MDR Analysis Research Articles

Assessment of DNA repair susceptibility genes identified by whole exome sequencing in head and neck cancer

Head and neck cancer (HNC), the sixth most common cancer globally, stands second in India. In Northeast (NE) India, it is the sixth most common cause of death in males and seventh in females. Prolonged tobacco and alcohol consumption constitute the major etiological factors for HNC development, which induce DNA damage. Therefore, DNA repair pathway is a crucial system in maintaining genomic integrity and preventing carcinogenesis. The present work was aimed to predict the consequence of significant germline variants of the DNA repair genes in disease predisposition. Whole exome sequencing was performed in Ion Proton™ platform on 15 case-control samples from the HNC-prevalent states of Manipur, Mizoram, and Nagaland. Variant annotation was done in Ion Reporter™ as well as wANNOVAR. Subsequent statistical and bioinformatics analysis identified significant exonic and intronic variants associated with HNC. Amongst our observed variants, 78.6% occurred in ExAC, 94% reported in dbSNP and 5.8% & 9.3% variants were present in ClinVar and HGMD, respectively. The total variants were dispersed among 199 genes with DSBR and FA pathway being the most mutated pathways. The allelic association test suggested that the intronic variants in HLTF and RAD52 gene significantly associated (P < 0.05) with the risk (OR > 5), while intronic variants in PARP4, RECQL5, EXO1 and PER1 genes and exonic variant in TDP2 gene showed protection (OR < 1) for HNC. MDR analysis proposed the exonic variants in MSH6, BRCA2, PALB2 and TP53 genes and intronic variant in RECQL5 genetic region working together during certain phase of DNA repair mechanism for HNC causation. In addition, other intronic and 3′UTR variations caused modifications in the transcription factor binding sites and miRNA target sites associated with HNC. Large-scale validation in NE Indian population, in-depth structure prediction and subsequent simulation of our recognized polymorphisms is necessary to identify true causal variants related to HNC.

CYP2D6 (C2850T, G1846A, C100T) polymorphisms, haplotypes and MDR analysis in predicting coronary artery disease risk in north-west Indian population: A case-control study

AimsThe present study was aimed to evaluate the association of C2850T, G1846A and C100T polymorphisms of the CYP2D6 with coronary artery disease (CAD) in North-West Indian population. MethodsIn this case-control study, 200 patients with CAD and 200 age-, gender- and ethnicity-matched healthy controls were genotyped for C2850T, G1846A and C100T polymorphisms of CYP2D6 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. ResultsGenotype and allele distributions of C2850T and G1846A polymorphisms of the CYP2D6 were significantly different between cases and controls (p = 0.038, p = 0.021; p = 0.048, p = 0.012, respectively) whereas the distribution of genotype and allele for C100T polymorphism did not differ significantly (p = 0.098, p = 0.117, respectively). The 2850T and1846A variants were significantly associated with the increased risk of developing CAD, as observed from the odds ratios for the 2850 T/T and 1846 G/A genotypes (OR: 2.44, 95% CI: 1.99–4.99, p = 0.015 and OR: 1.62, 95% CI: 1.02–2.56, p = 0.041, respectively). Moreover, the recessive model in C2850T and the dominant model in G1846A are the best fit inheritance models to predict the susceptible gene effects (OR: 2. 07, 95% CI: 1.05–4.08, p = 0.031 and OR: 1.70, 95% CI: 1.10–2.62, p = 0.016, respectively). On gender stratification, these associations were observed only in females in addition to the C/T genotype of C2850T (OR: 2.52, 95% CI: 1.42–4.38, p = 0.001) and C100T (OR: 3.18, 95% CI: 1.52–6.67, p = 0.002). Furthermore, it is also observed that the CAT (OR: 2. 61, 95% CI: 1.07–6.34, p = 0.035) and TAC (OR: 15. 22, 95% CI: 1.97–117.58, p = 0.009) are high-risk haplotypes for CAD in the total group, whereas, the TGC (OR: 1. 64, 95% CI: 1.02–2.62, p = 0.042) and CAT (OR: 4. 21, 95% CI: 1.12–15.59, p = 0.035) haplotypes provide gender-specific risk in females. ConclusionsOur results indicate significant association of C2850T, G1846A and C100T polymorphisms of CYP2D6 with CAD especially in females of North-West Indian population.

