ABCMdb

ABCB1 p.Pro66Ser

Predicted by SNAP2:	A: D (75%), C: D (66%), D: D (85%), E: D (85%), F: D (85%), G: D (80%), H: D (80%), I: D (80%), K: D (85%), L: D (80%), M: D (80%), N: D (85%), Q: D (80%), R: D (85%), S: D (71%), T: D (80%), V: D (75%), W: D (91%), Y: D (85%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Identification of NR1I2 genetic variation using re... Eur J Clin Pharmacol. 2007 Jun;63(6):547-54. Epub 2007 Apr 3. King CR, Xiao M, Yu J, Minton MR, Addleman NJ, Van Booven DJ, Kwok PY, McLeod HL, Marsh S
Identification of NR1I2 genetic variation using resequencing.
Eur J Clin Pharmacol. 2007 Jun;63(6):547-54. Epub 2007 Apr 3., [PMID:17404718]

Abstract [show]
OBJECTIVE: The nuclear receptor NR1I2 (also called PXR or SXR) is primarily expressed in mouse and human liver and intestines. Direct activation of NR1I2 occurs in response to a range of xenobiotics, which causes the formation of a heterodimer with the RXR receptor. This heterodimer binds to the nuclear receptor response elements of downstream genes such as ABCB1, CYP2C, and CYP3A. This study determined the extent of NR1I2 variation in three world populations. METHODS: Variation in NR1I2 was identified by pooled resequencing in African, Asian, and European populations. Validation was performed in European and African populations using PCR and Pyrosequencing technology. RNA expression of NR1I2, ABCB1 and CYP3A4 was assessed using real-time PCR. RESULTS: Of 36 single nucleotide polymorphisms (SNPs) identified, 24 were in the untranslated region, 8 were intronic, and 4 exonic. Thirty-six percent were unique to the African population. In comparison with previously published data, we identified 13 novel polymorphisms. The NR1I2 -566A > C polymorphism was significantly associated with ABCB1 and CYP3A4 RNA expression in colon tumor (P = 0.04 in both cases), however, this polymorphism was not associated with NR1I2 expression. CONCLUSION: With NR1I2 playing such a large role in the regulation of genes involved in drug metabolism and transport, genetic variation contributing to altered NR1I2 function may have an important clinical impact.

