Effects Of Common Polymorphisms Research Articles

OS 31-02 ANTIHYPERTENSIVE RESPONSE TO BISOPROLOL WAS NOT RELATED TO POLYMORPHISMS IN ADRB1 Or CYP2D6 IN CHINESE HYPERTENSIVE PATIENTS

Abstract The blood pressure (BP) response to antihypertensive drugs varies considerably between different patients. The response to some beta-blockers has been associated with polymorphisms in the beta1-adrenergic receptor (ADRB1) or cytochrome P450 2D6 (CYP2D6) genes. We examined the effects of common polymorphisms in ADRB1 and CYP2D6 on the response to bisoprolol in 100 Chinese patients. Chinese patients with primary hypertension with sitting clinic systolic BP (SBP) 140-169 mmHg and/or diastolic BP (DBP) 90-109 mmHg after placebo run-in were treated with open-label bisoprolol 2.5 mg daily. Other antihypertensive treatments were discontinued except for amlodipine which was continued if necessary to achieve BPs in the defined range at the end of the run-in. Clinic and ambulatory BP (ABP) were measured after the placebo run-in and after 6 weeks treatment. Patients were genotyped for the Gly389Arg and Ser49Gly polymorphisms in ADRB1 and the CYP2D6*10 polymorphism. After 6 weeks of treatment with bisoprolol 2.5 mg daily, reductions in clinic BP and heart rate were 14.3 ± 10.9/8.4 ± 6.2 mmHg (p

Effects of common polymorphisms in miR-146a and miR-196a2 on lung cancer susceptibility: a meta-analysis.

MicroRNAs (miRNAs) may play an important role in organ development, cell differentiation, apoptosis, proliferation, cell growth regulation and act as tumor suppressor genes or proto-oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs are considered to be genetic factors to influence the susceptibility to lung cancer (LC). Rs2910164 in miR-146a and rs11614913 in miR-196a2 are shown to be associated with increased/decreased LC risk. The aim of this meta-analysis was to systematically summarize the possible association. The relevant articles were retrieved from several important databases. Studies were selected using specific inclusion and exclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between miRNA polymorphism and susceptibility to LC. All analyses were performed using the Stata software. Seven studies were included in this meta-analysis. There were 3,225 cases and 3,268 controls for SNP rs2910164 and 2,794 cases and 2,840 controls for SNP rs11614913. The significant associations between SNP rs2910164 and LC risk were observed (CC vs. GG: OR =1.30, 95% CI: 1.13-1.50; CC + GC vs. GG: OR =1.15, 95% CI: 1.02-1.29; CC vs. GC + GG: OR =1.27, 95% CI: 1.13-1.42; C vs. G: OR =1.15, 95% CI: 1.08-1.24). SNP rs11614913 was found to be associated with LC risk in most genetic models (TC vs. TT: OR =1.16, 95% CI: 1.02-1.32; CC vs. TT: OR =1.24, 95% CI: 1.06-1.44; CC + TC vs. TT: OR =1.19, 95% CI: 1.06-1.34; C vs. T: OR =1.11, 95% CI: 1.03-1.20). In the subgroup analysis by ethnicity, genotyping method and control characteristics, significantly affected LC risks were also suggested. The rs2910164 in miR-146a and the rs11614913 in miR-196a2 are likely to be associated with LC risks.

Effects of Common Polymorphisms in the MTHFR and ACE Genes on Diabetic Peripheral Neuropathy Progression: a Meta-Analysis.

Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus. The aim of this meta-analysis was to evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) 677 C>T and ACE I/D polymorphisms in the development of DPN. We systematically reviewed published studies on MTHFR 677 C>T and ACE I/D polymorphisms and DPN found in various types of electronic databases. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) quality score systems were used to determine the quality of the articles selected for inclusion. Odds ratios (ORs) and its corresponding 95% confidence interval (95% CI) were calculated. We used STATA statistical software (version 12.0, Stata Corporation, College Station, TX, USA) to deal with statistical data. Our results indicated an association of ACE D>I mutation (OR = 1.43, 95% CI 1.12-1.83, P = 0.004) and MTHFR 677 C>T mutation (OR = 1.43, 95% CI 1.08-1.90, P = 0.014) with DPN under the allele model, and similar results were also found under the dominant model (all P < 0.05). Subgroup analysis by country indicated that the MTHFR 677 C>T polymorphism may be the main risk factor for DPN in Turkey under four genetic models. ACE D>I mutation was correlated with DPN in Japanese and Pakistani populations in the majority of groups. The relationships of MTHFR 677 C>T and ACE I/D polymorphisms with DPN patients presented in this meta-analyses support the view that the MTHFR and ACE genes might play an important role in the development of DPN.

