Genetic Variation In Key Genes Research Articles

69 Association of TERC Related Genetic Variation and Telomerase Activity with Ventricular Arrhythmias in Ischaemic Cardiomtyopathy

<h3>Introduction</h3> Implantable cardioverter defibrillators (ICD) reduce mortality in ischaemic cardiomyopathy patients at a high risk of ventricular arrhythmias (VA), which are the commonest cause of sudden death. However, ICDs are associated with morbidity and mortality. Importantly 67% of patients never receive an appropriate shock after ICD implantation under current guidelines, suggesting a need for better risk stratification. Telomere and telomerase activity (TA) in leukocytes have recently been shown to correlate with biological ageing and pathogenesis of cardiovascular diseases. Telomerase maintains telomere length and is composed of reverse transcriptase TERT and RNA template TERC. Evidence suggests that genetic variation in key genes has a key impact on TA. Association of SNP12696304 on chromosome 3q26 (at a locus that includes TERC) with telomere length has been shown. We investigated the association between genetic variation in SNP12696304 and leukocyte TA with incidence of VA in ischaemic cardiomyopathy patients. <h3>Methods</h3> 90 ischaemic cardiomyopathy Caucasian patients with primary prevention ICDs were recruited. Genomic DNA was isolated from venous blood samples. TA was measured by the telomere repeat amplification protocol and genotyping done using Taqman SNP assay. Continuous data were compared by unpaired T-test and categorical data by Chi-square test. Logistic regression was used to determine correlation of genotype and TA with VA. <h3>Results</h3> There was no significant difference in baseline demographics between patients with VA(Cases) and no-VA(Controls) as shown in Table 1. The TA was significantly higher in the cases and correlated with incidence of VA (p-value 0.02). No significant correlation between the genotype and VA was identified (C/C OR 1; C/G OR 0.54, CI 0.21 – 1.417, p-value 0.343; G/G OR 0.80, CI 0.198 – 3.236, p-value 0.907). There was a significant correlation between risk of VA and TA increase in C/C genotype (OR7.5, CI1–56.6, p-value 0.04). This correlation was not significant in the G/G or C/G genotype as shown in Figure 1. <h3>Conclusion</h3> There is a significant correlation between TA and VA in ischaemic cardiomyopathy patients. Moreover, homozygosity for C allele of SNP 12696304 (encoding TERC) significantly effects telomerase expression. Thus, increased TA predisposes individuals with C/C genotype to a higher incidence of VA. TA in this genotype can be developed as a biomarker to predict VA and guide ICD prescription in ischaemic cardiomyopathy.

23Association of TERC related genetic variation and telomerase activity with ventricular arrhythmias in ischaemic cardiomyopathy

Introduction: Implantable cardioverter defibrillators (ICD) reduce mortality in ischaemic cardiomyopathy patients at a high risk of ventricular arrhythmias (VA), which are the commonest cause of sudden death. However, ICDs are associated with morbidity and mortality. Importantly, 67% of patients never receive an appropriate shock after ICD implantation under current guidelines, suggesting a need for better risk stratification.Telomere and telomerase activity (TA) in leukocytes have recently been shown to correlate with biological ageing and pathogenesis of cardiovascular diseases. Telomerase maintains telomere length and is composed of a reverse transcriptase, TERT, and an RNA template, TERC. Evidence suggests that genetic variation in key genes has a key impact on TA. Association of SNP12696304 on chromosome 3q26 (at a locus that includes TERC) with telomere length has been shown. We investigated the association between genetic variation in SNP12696304 and leukocyte TA with incidence of VA in ischaemic cardiomyopathy patients. Methods: 90 ischaemic cardiomyopathy Caucasian patients with primary prevention ICDs were recruited. Genomic DNA was isolated from venous blood samples. TA was measured by the telomere repeat amplification (TRAP) protocol and genotyping done using Taqman SNP assay. Continuous data were compared by unpaired T-test and categorical data by Chi-square test. Logistic regression was used to determine correlation of genotype and TA with VA. Results: There was no significant difference in baseline demographics including age, WCC, gender, LVEF, GFR and follow up since ICD implant between patients with VA (Cases) and no-VA (Controls). The TA was significantly higher in the cases and correlated with incidence of VA (p-value 0.02). No significant correlation between the genotype and VA was identified (C/C OR 1; C/G OR 0.54, CI 0.21–1.417, p-value 0.343; G/G OR 0.80, CI 0.198–3.236, p-value 0.907). There was a significant correlation between risk of VA and TA increase in C/C genotype (OR7.5, CI1-56.6, p-value 0.04). This correlation was not significant in the G/G or C/G genotype as shown in Conclusion: There is a significant correlation between TA and VA in ischaemic cardiomyopathy patients. Moreover, homozygosity for C-allele of SNP12696304 (encoding TERC) signifcantly effects telomerase expression. Thus, increased TA predisposes individuals with C/C genotype to a higher incidence of VA. This needs to be validated in prospective studies for clinical use. ![Graphic][1] Figure 1 TA and genotype - cases vs controls [1]: /embed/inline-graphic-1.gif

