| 1. |
- Boiso, Samuel, et al.
(författare)
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ABCB1 gene polymorphisms are associated with suicide in forensic autopsies
- 2013
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Ingår i: Pharmacogenetics & Genomics. - : Lippincott, Williams and Wilkins. - 1744-6872 .- 1744-6880. ; 23:9, s. 463-469
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Tidskriftsartikel (refereegranskat)abstract
- Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199Gandgt;A, 1236Candgt;T, 2677Gandgt;T/A, and 3435Candgt;T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.
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| 2. |
- Broberg Palmgren, Karin, et al.
(författare)
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The GSTP1 Ile105 Val polymorphism modifies the metabolism of toluene di-isocyanate.
- 2010
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 20:2, s. 104-111
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Toluene di-isocyanate (TDI) is widely used in the production of polyurethane foams and paints. As TDI causes respiratory disease in only a fraction of exposed workers, genetic factors may play a key role in disease susceptibility. Polymorphisms in TDI metabolising genes may affect elimination kinetics, resulting in differences in body retention, and in its turn differences in adverse effects. OBJECTIVES: To analyze how genotype modifies the associations between (i) TDI in air (2,4-TDI and 2,6-TDI) and its metabolites toluene diamine (TDA; 2,4-TDA and 2,6-TDA) in hydrolyzed urine; and (ii) 2,4-TDA and 2,6-TDA in hydrolyzed plasma and 2,4-TDA and 2,6-TDA in urine. METHODS: Workers exposed to TDI were analyzed for 2,4-TDI and 2,6-TDI in air (N=70), 2,4-TDA and 2,6-TDA in hydrolyzed urine (N=124) and in plasma (N=128), and genotype: CYP1A1*2A, CYP1A1*2B, GSTA1-52, GSTM1O, GSTM3B, GSTP1 I105V, GSTP1 A114V, GSTT1O, MPO-463, NAT1*3, *4, *10, *11, *14, *15, NAT2*5, *6, *7, and SULT1A1 R213H. RESULTS: GSTP1 105 strongly modified the relationship between 2,4-TDA in plasma and in urine: ValVal carriers had about twice as steep regression slope than IleIle carriers. A similar pattern was found for 2,6-TDA. CYP1A1*2A, GSTM1, GSTP1, GSTT1, and MPO possibly influenced the relationship between TDA in plasma and urine. CONCLUSION: Our results show, for the first time, genetic modification on the human TDI metabolism. The findings suggest that GSTP1 genotype should be considered when evaluating biomarkers of TDI exposure in urine and plasma. Moreover, the results support earlier findings of GSTP1 105 Val as protective against TDI-related asthma.
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| 3. |
- Cavallari, Larisa H., et al.
(författare)
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Association of the GGCX (CAA) 16/17 repeat polymorphism with higher warfarin dose requirements in African Americans
- 2012
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 22:2, s. 152-158
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Tidskriftsartikel (refereegranskat)abstract
- Objective Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the gamma-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population.Methods A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA) n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5mg/day alone and in the context of other variables known to influence dose variability.Results The GGCX rs10654848 (CAA) 16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P = 0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA) 16 repeat frequency of only 0.27% (P = 0.008 compared with African Americans).Conclusion These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA) 16/17 repeat compared with Caucasians. Pharmacogenetics and Genomics 22: 152-158 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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| 4. |
- Christensen, Mette M H, et al.
(författare)
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The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c
- 2011
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Ingår i: Pharmacogenetics & Genomics. - : Lippincott, Williams and Wilkins. - 1744-6872 .- 1744-6880. ; 21:12, s. 837-850
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this study was to evaluate the effect of genetic variations in OCT1, OCT2, MATE1, MATE 2, and PMAT on the trough steady-state plasma concentration of metformin and hemoglobin A1c (Hb1Ac). less thanbrgreater than less thanbrgreater thanMethod The South Danish Diabetes Study was a 2 x 2 x 2 factorial, prospective, randomized, double-blind, placebo-controlled, multicentre study. One hundred and fifty-nine patients received 1 g of metformin, twice daily continuously, and 415 repeated plasma metformin measurements were obtained after 3, 6, and 9 months of treatment. less thanbrgreater than less thanbrgreater thanResults The mean trough steady-state metformin plasma concentration was estimated to be 576 ng/ml (range, 54-4133 ng/ml, rho = 0.55) and correlated to the number of reduced function alleles in OCT1 (none, one or two: 642, 542, 397 ng/ml; P = 0.001). The absolute decrease in Hb1Ac both initially and long term was also correlated to the number of reduced function alleles in OCT1 resulting in diminished pharmacodynamic effect of metformin after 6 and 24 months. less thanbrgreater than less thanbrgreater thanConclusion In a large cohort of type 2 diabetics, we either confirm or show for the first time: (a) an enormous 80-fold) variability in trough steady-state metformin plasma concentration, (b) OCT1 activity affects metformin steady-state pharmacokinetics, and (c) OCT1 genotype has a bearing on HbA1c during metformin treatment.