RETRACTED ARTICLE: Effects of Common Polymorphisms in the MTHFR and ACE Genes on Diabetic Peripheral Neuropathy Progression: a Meta-Analysis

Diabetic peripheral neuropathy (DPN) is a microvascular complication of diabetes mellitus. The aim of this meta-analysis was to evaluate the effects of methylenetetrahydrofolate reductase (MTHFR) 677 C>T and ACE I/D polymorphisms in the development of DPN. We systematically reviewed published studies on MTHFR 677 C>T and ACE I/D polymorphisms and DPN found in various types of electronic databases. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) quality score systems were used to determine the quality of the articles selected for inclusion. Odds ratios (ORs) and its corresponding 95 % confidence interval (95 % CI) were calculated. We used STATA statistical software (version 12.0, Stata Corporation, College Station, TX, USA) to deal with statistical data. Our results indicated an association of ACE D>I mutation (OR = 1.43, 95 % CI 1.12–1.83, P = 0.004) and MTHFR 677 C>T mutation (OR = 1.43, 95 % CI 1.08–1.90, P = 0.014) with DPN under the allele model, and similar results were also found under the dominant model (all P T polymorphism may be the main risk factor for DPN in Turkey under four genetic models. ACE D>I mutation was correlated with DPN in Japanese and Pakistani populations in the majority of groups. The relationships of MTHFR 677 C>T and ACE I/D polymorphisms with DPN patients presented in this meta-analyses support the view that the MTHFR and ACE genes might play an important role in the development of DPN.

PP.42.08

Objective: Chaperone-mediated autophagy is a selective form of autophagy by which cytosolic proteins are recognized by a chaperone complex which targets them to lysosomes for degradation. The lysosomal uptake of these proteins requires their binding to the lysosome-associated membrane protein type 2A (LAMP-2A). LAMP-2A is one of the three splice variants of the LAMP2 gene, localized to Xq24. Mutations in LAMP2 are associated with development of hypertrophic cardiomyopathy and with other phenotypes related to Danon disease. However, the effects of common polymorphisms in the LAMP2 gene on blood pressure and cardiovascular diseases (CVD) are not known. Our objective was to investigate the association of common LAMP2 variants with blood pressure and myocardial infarction incidence in a high cardiovascular risk population. Design and method: We analyzed the participants in the PREDIMED-Valencia Study (n = 1094). PREDIMED is a multicenter randomized controlled trial aimed at assessing the effects of the Mediterranean diet in the prevention of CVD. Participants were high cardiovascular risk subjects, aged 67 ± 7 y. Blood pressure was measured at baseline by triplicate and clinical and lifestyle variables were obtained. Incidence of myocardial infarction (fatal and non-fatal) was identified after a median of 4.8 y follow-up. Common LAMP-2 polymorphisms (rs2748 and rs42889) were determined. Multivariable regression models were fitted to test associations. Results: Prevalence of the selected polymorphism (both intronic, in the 3UTR and in partial linkage disequilibrium) was as follows; in women: 40.9% TT, 41.1% TC and 18.0% CC for rs2748 and 37.8% CC, 44.4% CT and 17.8% TT for rs42889. In men: 46.2%T and 53.8% C (rs2748) and 57.2% C and 42.8% T (rs42889). We did not find any significant association between the polymorphisms and blood pressure (systolic or diastolic) at baseline. However we found a significant association of the rs42889 with myocardial infarction in women. Carriers of the variant allele had lower risk than CC homozygotes even after adjustment for age, dietary intervention, type-2 diabetes and smoking (OR: 0.19; 95% CI:0.04–0.94; P = 0.042). Conclusions: Our results suggest a potential role of the common LAMP2 polymorphism on myocardial infarction in women that requires further investigation.

