ABCMdb

PMID: 18176959

Meier Y, Zodan T, Lang C, Zimmermann R, Kullak-Ublick GA, Meier PJ, Stieger B, Pauli-Magnus C
Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump.
World J Gastroenterol. 2008 Jan 7;14(1):38-45., 2008-01-07 [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCB11 p.Val444Ala ABCC2 p.Cys1515Tyr paulic@uhbs.ch Telephone: + 41-61-3287715 Fax: + 41-61-2653708 Received: July 12, 2007 Revised: September 12, 2007 Abstract AIM: To study the association of three common ABCB11 and ABCC2 polymorphisms (ABCB11: 1331T>C V444A; ABCC2: 3563T>A V1188E and 4544G>A C1515Y) with intrahepatic cholestasis of pregnancy (ICP) and contraceptive-induced cholestasis (CIC). Login to comment 31 ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu Furthermore, two non-synonymous ABCC2 polymorphisms (V1188E and C1515Y) showed significant differences in hepatic MRP2 expression levels compared to the wildtype sequence, which could be relevant for the extent of BSEP trans inhibition[25] . Login to comment 59 ABCC2 p.Val417Ile ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu ABCC2: Three non-synonymous polymorphisms with a potential impact on MRP2 function and expression were chosen for genotyping[25] : 1249G>A variant (V417I, rs2273697), 3563T>A (V1188E, rs17222723) and 4544G>A (C1515Y, rs8187710). Login to comment 82 ABCC2 p.Val417Ile ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu Table 1 Primers and probes of real-time PCR for allelic discrimination of ABCC2 SNPs in Caucasians cDNA position 1 SNP Exon Amino acid change Eense-/antisense primer Probes 2 1249 G>A 10 V417I 5'-CCAACTTGGCCAGGAAGGA-3'/ VIC 5'-CTGTTTCTCCAACGGTGTA-3' 5'-GGCATCCACAGACATCAGGTT-3' FAM 5'-ACTGTTTCTCCAATGGTGTA-3' 3563 T>A 25 V1188E 5'-GCACCAGCAGCGATTTCTG-3'/ VIC 5'-ACACAATGAGGTGAGGAT-3' 5'-AGGTGATCCAGGAAAAGACACATTT-3' FAM 5'-ACAATGAGGAGAGGAT-3' 4544 G>A 32 C1515Y 5'-GTAATGGTCCTAGACAACGGGAAG-3'/ VIC 5'-AGAGTGCGGCAGCC-3' 5'-CCAGGGATTTGTAGCAGTTCTTCAG-3' FAM 5'-ATTATAGAGTACGGCAGCC-3' 1 cDNA sequence from GenBank accession numbers NM_000392 starting at the ATG; 2 For each SNP two probes were designed and labeled with the fluorescent reporter dyes VIC (allele 1) and FAM (allele 2). Login to comment 87 ABCB11 p.Val444Ala In contrast, the ABCB11 1331T>C → V444A polymorphism was significantly more frequent in ICP and CIC patients compared to the two control groups. Login to comment 88 ABCB11 p.Val444Ala ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu Specifically, the CC genotype was encountered in 57.1% of all ICP patients (ICPnew, 47.6% and ICPold, 67.7%) and 100% of CIC patients compared to 20 and 32.2% in pregnant Table 2 New group of patients with ICP (ICPnew) Patient ID Age (yr) Liver parameters Comments Genotypes of SNPs ALT (ULN) AP (ULN) g-GT (ULN) tBili (ULN) tBA (ULN) No of preg/ No ICP Others ABCB11 1331T>C (V444A) ABCC2 3600T>A (V1188E) ABCC2 4581G>A (C1515Y) 1 36 0.9 2.3 3.3 0.8 10.7 2/1 CC TA GA 2 31 1.6 2.5. Login to comment 90 ABCB11 p.Val444Ala ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu Table 3 Characteristics of patients with oral CIC Patient ID Oral contraceptive Age (yr) Exposure time Liver parameters Comments