ABCMdb

PMID: 20216337

Kim WJ, Lee JH, Yi J, Cho YJ, Heo K, Lee SH, Kim SW, Kim MK, Kim KH, In Lee B, Lee MG
A nonsynonymous variation in MRP2/ABCC2 is associated with neurological adverse drug reactions of carbamazepine in patients with epilepsy.
Pharmacogenet Genomics. 2010 Apr;20(4):249-56., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC2 p.Val417Ile Results A nonsynonymous polymorphism, c.1249G > A (p.V417I, rs2273697), showed a strong association with the neurological ADR caused by carbamazepine (P = 0.005). Login to comment 36 ABCC2 p.Val417Ile Here, we provide evidence that carbamazepine is a substrate of MRP2, and the V417I (c.1249G > A) nonsynonymous polymorphism in the human MRP2 gene is associated with CNS ADRs of carbamazepine. Methods Participants In the initial exploratory stage of the study, a total of 146 patients with epilepsy who had been prescribed carbamazepine from March 2004 to February 2006 at epilepsy clinics in Sinchon and Yongdong Severance Hospital, Seoul, Korea, were enrolled after giving informed consent. Login to comment 84 ABCC2 p.Val417Ile Of the five tag SNPs, the MRP2 c.1249G > A (p.V417I, rs2273697) polymorphism showed a strong association with CNS ADR. Login to comment 94 ABCC2 p.Val417Ile As MRP2 c.1249G > A (p.V417I, rs2273697) showed an association with CNS ADR of carbamazepine, this SNP was regenotyped in a larger independent set of cohort and the association was reevaluated (Table 4). Login to comment 102 ABCC2 p.Val417Ile Functional evaluation of the MRP2 c.1249G > A variant c.1249G > A is a nonsynonymous variation that causes substitution of a valine with an isoleucine at position 417. Login to comment 103 ABCC2 p.Val417Ile Earlier, it has been shown that the V417I variation did not greatly affect protein expression levels and membrane transport of CF, a standard substrate of MRP2 [13,24]. Login to comment 108 ABCC2 p.Val417Ile - 24C > T rs717620 C 0.809, 0.763 0.379 c.1249G > A (p.V417I) rs2273697 A 0.149, 0.061 0.013* c.2934G > A (p.S978S) rs3740070 G 0.968, 0.965 0.880 c.3972C > T (p.I1324I) rs3740066 C 0.798, 0.732 0.225 P values were obtained by comparing the CNS ADR Yes and No groups using the Pearson`s w2 or Fisher`s exact test (expected cell value < 5). Login to comment 117 ABCC2 p.Val417Ile - 24C > T C/C 74 (67.3) 30 (63.8) 61 (61.6) 0.284 rs717620 C/T 34 (30.9) 16 (34.0) 29 (29.3) T/T 2 (1.8) 1 (2.1) 9 (9.1) c.1249G > A G/G 92 (83.6) 33 (70.2) 88 (88.9) 0.009* (p.V417I) G/A 15 (13.6) 14 (29.8) 10 (10.1) 0.005*,b rs2273697 A/A 3 (2.7) 0 (0.0) 1 (1.0) c.2934G > A G/G 100 (90.9) 44 (93.6) 92 (92.2) > 0.999 (p.S978S) G/A 9 (8.2) 3 (6.4) 7 (7.1) rs3740070 A/A 1 (0.9) 0 (0.0) 0 (0.0) c.3972C > T C/C 61 (55.5) 29 (61.7) 56 (56.6) 0.234 (p.I1324I) C/T 47 (42.7) 17 (36.2) 33 (33.3) rs3740066 T/T 2 (1.8) 1 (2.1) 10 (10.1) P values were obtained by comparing the CNS ADR-Yes and CNS ADR-No groups using the Pearson`s w2 or Fisher`s exact test (expected cell value < 5). Login to comment 132 ABCC2 p.Val417Ile As an ABC transporter, MRP2 hydrolyzes ATP and liberates inorganic phosphates Table 4 Association study results for c.1249G > A (p.V417I, rs2273697) in MRP2 and CNS ADR caused by carbamazepine Exploratory stage Replication stage Variant CNS ADR-Yes CNS ADR-No CNS ADR-Yes CNS ADR-No Control Genotypes Number of individuals (%) G/G 33 (70.2) 88 (88.9) 55 (74.3) 174 (84.9) 92 (83.6) G/A 14 (29.8) 10 (10.1) 18 (24.3) 30 (14.6) 15 (13.6) A/A 0 (0.0) 1 (1.0) 1 (1.4) 1 (0.5) 3 (2.7) Total 47 (100.0) 99 (100.0) 74 (100.0) 205 (100.0) 110 (100.0) Alleles Number of chromosomes (%) G 80 (85.1) 186 (93.9) 128 (86.5) 378 (92.2) 199 (90.5) A 14 (14.9) 12 (6.1) 20 (13.5) 32 (7.8) 21 (9.5) Total 94 (100.0) 198 (100.0) 148 (100.0) 410 (100.0) 220 (100.0) Pgenotype in minor allele dominant mode, OR (95% CI) 0.005**, 3.40 (1.40-8.23) 0.042*, 1.94 (1.02-3.70) Joint Pgenotype 0.001**, 2.40 (1.43-4.02) Pallele, OR (95% CI) 0.013*, 2.72 (1.20-6.12) 0.041*, 1.85 (1.02-3.34) Joint Pallele 0.002**, 2.10 (1.30-3.37) P values were obtained by comparing the CNS ADR Yes and No groups using the Pearson`s w2 or Fisher`s exact test (expected cell value < 5). Login to comment