ABCB1 p.Ala80Gly
| Predicted by SNAP2: | C: N (53%), D: D (71%), E: D (71%), F: D (59%), G: N (61%), H: D (66%), I: N (93%), K: D (66%), L: N (82%), M: D (59%), N: N (61%), P: D (75%), Q: N (57%), R: N (53%), S: N (87%), T: N (93%), V: N (97%), W: D (63%), Y: D (71%), |
| Predicted by PROVEAN: | C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N, |
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[hide] Association of ABCB1/MDR1 and OPRM1 gene polymorph... Clin Pharmacol Ther. 2008 Apr;83(4):559-66. Epub 2007 Sep 26. Campa D, Gioia A, Tomei A, Poli P, Barale R
Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief.
Clin Pharmacol Ther. 2008 Apr;83(4):559-66. Epub 2007 Sep 26., [PMID:17898703]
Abstract [show]
The pharmacokinetics and pharmacodynamics of morphine are under the control of several polymorphic genes, which can account for part of the observed interindividual variation in pain relief. We focused on two such genes: ABCB1/MDR1, a major determinant of morphine bioavailability, and OPRM1, which encodes for the mu-opioid receptor, the primary site of action for morphine. One hundred and forty-five patients of Italian origin undergoing morphine therapy were genotyped for the single-nucleotide polymorphism (SNP) C3435T of ABCB1/MDR1 and for the A80G SNP of OPRM1. Pain relief variability was significantly (P<0.0001) associated with both polymorphisms. Combining the extreme genotypes of both genes, the association between patient polymorphism and pain relief improved (P<0.00001), allowing the detection of three groups: strong responders, responders, and non-responders, with sensitivity close to 100% and specificity more than 70%. This study provides a good example of the possible clinical use of pharmacogenetics.
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No. Sentence Comment
2 One hundred and forty-five patients of Italian origin undergoing morphine therapy were genotyped for the single-nucleotide polymorphism (SNP) C3435T of ABCB1/MDR1 and for the A80G SNP of OPRM1.
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ABCB1 p.Ala80Gly 17898703:2:175
status: NEW[hide] Genetic determinants of methotrexate toxicity in r... Eur J Clin Pharmacol. 2008 Nov;64(11):1057-68. Epub 2008 Jul 8. Bohanec Grabar P, Logar D, Lestan B, Dolzan V
Genetic determinants of methotrexate toxicity in rheumatoid arthritis patients: a study of polymorphisms affecting methotrexate transport and folate metabolism.
Eur J Clin Pharmacol. 2008 Nov;64(11):1057-68. Epub 2008 Jul 8., [PMID:18607581]
Abstract [show]
OBJECTIVE: Methotrexate (MTX) is a disease-modifying antirheumatic drug used in the treatment of rheumatoid arthritis (RA). Genetic polymorphisms of reduced folate carrier (RFC1 A80G), P-glycoprotein (MDR1 G2677T>A/C and C3435T), 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TS 2R-->3R), methionine synthase (MS A2756G) and methionine synthase reductase (MTRR A66G) modify MTX transport and metabolic effects and may influence the treatment response. METHODS: A genotyping approach was used to determine the studied polymorphisms in 213 RA patients. RESULTS: We observed that 56 (26.3%) patients discontinued MTX treatment due to poor response and/or toxicity. RFC1 A80G and MDR1 C3435T polymorphisms increased the risk for overall MTX toxicity (P = 0.039, OR = 3.574, 95% CI = 1.065-11.993 and P = 0.032, OR = 7.801, 95% CI = 1.194-50.960 respectively), while MTHFR A1298C polymorphism had a protective effect on overall MTX toxicity (P = 0.027, OR = 0.170, 95% CI = 0.035-0.820). CONCLUSION: Our results suggest that genetic polymorphisms in the folate metabolic pathway and MTX transporters modify the toxicity but not the efficacy of MTX treatment.
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1 Genetic polymorphisms of reduced folate carrier (RFC1 A80G), P-glycoprotein (MDR1 G2677T>A/C and C3435T), 5,10-methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), thymidylate synthase (TS 2R→3R), methionine synthase (MS A2756G) and methionine synthase reductase (MTRR A66G) modify MTX transport and metabolic effects and may influence the treatment response.