Role of matrix metalloproteinase-9 polymorphisms in basement membrane degradation and pathogenesis of oral submucous fibrosis

Oral submucous fibrosis (OSMF) is regarded as a collagen and collagenase metabolic disorder. Aberrant expression of matrix metalloproteinases (especially MMP-9) plays important role in remodeling of extracellular matrix (ECM) during development of OSMF. Single nucleotide polymorphisms (SNPs) in MMP-9 promoter and coding region have been demonstrated to be associated with several diseases. In this case-control study, 196 controls and 189 OSMF patients were genotyped at four MMP-9 polymorphic sites on −1562C>T, R279Q, P574R and R688Q loci by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) method to determine the susceptibility to OSMF. The functional effect of SNPs to the development of OSMF was analyzed by studying the expression of MMP-9, collagen type-I and IV in oral biopsy tissues. R279Q SNP was found to be associated with OSMF [OR 1.5, CI (1.04–2.43), p = 0.03]. The 574R and 668Q alleles were significantly associated with early age group at 2.08 (p = 0.007) and 2.12 (p = 0.011) fold risk to OSMF respectively. MDR analysis showed that -1562C>T and R688Q SNPs were in strong synergy (IG = 0.95%, p = 0.0032) with increased risk of OSMF. Genotypic and functional study revealed definitive role of MMP-9 coding SNPs R279Q, P574R and R668Q in the pathogenesis of OSMF with strong predictive and prognostic value to determine OSMF at early stages in the areca chewers. Pathologically, over-expression of MMP-9 leads to decrease in collagen type-IV and epithelial thinning which contribute to basement membrane degradation along with continuous accumulation of collagen type-I enhanced by MMP-9 −1562C>T, R279Q, P574R and R688Q SNPs, resulting into early onset of OSMF.

Biomarkers for Identifying Individuals at Risk of Alzheimer Disease

Background: Alzheimer Disease (AD), the most common form of dementia, is a progressive and irreversible neurodegenerative disorder. Promising preventative strategies includes identification of potential modifiable risk factors for AD that could help identify individual who are at risk of AD. This study focuses on identifying biochemical factors associated with non- familial AD. Methods: One hundred and ten individuals which included 55 AD patients and 55 healthy controls were recruited for the study. Patients clinically diagnosed by a neurologist as AD and controls with no clinical or family history of any neurological disease were subjected to Mini-Mental State Examination (MMSE) were evaluated for fourteen relevant biochemical markers using commercial kits. MDR analysis was carried out which is considered a basic machine learning tool for understanding the role of interaction and combination of the factors towards the outcome. PCA is performed to support the MDR interpretation. Through clustering analysis the probably causative factors towards the disease can be identified. Results: MDR analysis revealed that the overall best fit model included 10 factors which had a maximal testing accuracy of 61%, cross-validation consistency of 8/10. PCA analysis has further reduced the factors to Iron, TSAT, HDL, VitB12, FA, and Hcy which are important in disease initiation/progression. Apart from the cases, 9% of the controls who had lower MMSE also had low Iron, TSAT, HDL, VitB12, FA, and high Hcy. Conclusion: As per the results obtained, we would suggest a medical practice where, screening individuals above the age of 55 years with both MMSE and selected biochemical parameters (Iron, TSAT, HDL, VitB12, FA, and Hcy) should be carried out to identify those at risk of developing AD. Higher risk individuals can be suggested for modifications in diet/life style, enhancing certain nutritional components which may constitute promising strategies in postponing, slowing, and/or preventing cognitive decline in AD.

Interactive potential of genetic polymorphism in Xenobiotic metabolising and DNA repair genes for predicting lung cancer predisposition and overall survival in North Indians

