls. Significantly higher C allele frequency was observed in CVD+ patients compared to CVD- subgroup (53% vs. 32%, p<0.0001). The odds ratio for C allele was 2.4 (95% CI 1.99–2.9, p<0.0001) and for CC genotype 4.55 (95% CI 3.12–6.63, p<0.000). When the distribution of G(-174)C polymorphism was compared in subgroups with different clinical phenotypes of CVD, a significant association of CC genotype with myocardial infarction was observed. Forty eight percent of patients with MI had the CC genotype compared to 22% of patients without MI (p<0.0001). In conclusion, type 2 diabetes patients carrying the C allele of the IL-6 G(-174)C polymorphism have a significantly increased risk of CVD.

Influence of common variants of TLR4 and TLR9 on clinical outcomes of Plasmodium falciparum malaria in Odisha, India

BackgroundIn malaria, the toll-like receptors (TLRs) have recently emerged as major player of innate immunity. However, implication of TLR variants on clinical manifestations of malaria is conflicting. The present study aims to provide relevant information of growing interest in understanding the role of TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms on clinical outcomes of malaria. MethodsWe genotyped TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms by PCR-RFLP methods and subsequently analyzed in 200 uncomplicated patients and 200 severe patients. Further, the severe malaria categorized into sub-clinical groups such as cerebral malaria (CM), non-cerebral severe malaria (NCSM), single organ dysfunction (SOD) and multi-organ dysfunctions (MODS) are analyzed. ResultThe TLR9-1237CC genotype was observed at significantly low frequency in MODS (p=0.0008), while in heterozygous state (TC) it was proportionately more frequent in SOD (p=0.087) as compared to mild malaria. The TLR9T-1486C heterozygote was more common in all categories of severe malaria. However, pair wise LD analysis revealed significant linkage between T-1237C and T-1486C, whereas haplotype analysis showed significantly low frequency of C-T haplotype in CM (p=0.005, pc=0.02) and high frequency of T-C haplotype in NCSM as compared to mild malaria. ConclusionAlthough TLR9-1237C could be a risk factor for severe malaria in heterozygous state, negative association of CC genotype with MODS warrants caution of segregating severe malaria into its sub-clinical groups while interpreting data. Further, clinical outcome in malaria was observed to be apparently modulated by LD between TLR9 promoter variants.

Significance of a common variant in the CDKAL1 gene with susceptibility to type 2 diabetes mellitus in Iranian population.

Background:Type 2 diabetes mellitus (T2DM) is a worldwide problem that threatens the public health and economies of all countries. A multifactorial etiology and interaction between environmental factors and genetic components are responsible for triggering and progression of T2DM. Recently, rs7754840 single nucleotide polymorphism (SNP) in the CDKAL1 gene was reported to be associated with T2DM in various populations. However, due to inconsistent results in various populations about the association of rs7754840 with T2DM, and lack of information in the Iranian population, we have evaluated its association with T2DM in a subset of the Iranian population from Isfahan province, central part of Iran.Materials and Methods:The study included 140 patients and 140 controls selected based on the World Health Organization guidelines. Genomic DNA was extracted from blood samples and the rs7754840 SNP was genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay with specific primers and restriction enzyme (Ac1I).Results:The frequency of the C allele in the cases was higher than that in the controls (72.9% vs. 65%; P = 0.045). Using logistic regression analysis, we found a significant risk association of CC genotype with T2DM susceptibility (OR = 2.319, 95% CI = 1.436-3.744, P = 0.001). Furthermore, compared with the CC genotype, individuals with the GC genotype had a lower risk (protective association) of developing T2DM (OR = 0.332, 95% CI = 0.202-0.547, P < 0.001).Conclusions:We confirmed that there is a significant risk association between rs7754840 polymorphism and development of T2DM in a subset of the Iranian population from Isfahan province.

MDR1 C3435T polymorphism associated with the development of clinical features in Behçet's disease in Iranian Azeri Turkish patients.