RETRACTED ARTICLE: CD14 Promoter-159 Polymorphism Is Associated with Reduced Risk of Intestinal-Type Gastric Cancer in a Japanese Population

Host genetic factors may play a key role in determining the long-term outcome of the Helicobacter pylori infection. Toll-like receptor 4 (TLR4) and CD14-mediated recognition of lipo-polysaccharide (LPS) is required for efficient recognition of gram-negative bacterial infections. We investigated the effects of common polymorphisms of TLR4 Asp299Gly, Thr399Ile, and CD14 promoter-C159T on the risk of gastric cancer including its subtypes and clinicopathologic features. We also investigated the effects of these polymorphisms on histologic degree of H. pylori-induced gastritis. The study was performed in 149 gastric cancer (GC) cases [mean age 64.0 +/- 12.4, M:F = 109:40] and 94 patients without evidence of GC (mean age 64.1 +/- 12.3, M:F = 65:25, Peptic ulcer diseases = 43.6%, gastritis = 56.4%) as the control group. TLR4 Asp299Gly, Thr399Ile, and CD14 promoter-C159T were determined by PCR-RFLP in all the patients. Gastritis scores of non-cancerous gastric mucosa were assessed according to the updated Sydney system in H. pylori-positive subjects (n = 179). The frequencies of CD14-260 TT and T carrier were significantly lower in patents with intestinal-type gastric cancer than in controls (OR = 0.31; 95%CI = 0.12-0.78, OR = 0.38; 95%CI = 0.18-0.81, respectively). Compared to patients older than 61 years, the atrophy score in antrum was significantly lower in TT and CT patients. TLR4 Asp299Gly and Thr399Ile were not detected in all the patients. Our data suggests that CD14 promoter-159TT and T carrier were associated with a lower risk of developing gastric mucosal atrophy in H. pylori-infected patients of more than 61 years of age, and these genotypes may reduce the risk of intestinal-type gastric cancer.

Effect of common polymorphisms in folate uptake and metabolism genes on frequency of micronucleated lymphocytes in a South Australian cohort

Single nucleotide polymorphisms (SNPs) in genes that control folate uptake and metabolism may have an important effect on chromosomal stability. The present study investigated the effect of common SNPs in some of these critical genes on frequency of lymphocytes with micronuclei, a biomarker of chromosome breakage or loss. 164 individuals (94 males and 70 females) of different age ranging from 18 to 73 years participated in this study. Polymorphisms in GCPII (C1561T), RFC (G80A), MTR (A2756G), MTRR (A66G and C524T), TS (tandem repeats, 6 bp deletion in 3′-UTR region) and MTHFR (C677T and A1298C) were detected using PCR-based methods. Frequency of binucleated (BN) lymphocytes containing one or more micronuclei (BN-MN) was determined using the cytokinesis-block micronucleus (CBMN) assay and adjusted for the effects of age and gender. We did not find any significant association between BN-MN frequency and the common SNPs in GCPII, MTRR, TS and MTHFR genes. BN-MN frequency in individuals who carried at least one copy of the rarer G allele for MTR (A2756G) or were homozygotes for the more common G allele for RFC (G80A) had a 14% or 19% lower BN-MN frequency compared to the alternative genotypes for that SNP respectively. It was evident from genotype combination analyses that BN-MN frequency per 1000 BN cells was highest in those with the combined MTR (2756) AA and RFC (80) GA or AA genotype (13.6‰) and lowest in those with the combined MTR (2756) AG or GG and RFC (80) GG genotypes (9.5‰) ( P trend = 0.015). The RFC G80A and MTR A2756G polymorphisms and their combinations may be important variables that substantially affect lymphocyte BN-MN frequency in this South Australian cohort.

Polymorphisms in p53 and the p53 pathway: roles in cancer susceptibility and response to treatment

The p53 tumour suppressor protein lies at the crossroads of multiple cellular response pathways that control the fate of the cell in response to endogenous or exogenous stresses and inactivation of the p53 tumour suppressor signalling pathway is seen in most human cancers. Such aberrant p53 activity may be caused by mutations in the TP53 gene sequence producing truncated or inactive mutant proteins, or by aberrant production of other proteins that regulate p53 activity, such as gene amplification and overexpression of MDM2 or viral proteins that inhibit or degrade p53. Recent studies have also suggested that inherited genetic polymorphisms in the p53 pathway influence tumour formation, progression and/or response to therapy. In some cases, these variants are clearly associated with clinico-pathological variables or prognosis of cancer, whereas in other cases the evidence is less conclusive. Here, we review the evidence that common polymorphisms in various aspects of p53 biology have important consequences for overall tumour susceptibility, clinico-pathology and prognosis. We also suggest reasons for some of the reported discrepancies in the effects of common polymorphisms on tumourigenesis, which relate to the complexity of effects on tumour formation in combination with other oncogenic changes and other polymorphisms. It is likely that future studies of combinations of polymorphisms in the p53 pathway will be useful for predicting tumour susceptibility in the human population and may serve as predictive biomarkers of tumour response to standard therapies.