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ABCB1 p.Ala80Gly 18607581:1:54
status: NEW4 RFC1 A80G and MDR1 C3435T polymorphisms increased the risk for overall MTX toxicity (P=0.039, OR=3.574, 95% CI=1.065-11.993 and P=0.032, OR=7.801, 95% CI= 1.194-50.960 respectively), while MTHFR A1298C polymorphism had a protective effect on overall MTX toxicity (P=0.027, OR=0.170, 95% CI=0.035-0.820).
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ABCB1 p.Ala80Gly 18607581:4:5
status: NEW18 The most common SNP in RFC1 is A80G (rs1051266), which results in an amino acid substitution of Arg with His at position 27 that may alter the affinity for folate [8].
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ABCB1 p.Ala80Gly 18607581:18:31
status: NEW68 To determine RFC1 A80G polymorphism, the region encompassing the A80G polymorphic site was amplified and PCR products were digested with HhaII (New England Biolabs) as previously described [32].
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ABCB1 p.Ala80Gly 18607581:68:18
status: NEWX
ABCB1 p.Ala80Gly 18607581:68:65
status: NEW104 The frequencies of RFC1 A80G, MTHFR C677T and A1298C, MS A2756G, MTRR A66G, TS 2R→3R, MDR1 G2677A/T and MDR1 C3435T polymorphisms were determined in all the patients and are presented in Table 3.
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ABCB1 p.Ala80Gly 18607581:104:24
status: NEW107 No association between RFC1 A80G, MTHFR C677T and A1298C, MS A2756G, MTRR A66G, TS 2R→3R, MDR1 G2677A/T and MDR1 C3435T polymorphisms and ESR, CRP and DAS28 values was observed in a multiple regression model adjusted for sex, age, disease duration, treatment duration, RF seropositivity and MTX dose (data not shown).
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ABCB1 p.Ala80Gly 18607581:107:28
status: NEW110 Regarding MTX treatment response, RFC1 A80G, MTHFR C677T and A1298C, MS A2756G, MTRR A66G, TS 2R→3R, MDR1 G2677A/T and MDR1 C3435T polymorphisms did not influence the efficacy of the MTX treatment (data not shown).
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ABCB1 p.Ala80Gly 18607581:110:39
status: NEW111 Nevertheless, the frequencies of RFC1 A80G polymorphism were significantly different in patients suffering from AEs and in patients without the presence of AEs (AA+AG: 66.9 and 83.1%, GG: 33.1 and 16.9% respectively; P=0.038).
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ABCB1 p.Ala80Gly 18607581:111:38
status: NEW115 When patients receiving concomitant therapy with MTX and other DMARDs were excluded from the logistic regression model, an even stronger impact of RFC1 A80G polymorphism on the overall MTX toxicity was observed in the remaining 150 patients (P=0.039, OR=3.574, 95% CI= 1.065-11.993).
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ABCB1 p.Ala80Gly 18607581:115:152
status: NEW120 When AEs were specified, the data revealed strong association between the occurrence of infections and RFC1 A80G polymorphism, since patients with RFC1 80GG genotype had a 15.067-fold higher risk for developing infections as compared to patients with RFC1 80AA/ AG genotype (P=0.006, 95% CI=2.182-104.060, Table 4).
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ABCB1 p.Ala80Gly 18607581:120:108
status: NEW124 When investigating SNPs in MTX transporters we observed a significant association between RFC1 A80G polymorphism and low-dose MTX toxicity.
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ABCB1 p.Ala80Gly 18607581:124:95
status: NEW125 Of all the studied polymorphisms, RFC1 A80G had the strongest impact on the overall MTX toxicity and on the risk for developing infections, but did not influence MTX efficacy.
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ABCB1 p.Ala80Gly 18607581:125:39
status: NEW126 In vitro studies on human skin fibroblasts showed that RFC1 A80G polymorphism alters the affinity for folate and may thus result in altered cellular MTX concentrations [8].
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ABCB1 p.Ala80Gly 18607581:126:60
status: NEW130 Nevertheless, studies investigating the influence of the RFC1 A80G polymorphism and low-dose MTX treatment response reported contradictory results.
