ABCMdb

PMID: 14676821

Wadelius M, Sorlin K, Wallerman O, Karlsson J, Yue QY, Magnusson PK, Wadelius C, Melhus H
Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors.
Pharmacogenomics J. 2004;4(1):40-8., [PubMed]

Sentences

No. Mutations Sentence Comment

23 ABCB1 p.Ser400Asn There are many known polymorphisms in ABCB1: for example, À12T4C in exon 1 in the 50 untranslated region, À1G4A at the initiation of translation in exon 2, 1199G4A in exon 11 leading to amino-acid change S400N, 1236C4T in exon 12 at a wobble position G412G, 2677G4T or G4A in exon 21 leading to A893S or T, and in exon 26 two polymorphisms at wobble positions, 3396C4T A1132A and 3435C4T I1145I.28,30 Polymorphisms of ABCB1 are suggested to be important for variability in drug bioavailability, but the pharmacological implication of these polymorphisms has not been fully established.30 Haemorrhage is the most common adverse reaction to coumarin anticoagulants, and a great under-reporting of these events is believed to exist.3,31 Swedish studies have shown that 4.5% of warfarin-treated patients experience major bleeding and 0.5% suffer fatal complications.31 The risk of bleeding is 10 times higher during the first month compared to after the first year.5 There is a clear relationship between haemorrhage and the intensity of treatment, with PT INR elevation being a strong predictor.3,5,10,32 Age, concurrent medication, specific comorbid conditions, especially cerebrovascular, kidney, heart and liver disease as well as prosthetic heart valves, are independent risk factors.5,32 Several studies suggest that patients with CYP2C9 variant alleles have a higher incidence of bleeding complications than carriers of the wild-type genotype.15,16,20,22 The risk of haemorrhage must always be weighed against the prevention of thromboembolism, and in most patients the preventive effect outweighs the risk of bleeding.4,32 The aim of the study was to identify factors that influence the effect of warfarin and the required dose. Login to comment 74 ABCB1 p.Ser400Asn Table 5 Alignment and frequencies of predicted ABCB1 haplotypes in the dose requirement study ABCB1 haplotypes A B C D E F G Others Variable sites Exon 1 (À12T4C 50 untranslated region) T T T T T T T Exon 2 (À1G4A translation initiation) G G A G G G G Exon 11 (1199G4A S400N) G G G G A G G Exon 12 (1236C4T G412G) T C C C C C T Exon 21 (2677G4T/A A893S/T) T G G G G A T Exon 26 (3396C4T A1132A) C C C C C C C Exon 26 (3435C4T I1145I) T C T T C T C Frequencies in dose study (201 patients)a 40.8% 33.3% 10.0% 5.0% 3.5% 2.5% 1.0% p1.0% each Distribution of haplotypes in three dose groups Low dose/BW (o0.33 mg/kg) 33.3% 34.8% 24.3% 60.0% 30.8% 40.0% 25.0% Medium dose/BW (0.33-0.46 mg/kg) 35.7% 30.4% 29.7% 25.0% 23.1% 20.0% 25.0% High dose/BW (40.46 mg/kg) 31.0% 34.8% 46.0% 15.0% 46.2% 40.0% 50.0% P w2 0.5575 0.6016 0.1786 0.0242 0.5623 0.6564 0.7749 P Fischer`s exact 0.5769 0.6369 0.1821 0.0348 0.6778 0.7767 1.00 P trend 0.5888 1.00 0.0745 0.0094 0.4824 1.00 0.5362 a Two out of 201 were not genotyped for Exon 1 (À12T4C), and their haplotypes are estimated as B/B and A/F, respectively, according to the results from polymorphisms in Exon s 2, 11, 12, 21, 26 and 26. Login to comment