Effect of common polymorphisms in the HNF4? promoter on susceptibility to type 2 diabetes in the French Caucasian population

The gene encoding HNF-4alpha, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4alpha P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population. Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4alpha region had been shown. The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4alpha was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage. None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4alpha and type 2 diabetes in several ethnic groups.

Pharmacogenetics of lipid diseases

The genetic basis for most of the rare lipid monogenic disorders have been elucidated, but the challenge remains in determining the combination of genes that contribute to the genetic variability in lipid levels in the general population; this has been estimated to be in the range of 40-60 per cent of the total variability. Therefore, the effect of common polymorphisms on lipid phenotypes will be greatly modulated by gene-gene and gene-environment interactions. This approach can also be used to characterise the individuality of the response to lipid-lowering therapies, whether using drugs (pharmacogenetics) or dietary interventions (nutrigenetics). In this regard, multiple studies have already described significant interactions between candidate genes for lipid and drug metabolism that modulate therapeutic response--although the outcomes of these studies have been controversial and call for more rigorous experimental design and analytical approaches. Once solid evidence about the predictive value of genetic panels is obtained, risk and therapeutic algorithms can begin to be generated that should provide an accurate measure of genetic predisposition, as well as targeted behavioural modifications or drugs of choice and personalised dosages of these drugs.

Polymorphisms in Drug-metabolizing Genes and Risk of Head and Neck Squamous Cell Carcinoma

One kind of defense mechanism against development of cancer involves activities of a series of enzymes that metabolize and excrete potentially toxic compounds and repair subtle mistakes in DNA. Head and neck squamous cell carcinoma (HNSCC) is causally associated with tobacco use alone and also in combination with alcohol consumption. Most of the carcinogens present in tobacco and tobacco smoke are converted into DNA-reactive metabolites by cytochrome P450 enzymes and detoxification of these metabolites are performed by glutathione S-transferases and N- acetyltransferases in humans. Several of these genes display polymorphisms that could modulate enzymatic activities like activation and detoxification of carcino- gens. Molecular epidemiological studies, to assess the risk associated with metabolic polymorphisms and HNSCC, have shown that overall effect of common polymorphisms is moderate in terms of penetrance and relative risk. However, it may have a great population impact to assess the risk of cancer caused by tobacco habit. In this review, we have discussed the reported prevalences of these common polymorphisms and risk of HNSCC causally related to tobacco habit in different populations. Although a large number of studies with small sample sizes have been conducted, the results have been inconsistent and therefore inconclusive. So, future studies should be conducted with sufficiently large sample sizes to detect the moderate or even small risks in a population.

Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylenetetrahydrofolate to methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms of the human enzyme have been identified: 677C>T, which leads to the substitution of Ala-222 by valine, and 1298A>C, which leads to the replacement of Glu-429 by alanine; the former polymorphism is the most frequent genetic cause of mild hyperhomocysteinemia, a risk factor for cardiovascular disease. By using a baculovirus expression system, recombinant human MTHFR has been expressed at high levels and purified to homogeneity in quantities suitable for biochemical characterization. The Glu429Ala protein has biochemical properties that are indistinguishable from the wild-type enzyme. The Ala222Val MTHFR, however, has an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution; the resulting loss of activity is slowed in the presence of methyltetrahydrofolate or adenosylmethionine. This biochemical phenotype is in good agreement with predictions made on the basis of studies comparing wild-type Escherichia coli MTHFR with a mutant, Ala177Val, homologous to the Ala222Val mutant human enzyme [Guenther, B. D., et al. (1999) Nat. Struct. Biol. 6, 359-365].

Additive effect of common polymorphisms in apolipoprotein E and B genes on plasma lipid levels

Additive effect of common polymorphisms in apolipoprotein E and B genes on plasma lipid levels