Genetic variation in key genes associated with statin therapy in the Azores Islands (Portugal) healthy population

Background: Inter-individual variation in response to statins (efficacy and toxicity) has been described and may be due to polymorphisms implicated in drug pharmacokinetics or pharmacodynamics.Aim: This study investigates clinically relevant pharmacogenes underlying statin response in 170 healthy Azoreans.Methods: Eight SNPs in candidate genes—HMGCR (rs3846662, rs17238540, rs17244841), CETP (rs708272), APOE (rs7412, rs429358) and SLCO1B1 (rs2306283, rs4149056)—were genotyped.Results: The allele frequencies were similar to those reported for European derived populations, excepting SLCO1B1 c.388A>G (rs2306283), which has a significant difference when compared with the HapMap CEU population (p = 1 × 10−8). The results of statin efficacy showed that 9.1% of Azoreans are APOE4 carriers. This allele has been associated with lower LDLc reduction from statin therapy and also higher LDLc levels at baseline. Regarding SLCO1B1, associated with statin toxicity, 1.8% of individuals have two reduced-function alleles (c.521CC).Conclusion: The results contribute to overcome the lack of knowledge regarding the frequency of pharmacogenetic SNPs and their corresponding haplotypes in targeted populations, such as Azores islands. Moreover, the present work constitutes an initial step to implementing pharmacogenomics in clinical practice where physicians could use a patient’s genetic make-up to optimize statin therapy, regarding efficiency and myopathy risk.

Common genetic variation within IGFI, IGFII, IGFBP-1, and IGFBP-3 and endometrial cancer risk

Objective.The insulin-like growth factor (IGF) pathway plays a critical role in the growth and development of the uterus and is believed to function as a mediator of steroid hormone actions in the endometrium. The local expression of genes encoding IGFs and IGF-binding proteins (IGFBPs) is important in determining IGF bioactivity in the uterus. Genetic variation in key genes within the IGF pathway may influence the rate of cellular proliferation and differentiation in the uterus and ultimately affect the risk of endometrial cancer. Our hypothesis is that variant alleles in key genes involved in the IGF pathway will influence the development of endometrial cancer. Methods.We conducted a case-control study nested within the Nurses' Health Study (NHS) and the Women's Health Study (WHS) to investigate the association between forty-four polymorphisms within IGFI, IGFII, IGFBP-1, and IGFBP-3 with endometrial cancer risk using 692 invasive endometrial cancer cases and 1723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer. Results.We observed an inverse association with IGFII rs3741211 and endometrial cancer risk (OR=0.79 (95% CI: 0.63, 0.99)) and IGFII rs1004446 and endometrial cancer risk (OR=0.80 (95% CI: 0.68, 0.94)). We also observed an inverse association with IGFBP-3 rs2453839 and endometrial cancer risk (OR=0.81 (95%CI: 0.67, 0.98). However, we did not observe any statistically significant associations with the polymorphisms in IGFI and IGFBP1 and endometrial cancer risk. Conclusions.Genetic variation with IGFII and IGFBP-3 may influence endometrial cancer risk in Caucasians. Polymorphisms in IGFI and IGFBP-1 were not associated with endometrial cancer risk, but further research is needed.

