Identification of novel polymorphisms in the 5 ' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance

K J Aitchison; F J Gonzalez; L C Quattrochi; A Sapone; J H Zhao; H Zaher; G Elizondo; C Bryant; J Munro; D A Collier; A J Makoff; R W Kerwin

doi:10.1097/00008571-200011000-00004

Identification of novel polymorphisms in the 5 ' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance

K J Aitchison, F J Gonzalez, L C Quattrochi, A Sapone, J H Zhao, H Zaher, G Elizondo, C Bryant, J Munro, D A Collier, A J Makoff, R W Kerwin

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Abstract

CYP1A2 activity has been demonstrated to be bimodally or trimodally distributed in several populations, consistent with a codominant or recessive functional genetic polymorphism. However, studies aimed at identifying polymorphisms in CYP1A2 have not yet adequately accounted for this distribution pattern. To search for functional polymorphisms, we performed genome-walking, polymerase chain reaction (PCR) sequencing, and cloning, and identified three novel polymorphisms in the 5' flanking region of CYP1A2: a T(-3591)G substitution, a G(-3595)T substitution, and a T-3605 insertion. The frequency of the T-3591G substitution was determined by a PCR-restriction fragment length polymorphism assay, and found to be significantly higher (P <0.0001) in Taiwanese (allele frequency 0.128, n = 125) compared to Caucasians (0.017, n = 87) or African Americans (0.024, n = 104). The functional consequence of the T(-3591)G and the G(-3595)T substitutions was determined by site-directed mutagenesis followed by transient transfection experiments. The T(-3591)G mutation was shown to be nonfunctional, while although the G(-3595)T mutation appeared to result in an increase in promoter activity, this was only to a small degree and therefore unlikely to be important in vivo. In addition, we report 532 bases of 5' flanking sequence further upstream than that reported to date, and four sequence discrepancies compared to the original published sequence (G(-3649)C, T-3650, DeltaA(-4072), and C-4093 ins). Pharmacogenetics 10:695-704 (C) 2000 Lippincott Williams & Wilkins.

Original language	English
Pages (from-to)	695 - 704
Number of pages	10
Journal	Pharmacogenetics
Volume	10
Issue number	8
DOIs	https://doi.org/10.1097/00008571-200011000-00004
Publication status	Published - 2000

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Aitchison, K. J., Gonzalez, F. J., Quattrochi, L. C., Sapone, A., Zhao, J. H., Zaher, H., Elizondo, G., Bryant, C., Munro, J., Collier, D. A., Makoff, A. J., & Kerwin, R. W. (2000). Identification of novel polymorphisms in the 5 ' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance. Pharmacogenetics, 10(8), 695 - 704. https://doi.org/10.1097/00008571-200011000-00004

@article{803b8696cf7143b29ae046e5bef811fd,

title = "Identification of novel polymorphisms in the 5 ' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance",

abstract = "CYP1A2 activity has been demonstrated to be bimodally or trimodally distributed in several populations, consistent with a codominant or recessive functional genetic polymorphism. However, studies aimed at identifying polymorphisms in CYP1A2 have not yet adequately accounted for this distribution pattern. To search for functional polymorphisms, we performed genome-walking, polymerase chain reaction (PCR) sequencing, and cloning, and identified three novel polymorphisms in the 5' flanking region of CYP1A2: a T(-3591)G substitution, a G(-3595)T substitution, and a T-3605 insertion. The frequency of the T-3591G substitution was determined by a PCR-restriction fragment length polymorphism assay, and found to be significantly higher (P <0.0001) in Taiwanese (allele frequency 0.128, n = 125) compared to Caucasians (0.017, n = 87) or African Americans (0.024, n = 104). The functional consequence of the T(-3591)G and the G(-3595)T substitutions was determined by site-directed mutagenesis followed by transient transfection experiments. The T(-3591)G mutation was shown to be nonfunctional, while although the G(-3595)T mutation appeared to result in an increase in promoter activity, this was only to a small degree and therefore unlikely to be important in vivo. In addition, we report 532 bases of 5' flanking sequence further upstream than that reported to date, and four sequence discrepancies compared to the original published sequence (G(-3649)C, T-3650, DeltaA(-4072), and C-4093 ins). Pharmacogenetics 10:695-704 (C) 2000 Lippincott Williams & Wilkins.",

author = "Aitchison, {K J} and Gonzalez, {F J} and Quattrochi, {L C} and A Sapone and Zhao, {J H} and H Zaher and G Elizondo and C Bryant and J Munro and Collier, {D A} and Makoff, {A J} and Kerwin, {R W}",

year = "2000",

doi = "10.1097/00008571-200011000-00004",

language = "English",

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Aitchison, KJ, Gonzalez, FJ, Quattrochi, LC, Sapone, A, Zhao, JH, Zaher, H, Elizondo, G, Bryant, C, Munro, J , Collier, DA , Makoff, AJ & Kerwin, RW 2000, 'Identification of novel polymorphisms in the 5 ' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance', Pharmacogenetics, vol. 10, no. 8, pp. 695 - 704. https://doi.org/10.1097/00008571-200011000-00004

