ABCMdb

PMID: 14610718

Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, Zhang L, Swanson E, Datta LW, Moran T, Ravenhill G, Duerr RH, Achkar JP, Karban AS, Cho JH
MDR1 Ala893 polymorphism is associated with inflammatory bowel disease.
Am J Hum Genet. 2003 Dec;73(6):1282-92. Epub 2003 Nov 7., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCB1 p.Asn21Asp Two missense mutations, Asn21Asp and Ala893Ser/Thr, as well as the expression-associated polymorphism C3435T, described elsewhere, were genotyped in the entire cohort. Login to comment 5 ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp Significant association of Ala893 with IBD was observed by both case-control analysis ( ) and the pedigreeP p .002 disequilibrium test (PDT [ ]) but not for the Asn21Asp or C3435T polymorphisms. Login to comment 6 ABCB1 p.Asn21Asp Significant association of Ala893 with IBD was observed by both case-control analysis ( ) and the pedigree P p .002 disequilibrium test (PDT [ ]) but not for the Asn21Asp or C3435T polymorphisms. Login to comment 41 ABCB1 p.Asn21Asp In this article, we examine the Asn21Asp variant, as well as functionally associated polymorphisms on Ala893Ser/Thr and C3435T. Login to comment 65 ABCB1 p.Asn21Asp The Asn21Asp (forward primer: 5-ATGGAGGAGCAAAGAAGAAG- AACTT-3; reverse primer: 5-CGCAACTATGTAAAC- TATGAAAATGAAAC-3; VIC [WT probe]: 5-AACTG- AACAATAAAAGG-3; FAM [rare probe]: 5-CTGAAC- GATAAAAGG-3) and C3435T polymorphisms (forward primer: 5 -AACAGCCGGGTGGTGTCA-3 ; reverse primer: 5 -ATGTATGTTGGCCTCCTTTGCT-3 ; VIC [WT probe]: 5 -CTCACGATCTCTTC-3 ; FAM [rare probe]: 5-CCTCACAATCTCTT-3) were genotyped using Taqman amplification and were detected using the ABI Prism 7700 Sequence Detection System. Login to comment 82 ABCB1 p.Asn21Asp We identified four exonic SNPs: in exon 2 (A61G-Asn21Asp), exon 12 (C1236T), exon 21 (G2677T/A-Ala893Ser/Thr), and exon 26 (C3435T) (table 2). Login to comment 86 ABCB1 p.Asn21Asp Because the Ala893Ser/Thr and C3435T polymorphisms have been associated with altered MDR1function, and because the Asn21Asp polymorphism represents a nonconserved amino acid variation that could potentially alter function, we typed these variants in a large cohort of patients with IBD to test for disease association. Login to comment 88 ABCB1 p.Asn21Asp For the Asn21Asp variant, no evidence for IBD association was observed ( ). Login to comment 101 ABCB1 p.Asn21Asp The combined analysis of the two ethnic groups (calculated as the sum of the individual cohort statistics) was for alleles and was for genotypes.P p .002 P p .008 Table 4 Global P Values by PDT Analysis of Exonic SNPs SNP GLOBAL P FOR PDT ANALYSIS FOR CD UC IBD Sum Average Sum Average Sum Average Asn21Asp .24 .15 .26 .56 .8 .39 Ala893Ser/Thr .0014 .00090 .29 .16 .00030 .00020 C3435T .42 .31 .93 .60 .63 .35 limited power to identify modest differences. Login to comment 102 ABCB1 p.Asn21Asp P p .002 P p .008 Table 4 Global P Values by PDT Analysis of Exonic SNPs SNP GLOBAL P FOR PDT ANALYSIS FOR CD UC IBD Sum Average Sum Average Sum Average Asn21Asp .24 .15 .26 .56 .8 .39 Ala893Ser/Thr .0014 .00090 .29 .16 .00030 .00020 C3435T .42 .31 .93 .60 .63 .35 limited power to identify modest differences. Login to comment 110 ABCB1 p.Asn21Asp Table 4 demonstrates the results by PDT for the Asn21Asp, Ala893Ser/ Thr, and C3435T polymorphisms among patients with CD, UC, and IBD. Login to