IntroductionCancer, a multi-step, multifactorial and multi-gene disease, not only damages the genomic integrity of the cell but also hinders the DNA repair mechanisms of the body. Gene-gene and gene environment interactions amongst the genetic polymorphisms together modulate the susceptibility towards a cancer. We have studied the high order gene interactions between the genetic polymorphism of detoxifying genes (CYP1A1, Ahr, XRCC and GST1) that play a key role in the metabolism of the xenobiotics and have been proved to be prognostic markers for lung cancer Methods237 cases and 250 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used and to analyse high order interactions MDR and CART was used. ResultsIn the MDR analysis, the best model was one factor model which included GSTM1 (CVC 10/10, Prediction error = 0.43, p < .001). The best three factor model comprised of XRCC1 632, XRCC1 206, GSTM1 (CVC 10/10, Prediction error = 0.45, p < .0001). The CART analysis exhibited that Node 1 carrying mutant type of GSTM1 imposed the highest risk towards lung cancer (OR = 11.0, 95%C.I. = 6.05-20.03, p = .000001). Wild type of GSTM1 when combined with mutant type of CYP1A1 M2 and XRCC1 632, an 8 fold risk towards lung cancer was observed (95%C.I. = 4.07-16.29, p = .00001). The high order interactions were used to predict the prognosis of lung cancer patients. Of all the genetic variants, XRCC1 632, GSTM1 and AhR rs2066853 was the most important determinant of overall survival of lung cancer patients ConclusionThrough the study we introduced the concept of polygenic approach to get an insight about the various polymorphic variants in determining cancer susceptibility. Lesser number of subjects were found in the high risk subgroups. Further studies with larger sample size are required to warranty the above findings.

Synergistic effect of collagenase-1 (MMP1), stromelysin-1 (MMP3) and gelatinase-B (MMP9) gene polymorphisms in breast cancer.

BackgroundExtracellular matrix degradation by matrix metalloproteinases (MMPs) is an important mechanism involved in tumor invasion and metastasis. Genetic variations of MMPs have shown association with multiple cancers. The present study is focused to elucidate the association of MMP-1, 3 and 9 genetic variants with respect to epidemiological and clinicopathological variables by haplotype, LD, MDR, survival in silico analyses among South Indian women.Material and methodsMMP3–1171 5A/6A and MMP9–1562 C/T SNPs were genotyped by Allele specific polymerase chain reaction and MMP1-1607 1G/2G polymorphism by restriction fragment length polymorphism assays respectively, in 300 BC patients and age-matched 300 healthy controls. Statistical analysis was performed using the SNPStats and SPSS software. Linkage disequilibrium and gene-gene interactions were performed using Haploview and MDR software respectively. Further, transcription factor binding sites in the promoter regions of SNPs under study were carried out using AliBaba2.1 software.ResultsWe have observed an increased frequency of 2G-allele of MMP1, 6A-allele of MMP3 and T-allele of MMP9 (p<0.05) respectively in BC subjects. The 2G-6A haplotype (minor alleles of MMP-1 and MMP-3 respectively) has shown an increased susceptibility to BC. Further, MMP polymorphisms were associated with the clinical characteristics of BC patients such as steroid hormone receptor status, lymph node involvement and metastasis. SNP combinations were in perfect LD in controls. MDR analysis revealed a positive interaction between the SNPs. 5-years survival rate and cox-regression analysis showed a significant association with clinicopathological variables.ConclusionOur results suggest that MMP1–1607 1G/2G, MMP3–1171 5A/6A and MMP9–1562 C/T gene polymorphisms have synergistic effect on breast cancer. The interactions of MMPs clinical risk factors such as lymph node involvement has shown a strong correlation and might influence the 5-years survival rate, suggesting their potential role in the breast carcinogenesis.

Polymorphism of genes of the antioxidant system in the development of predispositions to lung cancer

We analyzed the polymorphic loci in the genes of the antioxidant system enzymes, such as GSTP1 (313A>G and 341C>T), MnSOD (47С>Т), GPx1 (599C>T), and CAT (–262C>>T), among 497 residents of Kemerovo oblast (Western Siberia, Russia). The analysis of the single-locus effects demonstrated a significant protective effect of the major C allele in the GPx1 (599C>T) locus. The MDR analysis of the gene-gene interactions showed that the GPx1 and the CAT genes work in close cooperation and mutually reinforce the risk of development of squamous cell lung cancer among the inhabitants of the industrial region.

