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Polymorphisms in K13 and falcipain-2 associated with artemisinin resistance are not prevalent in Plasmodium falciparum isolated from Ugandan children.
Conrad, MD, Bigira, V, Kapisi, J, Muhindo, M, Kamya, MR, Havlir, DV, Dorsey, G, Rosenthal, PJ
PloS one. 2014;(8):e105690
Abstract
The emergence of resistance to artemisinin derivatives in Southeast Asia, manifested as delayed clearance of Plasmodium falciparum following treatment with artemisinins, is a major concern. Recently, the artemisinin resistance phenotype was attributed to mutations in portions of a P. falciparum gene (PF3D7_1343700) encoding kelch (K13) propeller domains, providing a molecular marker to monitor the spread of resistance. The P. falciparum cysteine protease falcipain-2 (FP2; PF3D7_1115700) has been shown to contribute to artemisinin action, as hemoglobin degradation is required for potent drug activity, and a stop mutation in the FP2 gene was identified in parasites selected for artemisinin resistance. Although delayed parasite clearance after artemisinin-based combination therapy (ACT) has not yet been noted in Uganda and ACTs remain highly efficacious, characterizing the diversity of these genes is important to assess the potential for resistance selection and to provide a baseline for future surveillance. We therefore sequenced the K13-propeller domain and FP2 gene in P. falciparum isolates from children previously treated with ACT in Uganda, including samples from 2006-7 (n = 49) and from 2010-12 (n = 175). Using 3D7 as the reference genome, we identified 5 non-synonymous polymorphisms in the K13-propeller domain (133 isolates) and 35 in FP2 (160 isolates); these did not include the polymorphisms recently associated with resistance after in vitro selection or identified in isolates from Asia. The prevalence of K13-propeller and FP2 polymorphisms did not increase over time, and was not associated with either time since prior receipt of an ACT or the persistence of parasites ≥2 days following treatment with an ACT. Thus, the K13-propeller and FP2 polymorphisms associated with artemisinin resistance are not prevalent in Uganda, and we did not see evidence for selection of polymorphisms in these genes.
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Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder.
Meira-Lima, I, Shavitt, RG, Miguita, K, Ikenaga, E, Miguel, EC, Vallada, H
Genes, brain, and behavior. 2004;(2):75-9
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Family and twin studies have supported a strong genetic factor in the etiology of obsessive-compulsive disorder (OCD), although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. In this cross-sectional study, we have examined the allelic and genotypic frequencies of a Val-158-Met substitution in the COMT gene, a 44-base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5-HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects. There were no observed differences in the frequencies of allele and genotype between patients and control groups for the COMT, the 5HTTLPR and the T102C 5HT2A gene polymorphisms. In contrast, a statistically significant difference between OCD patients and controls was observed on the genotypic distribution (chi(2) = 16.7, 2df, P = 0.0002) and on the allelic frequencies (chi(2) = 15.8, 1df, P = 0.00007) for the C516T 5HT2A gene polymorphism. The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in our sample. However, further studies using larger samples and family based methods are recommended to confirm these findings.
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Apolipoprotein E gene promoter -219G->T polymorphism increases LDL-cholesterol concentrations and susceptibility to oxidation in response to a diet rich in saturated fat.