comment 111 ABCB1 p.Asn21Asp Table 4 demonstrates the results by PDT for the Asn21Asp, Ala893Ser/ Thr, and C3435T polymorphisms among patients with CD, UC, and IBD. Login to comment 112 ABCB1 p.Asn21Asp For the entire cohort with IBD, significant evidence for association was observed for the Ala893Ser/Thr polymorphism ( ), and no evidence was observedP p .00020-.00030 for the Asn21Asp or C3435T polymorphisms. Login to comment 113 ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp Separate evaluation by CD and UC phenotypes showed no evidence of a CD association for the Asn21Asp or the C3435T polymorphisms. Login to comment 114 ABCB1 p.Asn21Asp Separate evaluation by CD and UC phenotypes showed no evidence of a CD association for the Asn21Asp or the C3435T polymorphisms. Login to comment 116 ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp Because the numberP p .16-.29 of subjects with UC is significantly smaller than the num- Table 5 PDT Analysis of the Tri-Allelic Exon 21 SNP ALLELE TRANSMISSION P FOR PDT ANALYSIS FOR CD UC IBD Sum Average Sum Average Sum Average Ala893 Overtransmitted .0072 .0040 .31 .15 .0021 .0010 893Ser Undertransmitted .036 .028 .43 .23 .016 .0093 893Thr Undertransmitted .0046 .0046 .16 .16 .0025 .0032 Global score .0014 .00090 .29 .16 .00030 .00020 Table 6 Linkage Disequilibrium Values SNP Pair r2 Asn21Asp and Ala893Ser/Thr .10 Ala893Ser/Thr and C3435T .52 Asn21Asp and C3435T .09 ber of subjects with CD in this cohort, these trends do not support a significant association of the Ala893Ser/ Thr polymorphism with UC. Login to comment 117 ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp In the cohort with UC, in contrast to a prior case-control study (Schwab et al. 2003), we observed no evidence for association with the 3435T polymorphism, nor was evidence observed for the Asn21Asp. Login to comment 118 ABCB1 p.Asn21Asp In the cohort with UC, in contrast to a prior case-control study (Schwab et al. 2003), we observed no evidence for association with the 3435T polymorphism, nor was evidence observed for the Asn21Asp. Login to comment 126 ABCB1 p.Asn21Asp Two-locus-haplotype analysis of the Asn21Asp-Ala893Ser/Thr haplotype demonstrates that the less common 21Asp variant occurs solely on the Ser893 background, which is unassociated with disease. Login to comment 128 ABCB1 p.Asn21Asp Two-locus-haplotype analysis of the Asn21Asp-Ala893Ser/Thr haplotype demonstrates that the less common 21Asp variant occurs solely on the Ser893 background, which is unassociated with disease. Login to comment 135 ABCB1 p.Asn21Asp OF HAPLOTYPES Transmitted Untransmitted Asn21Asp-Ala893Ser/Thr: Asn21-Thr893 2 17 Asn21-Ala893 203 128 Asn21-Ser893 131 188 21Asp-Ser893 48 51 Ala893Ser/Thr-C3435T: 893Thr-C3435 0 14 893Thr-3435T 2 2 Ala893-C3435 174 133 Ala893-3435T 69 51 893Ser-C3435 14 31 893Ser-3435T 130 158 NOTE.-Haplotypes were constructed using Genehunter, version 2.1; all affected individuals were included. Login to comment 137 ABCB1 p.Asn21Asp OF HAPLOTYPES Transmitted Untransmitted Asn21Asp-Ala893Ser/Thr: Asn21-Thr893 2 17 Asn21-Ala893 203 128 Asn21-Ser893 131 188 21Asp-Ser893 48 51 Ala893Ser/Thr-C3435T: 893Thr-C3435 0 14 893Thr-3435T 2 2 Ala893-C3435 174 133 Ala893-3435T 69 51 893Ser-C3435 14 31 893Ser-3435T 130 158 NOTE.-Haplotypes were constructed using Genehunter, version 2.1; all affected individuals were included. Login to comment