Polymorphic variants of Caspase genes (8 & 3) in the risk prediction of Coronary Artery Disease

Apoptosis has been involved in a number of pathological conditions including coronary artery disease (CAD). Caspases (CASP) are important regulators and executioners in both extrinsic and intrinsic apoptotic pathways. The aim of the present study is to examine the role of Caspase 8 and 3 polymorphisms in the pathogenesis of CAD. CAD patients (n=300) and healthy controls (n=300) were genotyped for polymorphisms in CASP8 (−652 6N del/ins, IVS12-19G>A), CASP3 (rs4647601;G>T) by PCR-RFLP. Splicing defects were determined by HSF. Gene interactions, Linkage disequilibrium and haplotype analysis were carried out by MDR analysis and Haploview software respectively. Molecular analysis revealed that insertion genotype (II) of CASP8 −652 6N del/ins and TT genotype of CASP3 rs4647601;G>T polymorphism conferred risk for the development of CAD. HSF analysis showed that intronic cryptic donor site for CASP8 -652 6N del/ins and a new ESE site for CASP3 rs4647601;G>T polymorphisms. SNP combinations of Caspase 8 and 3 were in perfect LD (D′=1) in controls. D-A, I-G haplotypes of Caspase 8 polymorphisms (−652 6N del/ins & IVS12-19G>A) were found to be significantly predominant in the disease group. The present study suggests that CASP8 & 3 polymorphic variants might be used as markers for susceptibility to CAD.

Association study between genetic variations in Axin2 gene and lung cancer risk in North Indian population: A multiple interaction analysis.

Wnt pathway has been implicated in the process of human carcinogenesis. Axis inhibition protein2 ( Axin2), a major scaffold protein is an antagonist of Wnt pathway and is potent to act as a tumor suppressor gene in various human cancers. Therefore, the seven polymorphic sites of Axin2 gene were analyzed, in relation to lung cancer susceptibility in North Indians. A total of 608 subjects were genotyped using PCR-RFLP technique for each polymorphic site including 303 cases and 305 controls. Further association analysis was carried out using logistic regression approach to obtain adjusted odds ratio and statistical significance. MDR and CART analysis were applied to evaluate high order interactions between the SNP's. Three out of seven studied polymorphic sites showed a strong protective effect in subjects having mutant genotype for Axin2 148 C >T and heterozygous genotype for 1365 G > A and 1712 + 19 G > T towards lung cancer risk. The other important finding was the significant association of Axin2 148 C >T in SQCC patients having variant (TT) genotype. Axin2 1712 + 19 G >T showed a decreased risk for all the histological subtypes in patients with heterozygous (GT) genotype. MDR analysis predicted a best interaction model ( Axin2 148, Axin2 2062 and Axin2 1712 +19) with maximum CVC (10/10) and minimum prediction error (0.38) along with significant permutation p-value. CART analysis gave a wide spectrum of interactive combinations which exhibited a major contribution in modulating lung cancer susceptibility. Axin2 148 and Axin2 1712 + 19 were found to play a major role in modulating lung cancer risk.

The genetic variants in the PTEN/PI3K/AKT pathway predict susceptibility and CE(A)F chemotherapy response to breast cancer and clinical outcomes.

The PI3K/PTEN/AKT pathway play a critical role in balancing cell growth and death. Epidemiologic studies suggested that mutations of the PI3K/PTEN/AKT pathway genes are associated with cancer risk, yet no data are available for PTEN rs701848, PIK3CA rs2699887, and AKT1 rs2494752 polymorphism and breast cancer(BC) risk. A case-control study was performed in 920 BC patients and 908 healthy controls using the TaqMan assay method. Overall, individuals with PTEN rs701848 TC, CC and TC/CC genotypes showed significant increased BC risk (P=0.043, P=0.002, P=0.008, respectively), and the C allele carriers had a 1.224-fold significantly increased risk of developing BC (P= 0.003). Moreover, a higher frequency of AKT rs2494752 AG genotype was observed among cases (P=0.045). Individuals harboring rs2494752 AG/AA genotype had a vital increased susceptibility to BC in the dominant model (P=0.039). More importantly, AKT1 rs2494752 GG genotype showed significantly rates of response to NCT chemotherapy (P=0.048). Furthermore, AKT1 rs2494752 AG genotype carriers showed significantly shorter DFS time, and GG genotype as the independent prognostic factor (DFS: adjusted HR=1.523, 95% CI=1.012-2.293, P=0.044; OS: adjusted HR=2.321, 95% CI=1.281-4.204, P=0.005). Moreover, MDR analysis consistently revealed that the combination of 3 selected SNPs and 7 known risk factors represented the best model to predicting BC prognosis. The luciferase assay showed that the G allele of rs2494752 significantly increased AKT1 promoter activity. These results suggest that PTEN rs701848 and AKT1 rs2494752 polymorphisms might be a candidate pharmacogenomic factor to assess the susceptibility of BC and response and prognosis prediction for interindividualized CE(A)F chemotherapy in BC patients.

Interaction between susceptibility loci in cGAS-STING pathway, MHC gene and HPV infection on the risk of cervical precancerous lesions in Chinese population.

Human papillomavirus (HPV) infection is a definite risk factor for cervical cancer. Nevertheless, only some infected individuals actually develop cervical cancer. The cGAS-STING pathway in innate immunity plays an important role in protecting against HPV infection. Chen et al. described that the rs2516448 SNP in the MHC locus may affect susceptibility to cervical cancer, a finding that we attempted to replicate in a Chinese population. To investigate the effects of cGAS, STING and MHC polymorphisms on susceptibility to cervical precancerous lesions, 9 SNPs were analyzed in 164 cervical precancerous lesion cases and 428 controls. Gene-gene and gene-environment interactions were also evaluated. We found a significantly decreased risk of cervical precancerous lesions for the GG genotype of rs311678 in the cGAS gene (ORadjusted = 0.40, 95% CI: 0.16−0.98). Moreover, MDR analysis identified a significant three-locus interaction model, involving HPV infection, age at menarche and rs311678 in cGAS. Additionally, a significant antagonistic interaction between HPV infection and rs311678 was found on an additive scale. In conclusion, our results indicate that the rs311678 polymorphism in the cGAS gene confers genetic susceptibility to cervical precancerous lesions. Moreover, the three-way gene-environment interactions further demonstrate that the rs311678 polymorphism in cGAS can significantly decrease the risk of HPV infection and the elder at menarche.

Association study of inflammatory genes with rheumatic heart disease in North Indian population: A multi-analytical approach

Rheumatic heart disease (RHD) is an inflammatory, autoimmune disease; occurring as a consequence of group A streptococcal infection complicated by rheumatic fever (RF). An inappropriate immune response is the central signature tune to the complex pathogenesis of RHD. However, some of those infected develop RHD, and genetic host susceptibility factors are thought to play a key role in diseasedevelopment. Therefore, the present study was designed to explore the role of genetic variants in inflammatory genes in conferring risk of RHD. The study recruited total of 700 subjects, including 400 RHD patients and 300 healthy controls. We examined the associations of 8 selected polymorphisms in seven inflammatory genes: IL-6 [rs1800795G/C], IL-10 [rs1800896G/A], TNF-A [rs1800629G/A], IL-1β [rs2853550C/T], IL-1VNTR [rs2234663], TGF-β1 [rs1800469C/T]; [rs1982073T/C], and CTLA-4 [rs5742909C/T] with RHD risk. Genotyping for all the polymorphisms was done using PCR-ARMS/PCR/RFLP methods. Multifactor dimensionality reduction and classification and regression tree approaches were combined with logistic regression to discover high-order gene-gene interactions in studiedgenes involved in RHD susceptibility.In univariate logistic regression analysis, we found significant association of variant-containing genotypes (CT&TT) of TGF-β1 869T/C [rs1982073]; [p=0.0.004 & 0.001, OR (95% CI)=1.65 (1.2–2.3) & 2.25 (1.4–3.6) respectively], variant genotype (CC) of IL-1β −511C/T [rs2853550]; [p=0.001, OR (95% CI)=2.33 (1.4–3.8)] and IL-1 VNTR [rs2234663]; [p=0.03, OR (95% CI)=5.25 (1.2–23.4)] SNPs with RHD risk. CART analysis revealed that individuals with the combined genotypes of TGF-β1T/C_ rs1982073 (CT/TT) and IL-1 β_ rs2853550 (CC) had significantly higher susceptibility for RHD [p=0.0005, OR (95% CI)=5.91 (2.9–12.5)]. In MDR analysis, TGF-β1 869T>C yielded the highest testing accuracy of 0.562. In conclusion, using multi-analytical approaches, our study revealed important role of TGF-β1 869T/C [rs1982073] in RHD susceptibility.

Xenobiotic Pathway Gene Polymorphisms Associated with Gastric Cancer in High Risk Mizo-Mongoloid Population, Northeast India.

The aim of this study was to evaluate the risk of gastric cancer associated with individual or combined glutathione S-transferases (GSTs) polymorphism and their interaction with environmental factors. Genotyping by PCR was carried out for 80 cases and controls each for GSTM1, GSTT1, and GSTP1 polymorphism and mapped for gene-environment association studies. The samples were subjected to pathogen detection and GSTP1 expression for analyzing their association with different genotypes. Logistic regression analyses were conducted to compute the influence of both genetic and environmental factors for gastric cancer. MDR analysis was performed to assess the risk of gastric cancer by studying the gene-gene and gene-environment effect on the basis of GST genotyping and GSTP1 gene expression. Infection with Helicobacter pylori and CagA+ strains was more frequent in patients with GSTM1/T1 null genotype. Intake of high fermented fat and smoked meat was found to be significantly associated with gastric cancer. The G/G, A/G (rs1695), and T/T (rs1138272) were found to be significantly associated with low expression of GSTP1 gene in cancer tissue. Presence of H. pylori with CagA genotype showed significant individual effect with GSTT1 polymorphism as well as strong synergistic effect in gastric cancer risk. Majority of the gastric cancer samples showed significant negative expression in G/G, A/G (rs1695), and T/T (rs1138272) genotypes. This study shows that GST gene polymorphism was significantly relevant for determining the individual susceptibility to gastric cancer.

The association of six polymorphisms of five genes involved in three steps of nucleotide excision repair pathways with hepatocellular cancer risk

BackgroundHundreds of single nucleotide polymorphisms (SNPs) of the genes encoding nucleotide excision repair (NER) proteins are involved in every step of the DNA recognition–unwinding–incision process, which may affect cancer risk. However, only a limited number of studies have examined the association of NER SNPs with hepatocellular cancer (HCC) risk.ResultsIn screening stage, single-locus analysis showed that six SNPs in five genes were associated with HCC risk, including three risk SNPs (XPA rs10817938, XPC rs1870134 and ERCC2 rs238417) and three protective SNPs (ERCC1 rs2298881 and rs3212961, and ERCC5 rs873601). In verification stage, only XPC rs1870134 was verified to be associated with HCC risk (P = 4.7 × 10−4). Furthermore, multivariate logistic regression and MDR analysis consistently revealed a gene–gene interaction among ERCC1 rs2298881 and XPC rs1870134 SNPs associated with HCC risk (Pinteraction = 0.023). When analyzing the effect of the positive SNP on the mRNA expression, we found XPC rs1870134 GG genotype which was associated with an increased HCC risk showed lower XPC mRNA expression.MethodsThis study designed as “screening-verification” experiments and included a total of 1472 participants (570 HCC patients vs. 902 controls). We explored 39 SNPs in eight genes involved in NER Pathways, including XPA, XPC, DDB2, ERCC3, ERCC2, ERCC1, ERCC4 and ERCC5, using Sequenom MassARRAY and KASPar platform. Eighty-six cases of HCC and the neighboring noncancerous tissues were subjected to the measurement of mRNA expression level of the promising gene.ConclusionsXPC promoter rs1870134 SNP and SNP-SNP interaction were associated with HCC risk.

Polymorphisms of extrinsic death receptor apoptotic genes (FAS -670 G>A, FASL -844 T>C) in coronary artery disease.

Apoptosis plays an important role in atherogenesis and rupture of vulnerable plaques in coronary artery disease. FAS and FAS ligand (FASL) induce apoptosis when FAS binds to FAS-L. However sFas blocks apoptosis by binding to FAS and FASL or sFasL. The present study is sought to examine the role of extrinsic apoptotic genes (FAS, FASL) polymorphism and serum levels of FAS, FASL in the pathogenesis and susceptibility to CAD in south Indian population. The study included 300 CAD patients and 300 healthy controls. Lipid profiles, sFas, sFasL were estimated by commercially available kits. FAS -670 G>A, FASL -844 T>C genotypes were analyzed by PCR-RFLP. Secondary structures of pre mRNA were analyzed by the Vienna RNA webserver and gene-gene and gene-environment interactions were determined by MDR analysis. Total cholesterol, triglyceride and LDL levels were significantly high in CAD patients compared to the controls. Molecular analysis revealed that the frequency of the AA genotype of FAS (54% vs 27%) and CC genotypes of FASL (10.3% vs 1.3%) were high in CAD patients compared to controls. Secondary structure analysis of FAS and FASL confirmed our molecular analysis. sFas levels were low while serum sFasL were high in CAD patients. MDR analysis revealed synergistic effects of gene polymorphisms and additive effects of epidemiological factors on risk of CAD. Polymorphisms of FAS (-670 G/A), FASL (-844 T/C) and their circulating levels play an important role in the pathology of CAD.