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96 Table 2 Validated NR1I2 allele frequencies NR1I2 -2098 C>T NR1I2 -566 A>C NR1I2 -205[GAGAAG] NRI12 IVS2+55 A>G NR1I2 IVS2+78 A>G NR1I2 IVS6-17 C>T NR1I2 +1792 A>G European African European African European African European African European African European African European African n 89 94 82 94 77 82 75 92 89 94 92 92 95 89 Wt 31 80 28 74 27 42 39 88 40 55 65 31 64 45 Het 48 14 43 20 40 27 30 4 30 34 25 49 29 36 Var 10 0 11 0 10 13 6 0 19 5 2 12 2 8 p c-0.62 c-0.07 a-0.60 a-0.11 [+] 0.61 [+] 0.68 a-0.72 a-0.02 a-0.62 a-0.23 c-0.84 c-0.60 a-0.83 a-0.29 q t-0.38 t-0.93 c-0.40 c-0.89 [-] 0.39 [-] 0.32 g-0.28 g-0.98 g-0.38 g-0.77 t-0.16 t-0.40 g-0.17 g-0.71 n Number of subjects, wt wild type, het heterozygote, var variant, p wild-type allele frequency, q variant allele frequency, [+] presence of indel, [-] absence of indel Table 3 Genetic variants in NR1I2 with allele frequencies above 10% Allele frequency SNP location [alternative name] SNP Source African American European Asian -3151 C/T Resequencing 0.16 T 0.0 T 0.0 T -2797 T/C Resequencing 0.43 C 0.0 C 0.0 C -2098 T/C Resequencing 0.28 C 0.70 C 0.67 C -1997 G/A Resequencing 0.16 A 0.0 A 0.01 A -1570 [-25385] C/T [34] 0.32 T 0.39 T N/E -1570 [-25385] C/T [4] N/E 0.36 T N/E -1570 C/T Resequencing 0.34 T 0.50 T 0.21 T -941[-24756] G/A [34] 0.14 A 0.01 A N/E -941[-24756] G/A [4] N/E 0.01 A N/E -941 G/A Resequencing 0.13 A 0.0 A 0.0 A -566 [-24381] A/C [34] 0.73 C 0.41 C N/E -566 [-24381] A/C [4] N/E 0.54 C N/E -566 A/C Resequencing 0.50 C 0.69 C 0.33 C -298 [-24113] G/A [34] 0.32 A 0.39 A N/E -298 G/A Resequencing 0.32 A 0.41 A 0.28 A -205 [-206 DEL] -/GAGAAG [29] N/E N/E 0.72 GAGAAG IVS1-20 [-42] T/C [34] 0.23 C 0.0 C N/E IVS1-20 T/C Resequencing 0.10 C 0.0 C 0.063 C 196 [PXR*2; P66S] C/T [34] 0.20 T 0.0 T N/E 196 [PXR*2; P66S] C/T Resequencing 0.03 T 0.0 T 0.0 T 196 [PXR*2; P66S] C/T [13] 0.15 Ta 0.0 T N/E 196 [PXR*2; P66S] C/T [4] N/E 0.0 T N/E IVS2+55 [+252] A/G [34] 0.64 G 0.28 G N/E IVS2+55 [+252] A/G [4] N/E 0.34 G N/E IVS2+55 A/G Resequencing 0.76 G 0.25 G 0.40 G IVS2+78 A/G Resequencing 0.77 G 0.28 G 0.34 G IVS2+78 [+275] A/G [4] N/E 0.34 G N/E IVS4+285 [+4760] G/A [4] N/E 0.69 A N/E IVS5-93 [+7635] A/G [34] 0.77 G 0.35 G N/E IVS5-93 [+7635] A/G [4] N/E 0.32 G N/E IVS5-93 A/G Resequencing 0.80 G 0.33 G 0.48 G IVS5-53 [+7675] C/T [34] 0.05 T 0.04 T N/E IVS5-53 [+7675] C/T [4] N/E 0.05 T N/E IVS5-53 C/T Resequencing 0.25 T 0.0 T 0.0 T IVS6-17 [+8055] C/T [34] 0.18 T 0.15 T N/E IVS6-17 [+8055] C/T [4] N/E 0.16 T N/E IVS6-17 C/T Resequencing 0.20 T 0.39 T 0.51 T 1437 [+9976] G/A [34] 0.36 A 0.0 A N/E 1437 G/A Resequencing 0.05 A 0.0 A 0.02 A 1792 A/G Resequencing 0.69 G 0.33G 0.59 G 1792 [+10331] A/G [4] N/E 0.20 G N/E 1922 C/A Resequencing 0.06 A 0.0 A 0.10 A 1922 [+10461] C/A [4] N/E 0.12 A N/E 1944 T/C Resequencing 0.69 C 0.23 C 0.65 C 1944 [+10483] T/C [4] N/E 0.24 C N/E 2081 [+10620] C/T [34] 0.14 T 0.11 T N/E 2081 [+10620] C/T [4] N/E 0.08 T N/E 2081 C/T Resequencing 0.03 T 0.01 T 0.0 T 2180 [+10719] A/G [34] 0.0 G 0.05 G N/E 2180 [+10719] A/G [4] N/E 0.05 G N/E 2180 A/G Resequencing 0.18 G 0.0 G 0.0 G 2260 [+10799] G/A [34] 0.14 A 0.13 A N/E 2260 [+10799] G/A [4] N/E 0.12 A N/E 2260 G/A Resequencing 0.06 A 0.05 A 0.0 A 2617 [+11156] A/C [34] 0.33 C 0.16 C N/E 2617 A/C Resequencing 0.43 C 0.09 C 0.50 C 2654 [+11193] T/C [34] 0.30 C 0.16 C N/E 2654 T/C Resequencing 0.54 C 0.14 C 0.53 C 3104 G/A Resequencing 0.24 A 0.0A 0.06 A Previously published naming is included in brackets in the SNP location column [4, 13, 29, 34]. Login to comment
109 Only one of the six SNPs, P66S, had an allele frequency above 10% in the African population alone. Login to comment
110 P66S was not found to alter basal CYP3A4 and/or induce its transactivation (as were V179M, D202G, and A409T) [13]. Login to comment
111 Of the six polymorphisms examined, four were found to be specific to the African population (E57K, P66S, D202G, and A409T), and two were specific to the European population (G75R and V179M) [13]. Login to comment
112 Two of these six polymorphisms were found through resequencing in the current study (P66S and G75R). Login to comment
113 P66S was monomorphic in European and Asian populations, however allele frequencies of 0.20 T, 0.15 T, and 0.03 T were found in African and African American populations by Zhang et al [34], Hustert et al. [13], and resequencing, respectively. Login to comment