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| 5. |
- Edvardsen, Hege, et al.
(författare)
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Experimental validation of data mined single nucleotide polymorphisms from several databases and consecutive dbSNP builds
- 2006
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Ingår i: Pharmacogenetics & Genomics. - : Ovid Technologies (Wolters Kluwer Health). - 1744-6872 .- 1744-6880. ; 16:3, s. 207-217
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Tidskriftsartikel (refereegranskat)abstract
- Rapid development in the annotation of human genetic variation has increased the numbers of single nucleotide polymorphisms (SNPs) in candidate genes by several orders of magnitude. The selection of both useful target SNPs; for disease-gene association studies and SNPs associated with the treatment response is therefore an increasingly challenging task. We describe a workflow for selecting SNPs based on their putative function and frequency in candidate genes extracted from PubMed resources. The annotation of each SNP and its frequency in a Caucasian population was assessed in several databases. Approximately 4000 SNPs were identified from an initial 233 candidate genes. In a case study, we performed actual genotyping of 1030 of these SNPs in 213 genes and obtained 710 successfully genotyped SNPs. Using the flow-chart outlined here, only 87 SNPs were monomorphic (approximately 12%). This study reports the frequency of SNPs in a Caucasian population, selected in silico, using a candidate gene approach and validated by actually genotyping 193 individuals. The selected genotypes represent a valuable set of verified candidate SNPs for pharmacogenetic studies in Caucasian populations.
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| 6. |
- Gardner, Renee M, et al.
(författare)
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Pregnancy and the methyltransferase genotype independently influence the arsenic methylation phenotype.
- 2012
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 22:7, s. 508-516
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The methyltransferase genotype and pregnancy both influence the arsenic metabolism phenotype, but it is unknown whether these factors interact, explaining the drastic changes in the efficiency of arsenic metabolism observed among pregnant women. The aim of this study was to evaluate the relative contribution of the methyltransferase genotype and pregnancy to the arsenic metabolism phenotype. METHODS: We studied longitudinally the arsenic metabolite pattern in urine (at approximately gestational weeks 8, 14, and 30) of 303 women exposed to arsenic through drinking water and food in rural Bangladesh. Urinary arsenic metabolites were measured by high-performance liquid chromatography-inductively coupled plasma mass spectrometry. Data were available on genotypes for 16 polymorphisms, combined as haplotypes, in three methyltransferases: arsenic(+III)methyltransferase (AS3MT) and DNA-methyltransferases 1a and 3b (DNMT1a and DNMT3b). Changes in the arsenic metabolite pattern over time were evaluated by haplotype using logistic quantile regression. RESULTS: All four AS3MT haplotypes and all three DNMT1a haplotypes significantly influenced the metabolite pattern in the pregnant women, with consistent effects of genotype over the entire course of pregnancy. No interaction was found between the haplotypes and pregnancy-related changes in the arsenic metabolism phenotype. DNMT3b haplotypes did not significantly influence the metabolite pattern. We observed a pregnancy-attributable decrease of 5.7% in the most risk-associated monomethylated metabolite, methylarsonic acid, whereas changes between 1.6 and 5.3% of methylarsonic acid could be attributed to haplotypes of AS3MT and DNMT1a. CONCLUSION: Independent of the genotype, the efficiency of arsenic methylation increased markedly over the course of pregnancy. The effect of pregnancy on the metabolite pattern during the observational period was greater than the effect of genotype.
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| 7. |
- Lindqvist Appell, Malin, et al.
(författare)
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Characterization of a novel sequence variant, TPMT*28, in the human thiopurine methyltransferase gene
- 2010
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 20:11, s. 700-707
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Tidskriftsartikel (refereegranskat)abstract
- Background The activity of the human enzyme thiopurine methyltransferase (TPMT) varies greatly between individuals because of genetic polymorphism. TPMT is involved in the detoxification and activation of thiopurines such as 6-mercaptopurine, 6-thioguanine, and azathioprine. These drugs are used in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. A total of 29 sequence variants have been identified so far in the TPMT gene. However, most of these variants are rare and not fully characterized. Methods and results In this study, we describe the identification and characterization of a novel TPMT sequence variant, originally found in a Swedish man of Italian origin. Sequencing of the variable number tandem repeats region of the TPMT promoter and exons III-X revealed a T-to-C transition at nucleotide 611, causing an amino acid substitution from isoleucine to threonine at amino acid 204, positioned in an alpha-helix, approximately 16A from the active site. This new variant was found in the patient and in his son. Both had intermediate enzyme activity (8.1 U/ml packed red blood cells and 8.8 U/ml packed red blood cells, respectively) and neither carried other variants in the coding region of the gene. To be able to study this variant in more detail, the TPMT*28 variant was expressed in Escherichia coli, and an in-vitro characterization of the variant revealed that the protein was destabilized and showed a stronger tendency towards degradation at 37 degrees C than the wild-type protein. The individuals carrying the TPMT*28 variant had less TPMT protein and lower TPMT activity in both red and white blood cells compared with a wild-type control. Conclusions We present a detailed in-vivo and in-vitro characterization of a novel TPMT sequence variant (TPMT*28) causing decreased TPMT activity. Individuals carrying TPMT*28 might have an increased risk for developing severe side effects if treated with conventional doses of thiopurines. Pharmacogenetics and Genomics 20: 700-707 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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| 8. |
- Lindqvist Appell, Malin, et al.