Genotypes of SNPs ALT AP gGT tBili tBA Clinical features Histology ABCB11 1331T>C (V444A) ABCC2 3600T>A (V1188E) ABCC2 4581G>A (C1515Y) (ULN) (ULN) (ULN) (ULN) (ULN) 11 30 ʼg ethinylestradiol/ 75 ʼg gestodene 32 nd 4.9 1.7 1 10.9 22.3 Jaundice Intrahepatic cholestasis CC TT GG 2 30 ʼg ethinylestradiol/ 150 ʼg levonorgestrel 15 21 d 1 3 1 4.2 nd Jaundice, nausea, pruritus Extensive intrahepatic cholestasis CC TT GG 3 35 ʼg ethinylestradiol/ 50 ʼg levonorgestrel 40 2 yr 3.9 2.8 3.6 0.5 1.6 Pruritus Bland CC TT GG 4 35 ʼg ethinylestradio/ 2 mg cyproteron 34 nd 1 1.3 nd 2.8 1.6 Jaundice Extensive canalicular cholestasis, mild portal inflamation CC TA GA 1 Patient exhibited previous episodes of ICP. Login to comment 105 ABCB11 p.Val444Ala ABCC2 p.Cys1515Tyr ABCC2 p.Val1188Glu DISCUSSION We investigated the risk association between different ABCB11 and ABCC2 polymorphisms in ICP and CIC, and correlated different genotypes with serum bile acid levels Table 4 Genotype distribution of non-synonymous ABCB11 variant site 1331T>C in patients and controls Genotype SNP ICPold ICPnew ICPtotal Pregnant controls Caucasian controls n (%) 95 % CI n (%) 95 % CI n (%) 95 % CI n (%) 95 % CI n (%) 95 % CI ABCB11 1331T>C (V444A) 21 (100) 21 (100) 42 (100) 40 (100) 205 (100) TT (VV) - - 2 (9.5) 0.0-22.1 2 (4.8) 0.0-13.9 7 (17.5) 5.7-29.3 38(18.5) 13.2-23.9 CC (AA) 14 (67.7) 46.5 -86.8 10 (47.6) 26.3-69.0 24 (57.1) 36.0-78.3 8 (20) 7.6-32.4 66 (32.2) 25.8-38.6 TC (VA) 7 (33.3) 13.2-53.5 9 (42.9) 21.7-64.0 16 (38.1) 17.3-58.9 25 (62.5) 47.5-77.5 101 (49.3) 42.4-56.1 Frequency C allele 35 (83.3) 67.4-99.3 29 (69.0) 49.3-88.8 64 (76.2) 58.0-94.4 41 (51.3) 35.8-66.7 233 (56.8) 50.1-63.6 Frequency T allele 7 (16.7) 0.7-32.6 13 (31.0) 11.2-50.7 20 (23.8) 5.6-42.0 39 (48.8) 33.3-64.2 177 (43.2) 36.4-50.0 ABCC2 3563T>A (V1188E) 16 (100) 17 (100) 33 (100) 42 (100) 110 (100) TT (VV) 15 (93.8) 71.3-98.6 13 (76.5) 52.3-90.4 28 (84.8) 68.9-93.3 37 (88.1) 74.3-96.1 95 (86.4) 68.9-93.3 AA (EE) - - - - - - - - 1 (0.9) 0.0-5.0 TA (VE) 1 (3.1) 0.0-15.8 4 (23.5) 9.6-47.7 5 (15.2) 6.7-31.1 5 (11.9) 3.9-25.7 14 (12.7) 7.1-20.5 ABCC2 4544G>A (C1515Y) 16 (100) 17 (100) 33 (100) 42 (100) 110 (100) GG (CC) 15 (93.8) 71.3-98.6 13 (76.5) 52.3-90.4 28 (84.8) 68.9-93.3 36 (85.7) 71.4-94.6 95 (86.4) 68.9-93.3 AA (YY) - - - - - - - - 1 (0.9) 0.0-5.0 GA (CY) 1 (3.1) 0.0-15.8 4 (23.5) 9.6-47.7 5 (15.2) 6.7-31.1 6 (14.3) 5.4-28.6 14 (12.7) 7.1-20.5 Results are given with 95 percent confidence interval (95% CI). Login to comment 107 ABCB11 p.Val444Ala CC vs TT C vs T Fisher Odds ratio 95% CI Fisher Odds ratio 95% CI ICPold vs Pregnant controls 0.0041 nd1 - 0.0004 4.8 2.2-15.0 ICPold vs Caucasian controls 0.0029 nd1 - 0.0005 3.8 1.9-11.1 ICPnew vs Pregnant controls 0.1082 4.4 0.7-27.2 0.0441 2.1 1.0-4.7 ICnew vs Caucasian controls 0.1461 2.9 0.6-13.8 0.0850 1.7 0.9-3.4 ICPtotal vs Pregnant controls 0.0065 10.5 1.9-63.7 0.0007 3.0 1.7-6.4 ICPtotal vs Caucasian controls 0.0025 6.9 1.6-32.1 0.0006 2.4 1.5-4.5 Table 5 1331T>C (V444A): Fisher's exact test and ORs for the presence of homozygous CC variant and the C allele in the different groups as a marker of cholestasis. Login to comment