TY - JOUR

T1 - Identification of novel polymorphisms in the 5 ' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance

AU - Aitchison, K J

AU - Gonzalez, F J

AU - Quattrochi, L C

AU - Sapone, A

AU - Zhao, J H

AU - Zaher, H

AU - Elizondo, G

AU - Bryant, C

AU - Munro, J

AU - Collier, D A

AU - Makoff, A J

AU - Kerwin, R W

PY - 2000

Y1 - 2000

N2 - CYP1A2 activity has been demonstrated to be bimodally or trimodally distributed in several populations, consistent with a codominant or recessive functional genetic polymorphism. However, studies aimed at identifying polymorphisms in CYP1A2 have not yet adequately accounted for this distribution pattern. To search for functional polymorphisms, we performed genome-walking, polymerase chain reaction (PCR) sequencing, and cloning, and identified three novel polymorphisms in the 5' flanking region of CYP1A2: a T(-3591)G substitution, a G(-3595)T substitution, and a T-3605 insertion. The frequency of the T-3591G substitution was determined by a PCR-restriction fragment length polymorphism assay, and found to be significantly higher (P <0.0001) in Taiwanese (allele frequency 0.128, n = 125) compared to Caucasians (0.017, n = 87) or African Americans (0.024, n = 104). The functional consequence of the T(-3591)G and the G(-3595)T substitutions was determined by site-directed mutagenesis followed by transient transfection experiments. The T(-3591)G mutation was shown to be nonfunctional, while although the G(-3595)T mutation appeared to result in an increase in promoter activity, this was only to a small degree and therefore unlikely to be important in vivo. In addition, we report 532 bases of 5' flanking sequence further upstream than that reported to date, and four sequence discrepancies compared to the original published sequence (G(-3649)C, T-3650, DeltaA(-4072), and C-4093 ins). Pharmacogenetics 10:695-704 (C) 2000 Lippincott Williams & Wilkins.

AB - CYP1A2 activity has been demonstrated to be bimodally or trimodally distributed in several populations, consistent with a codominant or recessive functional genetic polymorphism. However, studies aimed at identifying polymorphisms in CYP1A2 have not yet adequately accounted for this distribution pattern. To search for functional polymorphisms, we performed genome-walking, polymerase chain reaction (PCR) sequencing, and cloning, and identified three novel polymorphisms in the 5' flanking region of CYP1A2: a T(-3591)G substitution, a G(-3595)T substitution, and a T-3605 insertion. The frequency of the T-3591G substitution was determined by a PCR-restriction fragment length polymorphism assay, and found to be significantly higher (P <0.0001) in Taiwanese (allele frequency 0.128, n = 125) compared to Caucasians (0.017, n = 87) or African Americans (0.024, n = 104). The functional consequence of the T(-3591)G and the G(-3595)T substitutions was determined by site-directed mutagenesis followed by transient transfection experiments. The T(-3591)G mutation was shown to be nonfunctional, while although the G(-3595)T mutation appeared to result in an increase in promoter activity, this was only to a small degree and therefore unlikely to be important in vivo. In addition, we report 532 bases of 5' flanking sequence further upstream than that reported to date, and four sequence discrepancies compared to the original published sequence (G(-3649)C, T-3650, DeltaA(-4072), and C-4093 ins). Pharmacogenetics 10:695-704 (C) 2000 Lippincott Williams & Wilkins.

UR - http://www.scopus.com/inward/record.url?scp=0033661490&partnerID=8YFLogxK

U2 - 10.1097/00008571-200011000-00004

DO - 10.1097/00008571-200011000-00004

M3 - Article

VL - 10

SP - 695

EP - 704

JO - Pharmacogenetics

JF - Pharmacogenetics

IS - 8

ER -

Identification of novel polymorphisms in the 5 ' flanking region of CYP1A2, characterization of interethnic variability, and investigation of their functional significance

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