Genetic Factors Influencing Cytarabine Therapy

The mainstay of acute myeloid leukemia chemotherapy is the nucleoside analog cytarabine (ara-C). Numerous studies suggest that the intracellular concentrations of the ara-C active metabolite, ara-CTP, vary widely among patients and, in turn, are associated with variability in clinical response to acute myeloid leukemia treatment. Thus, genetic variation in key genes in the ara-C metabolic pathway--specifically, deoxycytidine kinase (a rate-limiting activating enzyme), 5 nucleotidase, cytidine deaminase and deoxycytidylate deaminase (all three are inactivating enzymes), human equilibrative nucleoside transporter (ara-C uptake transporter) and ribonucleotide reductase (RRM1 and RRM2--enzymes regulating intracellular deoxycytidine triphosphate pools)--form the molecular basis of the interpatient variability observed in intracellular ara-CTP concentrations and response to ara-C. Understanding genetic variants in the key candidate genes involved in the metabolic activation of ara-C, as well as the pharmacodynamic targets of ara-C, will provide an opportunity to identify patients at an increased risk of adverse reactions or decreased likelihood of response, based upon their genetic profile, which in future could help in dose optimization to reduce drug toxicity without compromising efficacy. The pharmacogenetic studies on ara-C would also be equally applicable to other nucleoside analogs, such as gemcitabine, decitabine, clofarabine and so on, which are metabolized by the same pathway.

Defining Targets for Investigating the Pharmacogenomics of Adverse Drug Reactions to Antifungal Agents

Adverse drug reactions (ADRs) associated with antifungal therapy are major problems in patients with invasive fungal infections. Whether by clinical history or patterns of genetic variation, the identification of patients at risk for ADRs should result in improved outcomes while minimizing deleterious side effects. A major contributing factor to ADRs with antifungal agents relates to drug distribution, metabolism and excretion. Genetic variation in key genes can alter the structure and expression of genes and gene products (e.g., proteins). Thus far, the effort has focused on identifying polymorphisms with either empirical or predicted in silico functional consequences; the best candidate genes encode phase I and II drug-metabolizing enzymes (e.g., CYP2C19 and N-acetyltransferase), plasma proteins (albumin and lipoproteins) and drug transporters (P-glycoprotein and multidrug resistance proteins), which can affect the disposition of antifungal agents, eventually leading to dose-dependent (type A) toxicity. Less is known regarding the key genes that interact with antifungal agents, resulting in idiosyncratic (type B) ADRs. The possible role of certain gene products and genetic polymorphisms in the toxicities of antifungal agents are discussed in this review. The preliminary data address the following: low-density lipoproteins and cholesteryl ester transfer protein in amphotericin B renal toxicity; toll-like receptor 1 and 2 in amphotericin B infusion-related ADRs; phosphodiesterase 6 in voriconazole visual adverse events; flavin-containing monooxygenase, glutathione transferases and multidrug resistance proteins 1 and 2 in ketoconazole and terbinafine hepatotoxicity; CYP enzymes and P-glycoprotein in drug interactions between azoles and coadministered medications; multidrug resistance proteins 8 and 9 on 5-flucytosine bone marrow toxicity; and mast cell activation in caspofungin histamine release. This will focus on high-priority candidate genes, which could provide a starting point for molecular studies to elucidate the potential mechanisms for understanding toxicity associated with antifungal drugs as well as identifying candidate genes for large population prospective genetic association studies.

Germ-Line Genetic Variation in the Key Androgen-Regulating Genes Androgen Receptor, Cytochrome P450, and Steroid-5-α-Reductase Type 2 Is Important for Prostate Cancer Development

Prostate cancer risk may be influenced by single genetic variants in the hormone-regulating genes androgen receptor (AR), cytochrome P450 (CYP17), and steroid-5-alpha-reductase type 2 (SRD5A2). In this study, we comprehensively investigated polymorphisms in these three loci and their joint effect in a large population-based study. We selected 23 haplotype-tagging single-nucleotide polymorphisms (htSNP) that could uniquely describe >95% of the haplotypes (6 in AR, 6 in CYP17, and 11 in SRD5A2). These htSNPs were then genotyped in the Cancer Prostate in Sweden population (2,826 case subjects and 1,705 controls). We observed significant association for several SNPs in the AR gene (P = 0.004-0.02) and CYP17 (P = 0.009-0.05) and one SNP in SRD5A2 (P = 0.02). Carriers of the most common AR haplotype had a significant excess risk to develop prostate cancer [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.1-1.5; P = 0.002], yielding an estimated population attributable risk of 16% (95% CI, 0.06-0.25). Combining risk alleles from these genes yielded a 12% risk increase for each additional high-risk allele carried (95% CI, 1.1-1.2; P for trend = 9.2 x 10(-5)), with an overall OR of 1.87 (95% CI, 1.0-3.4) for carriers of all five included risk alleles, an OR of 2.13 (P for trend = 8 x 10(-4)) for advanced disease, and an OR of 4.35 (P for trend = 7 x 10(-5)) for disease onset before age 65 years. Genetic variation in key genes in the androgen pathway is important for development of prostate cancer and may account for a considerable proportion of all prostate cancers. Carriers of five high-risk alleles in the AR, CYP17, and SRD5A2 genes are at approximately 2-fold excess risk to develop prostate cancer.

Immunohistochemical localization of insulin-like growth factor-I (IGF-I), its receptor and IGF-binding protein-1 (IGFBP-1) in the human placental membrane

The insulin-like growth factor (IGF) pathway plays a critical role in the growth and development of the uterus and is believed to function as a mediator of steroid hormone actions in the endometrium. The local expression of genes encoding IGFs and IGF-binding proteins (IGFBPs) is important in determining IGF bioactivity in the uterus. Genetic variation in key genes within the IGF pathway may influence the rate of cellular proliferation and differentiation in the uterus and ultimately affect the risk of endometrial cancer. Our hypothesis is that variant alleles in key genes involved in the IGF pathway will influence the development of endometrial cancer.We conducted a case-control study nested within the Nurses' Health Study (NHS) and the Women's Health Study (WHS) to investigate the association between forty-four polymorphisms within IGFI, IGFII, IGFBP-1, and IGFBP-3 with endometrial cancer risk using 692 invasive endometrial cancer cases and 1723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer.We observed an inverse association with IGFII rs3741211 and endometrial cancer risk (OR = 0.79 (95% CI: 0.63, 0.99)) and IGFII rs1004446 and endometrial cancer risk (OR = 0.80 (95% CI: 0.68, 0.94)). We also observed an inverse association with IGFBP-3 rs2453839 and endometrial cancer risk (OR = 0.81 (95%CI: 0.67, 0.98). However, we did not observe any statistically significant associations with the polymorphisms in IGFI and IGFBP1 and endometrial cancer risk.Genetic variation with IGFII and IGFBP-3 may influence endometrial cancer risk in Caucasians. Polymorphisms in IGFI and IGFBP-1 were not associated with endometrial cancer risk, but further research is needed.

Measurements of fetoplacental blood volume

The insulin-like growth factor (IGF) pathway plays a critical role in the growth and development of the uterus and is believed to function as a mediator of steroid hormone actions in the endometrium. The local expression of genes encoding IGFs and IGF-binding proteins (IGFBPs) is important in determining IGF bioactivity in the uterus. Genetic variation in key genes within the IGF pathway may influence the rate of cellular proliferation and differentiation in the uterus and ultimately affect the risk of endometrial cancer. Our hypothesis is that variant alleles in key genes involved in the IGF pathway will influence the development of endometrial cancer.We conducted a case-control study nested within the Nurses' Health Study (NHS) and the Women's Health Study (WHS) to investigate the association between forty-four polymorphisms within IGFI, IGFII, IGFBP-1, and IGFBP-3 with endometrial cancer risk using 692 invasive endometrial cancer cases and 1723 matched controls. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer.We observed an inverse association with IGFII rs3741211 and endometrial cancer risk (OR = 0.79 (95% CI: 0.63, 0.99)) and IGFII rs1004446 and endometrial cancer risk (OR = 0.80 (95% CI: 0.68, 0.94)). We also observed an inverse association with IGFBP-3 rs2453839 and endometrial cancer risk (OR = 0.81 (95%CI: 0.67, 0.98). However, we did not observe any statistically significant associations with the polymorphisms in IGFI and IGFBP1 and endometrial cancer risk.Genetic variation with IGFII and IGFBP-3 may influence endometrial cancer risk in Caucasians. Polymorphisms in IGFI and IGFBP-1 were not associated with endometrial cancer risk, but further research is needed.