(författare)
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Nomenclature for alleles of the thiopurine methyltransferase gene
- 2013
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Ingår i: Pharmacogenetics & Genomics. - : Lippincott, Williams and Wilkins. - 1744-6872 .- 1744-6880. ; 23:4, s. 242-248
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Forskningsöversikt (refereegranskat)abstract
- The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (Gandgt;A) from TPMT*24 to TPMT*30 and position 611 (Tandgt;C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged. Pharmacogenetics and Genomics 23: 242-248
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| 9. |
- Romerius, Patrik, et al.
(författare)
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Estrogen receptor α single nucleotide polymorphism modifies the risk of azoospermia in childhood cancer survivors
- 2011
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872 .- 1744-6880. ; 21:5, s. 263-269
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Cancer treatment in childhood leads to permanent azoospermia in a significant number of boys and those who are diagnosed with cancer before puberty do not have the option of pretreatment cryopreservation of spermatozoa. However, there is an interindividual variation in the sensitivity to gonadotoxic effects of cancer therapy, which probably is due to genetic factors. Identification of genetic markers for the risk of azoospermia in childhood cancer survivors may help in identifying boys to whom testicular cryopreservation should be offered. METHODS: Fifty-one single nucleotide polymorphisms (SNPs) being markers of 12 different haplotype blocks in the androgen receptor, estrogen receptor (ER) α and ER β genes were examined in 127 adult childhood cancer survivors. RESULTS: In ERα, markers of one specific haplotype block (rs2207396, rs9340958, rs9340978) were associated with an increased risk of azoospermia. Compared with those with the GG genotype, patients being heterozygous for the A allele in rs2207396 had a significantly increased risk of azoospermia [odds ratio (OR): 3.8; 95% confidence interval: 1.5-9.5; P=0.008], this OR being even higher in the subgroup treated with alkylating drugs (OR: 8.8; 95% confidence interval: 2.1-36; P=0.004). In this subgroup, 48% of the patients carried the A allele of rs2207396, this proportion being 70% among the azoospermic patients. CONCLUSION: Use of genetic markers of high risk of posttreatment azoospermia may, in the future, prove an important clinical tool in selection of boys to whom preservation of testicular tissue before cancer therapy should be offered.
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| 10. |
- Schimek, Vanessa, et al.
(författare)
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JMJD1C knockdown affects myeloid cell lines proliferation, viability, and gemcitabine/carboplatin-sensitivity
- 2021
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Ingår i: Pharmacogenetics & Genomics. - : LIPPINCOTT WILLIAMS & WILKINS. - 1744-6872 .- 1744-6880. ; 31:3, s. 60-67
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Chemotherapy-induced hematological toxicities are potentially life-threatening adverse drug reactions that vary between individuals. Recently, JMJD1C has been associated with gemcitabine/carboplatin-induced thrombocytopenia in non-small-cell lung cancer patients, making it a candidate marker for predicting the risk of toxicity. This study investigates if JMJD1C knockdown affects gemcitabine/carboplatin-sensitivity in cell lines. Methods Lentiviral transduction-mediated shRNA knockdown of JMJD1C in the cell lines K562 and MEG-01 were performed using shRNA#32 and shRNA#33. The knockdown was evaluated using qPCR. Cell proliferation, viability, and gemcitabine/carboplatin-sensitivity were subsequently determined using cell counts, trypan blue, and the MTT assay. Results ShRNA#33 resulted in JMJD1C downregulation by 56.24% in K562 and 68.10% in MEG-01. Despite incomplete knockdown, proliferation (reduction of cell numbers by 61-68%, day 7 post-transduction) and viability (reduction by 21-53%, day 7 post-transduction) were impaired in K562 and MEG-01 cells. Moreover, JMJD1C knockdown reduced the gemcitabine IC50-value for K562 cells (P < 0.01) and MEG-01 cells (P < 0.05) compared to scrambled shRNA control transduced cells. Conclusions Our results suggest that JMJD1C is essential for proliferation, survival, and viability of K562 and MEG-01 cells. Further, JMJD1C also potentially affects the cells gemcitabine/carboplatin-sensitivity. Although further research is required, the findings show that JMJD1C could have an influential role for gemcitabine/carboplatin-sensitivity.
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