Gender-Specific Association of ATP2B1 Variants with Susceptibility to Essential Hypertension in the Han Chinese Population.

Previous genome-wide association studies (GWASs) found that several ATP2B1 variants are associated with essential hypertension (EHT). But the “genome-wide significant” ATP2B1 SNPs (rs2681472, rs2681492, rs17249754, and rs1105378) are in strong linkage disequilibrium (LD) and are located in the same LD block in Chinese populations. We asked whether there are other SNPs within the ATP2B1 gene associated with susceptibility to EHT in the Han Chinese population. Therefore, we performed a case-control study to investigate the association of seven tagSNPs within the ATP2B1 gene and EHT in the Han Chinese population, and we then analyzed the interaction among different SNPs and nongenetic risk factors for EHT. A total of 902 essential hypertensive cases and 902 normotensive controls were involved in the study. All 7 tagSNPs within the ATP2B1 gene were retrieved from HapMap, and genotyping was performed using the Tm-shift genotyping method. Chi-squared test, logistic regression, and propensity score analysis showed that rs17249754 was associated with EHT, particularly in females. The MDR analysis demonstrated that the interaction of rs2070759, rs17249754, TC, TG, and BMI increased the susceptibility to hypertension. Crossover analysis and stratified analysis indicated that BMI has a major effect on the development of hypertension, while ATP2B1 variants have a minor effect.

Association of genetic polymorphisms in CD8 + T cell inhibitory genes and susceptibility to and progression of chronic HBV infection

BackgroundPrevious studies have shown that multiple inhibitory genes play an important role in HBV-specific CD8+ T cell exhaustion and dysfunction in the setting of chronic HBV infection. Polymorphic variants of these genes are thought to be predisposing factors for HBV susceptibility, clearance, and disease progression. The aim of this retrospective study was to identify variants affecting chronic HBV infection in a Chinese Han population. MethodsWe chose 28 tgSNPs from HapMap data on 5 key genes. They were genotyped on a total of 858 chronic HBV patients, 429 patients who underwent spontaneous recovery, and 239 healthy controls. We evaluated the correlation between the polymorphisms and HBV susceptibility, spontaneous clearance, and disease progression. ResultsThe association of rs3827537 of BIM genotype TA and allele A was significantly different (P=0.016, OR=2.049; P=0.031, OR=1.925) between HBV patients and healthy controls. The rs36084323 of PD-1, as well as rs3766377, rs485618, rs4656942 of CD244 showed significant associations with the risk for HBV-related cirrhosis and hepatocellular carcinoma (HCC) (P=0.009, OR=0.482; P=0.009, OR=4.573; P=0.015, OR=0.580; P=0.028, OR=2.855). MDR analysis revealed that the four SNPs (rs36084323, rs3766377, rs485618, rs4656942) modulated the predisposition to cirrhosis and HCC in patients with chronic HBV infection (P=0.006). Using a luciferase reporter assay, we demonstrated that various alleles of rs3766377 had differential effects, and rs3766377 and rs485618 might have interactive effects. ConclusionsThe present study reveals genetic associations among PD-1 and CD244 variants that may be involved in the development of cirrhosis and HCC in patients with chronic HBV infection. The BIM variant was associated with HBV susceptibility.

Polymorphisms in MicroRNA Genes And Genes Involving in NMDAR Signaling and Schizophrenia: A Case-Control Study in Chinese Han Population.