Moreno, JA, Pérez-Jiménez, F, Marín, C, Gómez, P, Pérez-Martínez, P, Moreno, R, Bellido, C, Fuentes, F, López-Miranda, J
The American journal of clinical nutrition. 2004;(5):1404-9
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BACKGROUND The apolipoprotein E (APOE) gene promoter polymorphism (-219G-->T) has been associated with increased risk of myocardial infarction, premature coronary artery disease, and decreased plasma apolipoprotein E concentrations. OBJECTIVE We aimed to determine in healthy subjects whether this polymorphism modifies the susceptibility of LDL to oxidation and the lipid response to the content and quality of dietary fat. DESIGN Fifty-five healthy men with the APOE3/E3 genotype (7 GG, 38 GT, and 10 TT) completed 3 dietary periods, each lasting 4 wk. The first was a saturated fatty acid (SFA)-rich diet [38% fat-20% SFA and 12% monounsaturated fatty acid (MUFA)-and 47% carbohydrates (CHO)], which was followed by a CHO-rich diet (30% fat-<10% SFA and 12% MUFA-and 55% CHO) or a MUFA-rich diet (38% fat-<10% SFA and 22% MUFA-and 47% CHO) in a randomized crossover design. At the end of each dietary period, LDL oxidation susceptibility, lipids, and lipoproteins were measured. RESULTS Compared with carriers of the G allele, TT subjects had a significantly (P < 0.05) shorter lag time after the SFA diet. The replacement of the SFA diet by the CHO or MUFA diet induced a greater increase (P < 0.05) in lag time in the TT subjects than in the GG or GT subjects. Carriers of the T allele had higher LDL-cholesterol (P < 0.05) and apolipoprotein B (P < 0.05) plasma concentrations after the SFA diet than did GG subjects. Compared with GG subjects, carriers of the T allele had a significantly (P < 0.05) greater decrease in LDL cholesterol and apolipoprotein B when they changed from the SFA to the CHO diet. CONCLUSION The -219G-->T polymorphism may partially explain differences in individual responses to diet.
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Genetic polymorphism of GSTM1 and antioxidant supplementation influence lung function in relation to ozone exposure in asthmatic children in Mexico City.
Romieu, I, Sienra-Monge, JJ, Ramírez-Aguilar, M, Moreno-Macías, H, Reyes-Ruiz, NI, Estela del Río-Navarro, B, Hernández-Avila, M, London, SJ
Thorax. 2004;(1):8-10
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BACKGROUND We recently reported that antioxidant supplementation with vitamins C and E mitigated ozone related decline in forced expiratory flow (FEF(25-75)) in 158 asthmatic children in an area with high ozone exposure in Mexico City. METHODS A study was undertaken to determine whether deletion of glutathione S-transferase M1 (GSTM1 null genotype), a gene involved in response to oxidative stress, influences ozone related decline in FEF(25-75) and the benefit of antioxidant supplementation. RESULTS GSTM1 null children receiving placebo had significant ozone related decrements in FEF(25-75) (percentage change per 50 ppb of ozone 2.9 (95% CI -5.2 to -0.6), p=0.01); GSTM1 positive children did not. Conversely, the effect of antioxidants was stronger in children with the GSTM1 null genotype. CONCLUSIONS Asthmatic children with a genetic deficiency of GSTM1 may be more susceptible to the deleterious effects of ozone on the small airways and might derive greater benefit from antioxidant supplementation.
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Influence of polymorphisms in VDR and COLIA1 genes on the risk of osteoporotic fractures in aged men.
Alvarez-Hernández, D, Naves, M, Díaz-López, JB, Gómez, C, Santamaría, I, Cannata-Andía, JB
Kidney international. Supplement. 2003;(85):S14-8
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BACKGROUND Osteoporosis in chronic renal failure is a common finding caused by several factors, including age. In the last decade, the likely effect of genetic markers related with the appearance and evolution of osteoporosis has been mainly studied in women, with no categorical results. The aim of this study was to assess the influence of polymorphisms of the vitamin D receptor (VDR) and COLIA1 genes on the risk of osteoporotic fractures in men older than 50 years. METHODS The study population comprised 156 men, aged 64 +/- 9 (50-86), randomly selected from the population list of Oviedo, Spain. Prevalent vertebral fractures and incident non-vertebral fractures were identified, as well as several genetic polymorphisms. Prevalent vertebral fractures were considered according to the Genant grade 2 classifications. The analyzed genetic polymorphisms were located on restriction sites BsmI (B,b), ApaI (A,a), and TaqI (T,t) in the VDR and on Sp1 (S,s) in COLIA1. RESULTS Although none of the VDR gene polymorphisms separately analyzed showed any differences between fractured and non-fractured men, the utilization of haplotypes could be employed in order to find osteoporotic fractures in men. By contrast, the COLIA1 polymorphism was associated with osteoporotic fractures. The percentage of prevalent vertebral fractures was significantly higher in the "ss" genotype with respect to the other genotypes. These results show that in men, the "ss" genotype of COLIA1 polymorphism could be the best osteoporotic fracture risk genetic predictor, independent of bone mass values.