Behçet's disease (BD) is a systemic vasculitis of unknown cause with a higher prevalence along the ancient Silk Road. Behçet's occasional familial aggregation and its close association with genes of major histocompatibility complexes justify that genetic factors play an important role in the development of the disease. In this study, we evaluated the association of multidrug resistance (MDR1) C3435T polymorphism with the severity of BD. We investigated the distribution of MDR1 C3435T polymorphism in 69 patients from the Iranian Azeri Turks group with BD and 92 ethnically sex-matched healthy controls, via the polymerase chain reaction-restriction fragment length polymorphism technique. Although there was no significant association of MDR1 C3435T polymorphism between two groups of patients and healthy controls, our data showed a substantial association of CC genotype with the development of several clinical features, including erythema nodosum (P=0.001, OR=2.686, 95%), pseudofolliculitis (P=0.002, OR=2.812, 95%), and skin lesions (P=0.040, OR=1.934, 95%). These results suggest that CC genotype is a risk factor for the development of some clinical features of BD in patients from the Iranian Azeri Turk ethnic group.

RAD51 135G&gt;C and TP53 Arg72Pro polymorphisms and susceptibility to breast cancer in Serbian women

Breast cancer is a complex disease with both genetic and environmental factors involved in its etiology. An important role of polymorphisms in genes involved in DNA repair has been reported related to breast cancer risk. We conducted a case-control study in order to investigate the association of RAD51 135G>C and TP53 Arg72Pro polymorphisms with breast cancer in Serbian women.48 BRCA negative women with breast cancer and family history of breast/ovarian cancer (hereditary group), 107 women with breast cancer but without family history of the disease (sporadic group) and 114 healthy women without a history of the disease (control group) were included. Restriction fragment length polymorphism was used for genotyping. Genotype and allelic frequencies, the odds ratio (OR) and the 95% confidence interval (CI) were calculated as an estimate of relative risk. The Hardy-Weinberg equilibrium was tested using χ(2) test. Significance was considered for p<0.05. RAD51 135G>C showed statistically significant association of CC genotype and increased breast cancer risk (OR 10.28, 95% CI 1.12-94.5) in hereditary group of patients compared to the control group. Regarding the TP53 Arg72Pro, we showed statistical significance for ProPro+ProArg comparing to ArgArg (OR 2.34, 95%, CI 1.17-4.70) in hereditary compared to sporadic group. RAD51 135G>C contributes to hereditary breast cancer in Serbian population, with CC genotype as a risk factor. We also found that carriers of Pro allele of TP53 codon 72 is related to hereditary cancer comparing to sporadic one, which indicates it as a potential risk factor for hereditary form of disease.

GNAS1 (Gαs) Gene T393C Polymorphism and Renal Cell Carcinoma Risk in a North Indian Population: A Case–Control Study

Heterotrimeric G protein α-subunit Gαs is required for activation of adenylyl cyclase and generation of cyclic adenosine monophosphate (cAMP) in cells and plays a key role in multiple signal transduction pathways, linked to proapoptotic processes in cancer cells. This study investigated whether Gαs gene polymorphism was associated with increased renal cell carcinoma (RCC) risk in the North Indian population. In the present study, genotyping of GNAS1 gene in 196 RCC cases and 250 healthy controls was performed via polymerase chain reaction-restriction fragment length polymorphism. The frequency of homozygous genotype CC was 29.6%, heterozygous TC was 51.5%, and homozygous TT was 18.9% in cases, whereas in controls it was 16.8%, 50.8%, and 32.4%, respectively; thus, there was a significant difference between the two groups (p=0.0001) in the univariate model. Further, multivariate analysis also demonstrated significant association of CC genotype with RCC risk (p=0.002). The high-risk genotype CC of GNAS1 gene showed threefold increase in risk to RCC relative to the TT genotype (unadjusted odds ratio [OR]=3.023, 95% confidence interval [CI]: 1.734-5.270). Whereas multivariate analysis showed a twofold increase in RCC risk among the CC genotype compared with the TT genotype (adjusted OR=2.181, 95% CI: 1.344-3.538). The C allele frequency was found to be significantly higher in RCC patients (55.3%) than in controls (42.2%) as compared with the T allele frequency that was 44.64% in RCC cases and 57.8% in controls. Moreover, patients with the CC genotype showed the worst prognosis in terms of the highest frequency of individuals having higher stages of RCC, but did not show any association with histological grade. Our results suggest that a T393C SNP could be considered as a genetic marker implicated in the pathogenesis of RCC.

Association Between MicroRNA196a2 rs11614913 Genotypes and the Risk of Non-Small Cell Lung Cancer in Korean Population

ObjectivesThe microRNA (miRNA) miR-196a2 may play an important role in lung cancer development and survival by altering binding activity of target mRNA. In this study, we evaluated their associations with the susceptibility of non-small cell lung cancers (NSCLC) by case-control study in a Korean population.MethodsWe performed genotyping analyses for miR-196a2 rs11614913 T/C at miRNA regions in a case-control study using blood samples of 406 NSCLC patient and 428 cancer-free control groups.ResultsThe total C allele frequencies for miR-196a2 were 48.8% for the patients and 45.6% for the controls; and the genotype frequencies of TT, TC, and CC were 23.7%, 55.2%, and 21.1% for the patients and 31.1%, 46.35%, and 22.4% for the controls (p<0.05). Participants who possesses TC/CC genotypes showed high risk for NSCLC compared to those possessed TT genotypes (OR, 1.42; 95% CI, 1.03 to 1.96). The association was persisted in 60 and older age group, male, smokers, those without family history for cancer. However, no significant association of CC genotypes in recessive genetic model was observed.ConclusionsIn conclusion, this case-control study provides evidence that miR-196a2 rs11614913 C/T polymorphisms are associated with a significantly increased risk of NSCLC in a dominant model, indicating that common genetic polymorphisms in miR-196a2 rs11614913 are associated with NSCLC. The association of miR196a2 rs11614913 polymorphisms and NSCLC risk require confirmation through additional larger studies.

Association of CYP1A1 Gene Polymorphism with Ischemic Stroke in South Indian Population

Stroke is a major cause of morbidity and mortality worldwide. Genetic and environmental factors are involved in the pathogenesis of stroke. Hypertension, diabetes mellitus, and cigarette smoking are the major risk factors, and smoking doubles the risk of ischemic stroke. Smoking cessation decreased the risk for ischemic stroke. CYP1A1 is the phase I metabolizing enzyme which plays a key role in metabolic activation of polycyclic aromatic hydrocarbons which are present in cigarette smoke and considered carcinogenic. So far, the association of CYP1A1 gene polymorphism with stroke has not been investigated in Indian population. So, the study is taken up to evaluate the association of this polymorphism with ischemic stroke in a South Indian population. We genotyped 215 ischemic stroke patients and 162 age-matched controls using polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis showed that CYP1A1 "CC" genotype is associated with five times increased risk of ischemic stroke (odds ratio (OR) = 5.14; 95% confidence interval (95% CI) = 1.14-23.14, p = 0.01), while "TT" (OR = 0.78, 95% CI = 0.51-1.19, p = 0.25) and "TC" (OR = 1.04, 95% CI = 0.67-1.60, p = 0.85) genotypes were nonsignificant with the increased risk of stroke. T and C allele frequencies in stroke were 76.5% and 23.5% as against 81.8% and 18.2% in control group, respectively, thus, suggesting no statistically significant differences in the T (OR = 0.72, 95% CI = 0.50-1.03, p = 0.07) and C (OR = 1.37, 95% CI = 0.96-1.97, p = 0.07) allele frequencies between the two groups. The distribution of CYP1A1 genotypes and allelic frequency within the stroke subtypes showed a significant association of CC genotype only in intracranial large artery atherosclerosis (OR = 5.21, 95% CI = 1.03-26.38, p = 0.02) while other subtypes did not show any association. Further analysis of CYP1A1 genotypes in patients and control subjects with smoking habit also showed a similar trend. Hence, we conclude that the CYP1A1 CC genotype is associated with the increased risk of ischemic stroke.