Disturbances in glutamate signaling caused by disruption of N-methyl-D-aspartate-type glutamate receptor (NMDAR) have been implicated in schizophrenia. Findings suggested that miR-219, miR-132 and miR-107 could involve in NMDAR signaling by influencing the expression of pathway genes or the signaling transmission and single nucleotide polymorphisms (SNPs) within miRNA genes or miRNA target sites could result in their functional changes. Therefore, we hypothesized that SNPs in miRNAs and/or their target sites were associated with schizophrenia. 3 SNPs in hsa-pri-miR-219/132/107 and 6 SNPs in 3′UTRs of GRIN2A/2B/3A and CAMK2G were selected and genotyped in a case-control study of 1041 schizophrenia cases and 953 healthy controls in Chinese Han population. In the present study, GRIN2B rs890 showed significant associations with schizophrenia. Further functional analyses showed that the rs890 variant C allele led to significantly lower luciferase activity, compared with the A allele. MDR analysis showed that a 4-locus model including rs107822, rs2306327, rs890 and rs12342026 was the best model. These findings suggest that GRIN2B may be associated with schizophrenia and interaction effects of the polymorphisms in hsa-miR-219, CAKM2G, GRIN2B and GRIN3A may confer susceptibility to schizophrenia in the Chinese Han population.

Analysis of MC4R rs17782313, POMC rs1042571, APOE-Hha1 and AGRP rs3412352 genetic variants with susceptibility to obesity risk in North Indians

Background: Obesity is a multi-factorial disorder influenced by genetic and environmental factors. The physiological pathways associated with obesity are complex and involve several genes.Aim: The aim of this survey is to evaluate the association of genetic variants of melanocortin-4-receptor (MC4R), pro-opiomelanocortin (POMC), apolipoprotein E (APOE) and agouti-related protein (AGRP) with obesity in the North Indian population.Methods: MC4R rs17782313, POMC rs1042571, APOE-Hha1 and AGRP rs3412352 polymorphisms were investigated for their association in 396 obese individuals with BMI ≥ 30 kg/m2 and 300 healthy non-obese individuals with BMI < 30 kg/m2. Genotyping was performed using Taqman probes and PCR-RFLP methods. Single locus logistic regression analysis was conducted using (SPSS), ver.19 and PLINK software Version 1.01 and high order genetic interactions associated with obesity risk were analysed using MDR software (version 2.3.0.2).Results: The genotypes of MC4R rs17782313, POMC rs1042571 and APOE-Hha1 were significantly associated with obese individuals (BMI ≥ 30 kg/m2) when compared with non-obese individuals (BMI < 30 kg/m2). No association of AGRP rs34123523 was seen with obesity.Conclusions: The best interaction model for predicting obesity risk by MDR analysis was the three factor model including POMC (C > T), MC4R (T > C) and APOE (Hha1) polymorphisms. Genetic variants in MC4R, POMC and APOE genes might play significant roles in predisposing obesity (BMI ≥ 30 kg/m2) in the North Indian population.

Influence of Thrombophilic Genes; MTHFR (C677T), FVL (G1691A) and ACE (I28005D) In Pregnant Women with Pre-Eclampsia

Objective: Pre-eclampsia (PE) is a pregnancy complication and vascular disorder recognized by new onset gestational hypertension and proteinuria. It may lack of immunological mother and fetus signalization. The exact pathogenesis of PE remains uncertain. The aim of this study was to identify the selected polymorphisms in the genesis of PE. Methods: PE was identified in the second half of pregnancy, often in the latter part of the second or final trimesters, although it may occur earlier. This is a case-control study carried out in 105 cases and 100 age matched normal pregnant women (controls). We have selected three different genes: MTHFR, FVL, ACE to evaluate mutation/ polymorphisms in 677C>T, 1691G>A and I>D28005 genotypes by PCR followed by Restriction fragment length polymorphism and gel electrophoresis. Results: Statistical analysis was performed by Openepi software. Both the allele and genotype frequencies between PE cases and controls were contradictory and odds ratio with 95% confidence interval did not reveal statistical significant in either alleles or genotypes of any of the three snips. MDR analysis also failed to show the disease marker association in the PE women. It has found an interaction between MTHFR and FVL. These findings suggest the existence of population based differences in the association of candidate gene variants with PE emphasizes the importance of studying specific polymorphisms, which can be used as biomarkers uniquely for an ethnic group. Conclusion: In conclusion, the present case-control study in pregnant women appears as lack of association with the selected polymorphisms in the study population.