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ABCB1 p.Ala80Gly 18607581:130:62
status: NEW132 Patients with the MTHFR 677CT and/or TT genotype had significantly higher plasma total homocysteine concentrations as compared to patients with the MTHFR 677CC genotype Table 4 Occurrence of specific MTX-induced AEs according to risk genotypes Genotype Infections Dermatological complaint Bone-marrow toxicity Yes, n (%) No, n (%) Yes, n (%) No, n (%) Yes, n (%) No, n (%) RFC1 80 AA+AG 2 (22.2) 108 (76.6) 10 (55.6) 100 (75.8) 15 (13.6) 95 (86.4) GG 7 (77.8)a 33 (23.4)a 8 (44.4) 32 (24.2) 6 (15.0) 34 (85.0) MTRR 66 AA 2 (22.2) 25 (17.7) 7 (38.9) 20 (15.2) 2 (7.4) 25 (92.6) AG+GG 7 (77.8) 116 (82.3) 11 (61.1)b 112 (84.8)b 19 (15.4) 104 (84.6) TS 2R/2R+2R/3R 6 (6.3) 90 (93.8) 10 (10.4) 86 (89.6) 9 (9.4) 87 (90.6) 3R/3R+3R/4R 3 (5.6) 51 (94.4) 8 (14.8) 46 (85.2) 12 (22.2)c 42 (77.8)c Patients receiving cotreatment with other DMARDs were excluded from the analysis a P=0.006, OR=15.067, 95% CI=2.182-104.6 b P=0.007, OR=0.191, 95% CI=0.057-0.637 c P=0.028, OR=2.959, 95% CI=1.127-7.768 independent studies based on Japanese and Caucasian RA patients no association between the RFC1 A80G polymorphism and MTX efficacy and/or toxicity was observed [20, 42, 43].
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ABCB1 p.Ala80Gly 18607581:132:1088
status: NEW181 Our results suggest that RFC1 A80G and MDR1 C3435T polymorphisms influence the risk for MTX-induced AEs, while MTHFR A1298C polymorphism has a protective effect on MTX toxicity.
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ABCB1 p.Ala80Gly 18607581:181:30
status: NEW[hide] Genetic polymorphisms in metabolic and cellular tr... Drug Metab Pharmacokinet. 2012 Apr 25;27(2):192-9. Epub 2011 Nov 22. Kato T, Hamada A, Mori S, Saito H
Genetic polymorphisms in metabolic and cellular transport pathway of methotrexate impact clinical outcome of methotrexate monotherapy in Japanese patients with rheumatoid arthritis.
Drug Metab Pharmacokinet. 2012 Apr 25;27(2):192-9. Epub 2011 Nov 22., [PMID:22104130]
Abstract [show]
The aim of this study was to investigate the impact of genetic polymorphisms in the metabolic and cellular transport pathway of methotrexate (MTX) on the clinical outcome of MTX monotherapy in Japanese rheumatoid arthritis (RA) patients. Fifty-five patients were treated with MTX monotherapy at a dose of 4-10 mg/week. The total concentration of MTX-polyglutamates (MTX-PGs) was measured at steady-state in red blood cells (RBCs) by high performance liquid chromatography. The genotype at 16 polymorphic sites in 11 genes (ABCB1, ABCG2, ABCC2, RFC1, PCFT, SLCO1B1, MTHFR, GGH, ATIC, MTR, and MTRR) was analyzed. No significant association between the total concentration of MTX-PGs in RBCs and clinical outcome was found. However, patients with the ABCB1 3435TT genotype had a significantly lower mean disease activity score (DAS) 28 than did patients with the ABCB1 3435CC genotype (p = 0.02). Similarly, patients with the ABCB1 2677AA/AT/TT genotypes had a significantly lower mean DAS28 than did patients with the ABCB1 2677GG/GA/GT genotypes (p = 0.04). The patients with the MTHFR 1298AA genotype had a significantly lower mean DAS28 than those with the MTHFR 1298AC/CC genotypes (p = 0.04). In conclusion, the ABCB1 3435C>T, ABCB1 2677G>A/T, and MTHFR 1298A>C polymorphisms influenced the efficacy of MTX monotherapy.
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No. Sentence Comment
56 To determine the genotype at the RFC1 80AhG polymorphism, the region encompassing the A80G polymorphic site was amplified ¤forward primer: 5$-AGCGGTGGAGAAGCAGGT-3$, reverse primer: 5$-GGAGGTAGGGGGTGATGAAG-3$¥, and the PCR products were digested with HhaI ¤New England BioLabs, Tokyo, Japan¥ as previously described.24¥ To determine the genotype at the ABCB1 2677GhA/T polymorphism, the region encompassing the 2677GhA/T polymorphic site was amplified by PCR ¤forward primer: 5$-TCTTAGCAATTGTACCCATCATTG-3$, reverse primer: 5$-CAGGTTCTTGACCGAAACGA-3$¥, and the resulting PCR products were analyzed by direct sequencing.
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ABCB1 p.Ala80Gly 22104130:56:86
status: NEW