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Inducibility of CYP1A2 by omeprazole in vivo related to the genetic polymorphism of CYP1A2.
Han, XM, Ouyang, DS, Chen, XP, Shu, Y, Jiang, CH, Tan, ZR, Zhou, HH
British journal of clinical pharmacology. 2002;(5):540-3
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AIMS: To evaluate the effect of the CYP1A2*1C and CYP1A2*1F polymorphisms on the inducibility of CYP1A2 by omeprazole in healthy subjects. METHODS Mutations of CYP2C19 and CYP1A2 were identified by PCR-RFLP. Omeprazole, 120 mg day-1, was given to 12 extensive metabolizers (EM) with respect to CYP2C19 (six CYP1A2*1F/CYP1A2*1F and six CYP1A2*1C/CYP1A2*1F of CYP1A2) for 7 days. CYP1A2 activity was determined on three occasions, namely on day 1, day 9 and day 16 using the caffeine plasma index (the ratio of the concentrations of paraxanthine to caffeine), 6 h after oral administration of 200 mg caffeine. RESULTS There was a significant difference (P = 0.002) between the caffeine ratios for CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes on day 9, but not on day 1 or day 16 (P > 0.05). The changes in the ratios from day 9 to day 1 (48% +/- 20%vs 19% +/- 20%) and from day 9 to day 16 (50% +/- 31%vs 15% +/- 22%) were significantly different (P < 0.05) between the CYP1A2*1F/CYP1A2*1F and CYP1A2*1C/CYP1A2*1F genotypes. CONCLUSION The CYP1A2*1C and CYP1A2*1F genetic polymorphisms influenced the induction of CYP1A2 activity in vivo by omeprazole.
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Association between HERG K897T polymorphism and QT interval in middle-aged Finnish women.
Pietilä, E, Fodstad, H, Niskasaari, E, Laitinen P, PJ, Swan, H, Savolainen, M, Kesäniemi, YA, Kontula, K, Huikuri, HV
Journal of the American College of Cardiology. 2002;(3):511-4
Abstract
OBJECTIVES The aim of this study was to test whether a recently reported polymorphism in the HERG gene coding for the rapidly activating delayed rectifier K+ channel has influence on myocardial repolarization. BACKGROUND The length of myocardial repolarization, measured as the QT interval, has a hereditary component, but no genes that would explain the variability of repolarization have been identified in healthy subjects. METHODS QT intervals were measured from the 12-lead electrocardiogram in a random middle-aged population (226 men/187 women). The longest QT interval at any of the 12 leads (QTmax), QTV(2), and the Tpeak-Tend interval were used as measures of repolarization. Deoxyribonucleic acid samples were genotyped for the nucleotide 2690A>C variation of the HERG gene, corresponding to the HERG K(lysine)897T(threonine) amino acid polymorphism. RESULTS The allele frequencies were 0.84 (A) and 0.16 (C). Females with the genotype AC or CC had longer QTcmax (477 +/- 99 ms) and Tpeak-Tend intervals (143 +/- 95 ms) than females with the genotype AA (441 +/- 69 ms and 116 +/- 65 ms, p = 0.005 and p = 0.025, respectively). In males, the QTcmax and the Tpeak-Tend intervals did not differ between the genotypes. After adjustment for echocardiographic and various laboratory variables, the HERG K897T polymorphism remained as an independent predictor of QTcmax (p = 0.009) and the Tpeak-Tend intervals (p = 0.026) in females. CONCLUSIONS; The common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females.
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Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study.
Marian, AJ, Safavi, F, Ferlic, L, Dunn, JK, Gotto, AM, Ballantyne, CM
Journal of the American College of Cardiology. 2000;(1):89-95
Abstract
OBJECTIVES Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. BACKGROUND Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI). METHODS Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. RESULTS Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend. CONCLUSIONS Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD.