Allergy Asthma Immunol Res.  2011 Oct;3(4):273-276. 10.4168/aair.2011.3.4.273.

Polymorphisms of Aspirin-Metabolizing Enzymes CYP2C9, NAT2 and UGT1A6 in Aspirin-Intolerant Urticaria

• Palikhe NS
• Kim SH
• Nam YH
• Ye YM
• Park HS

• KMID: 2167079
• DOI: http://doi.org/10.4168/aair.2011.3.4.273

Abstract

Acetyl salicylic acid (ASA) is metabolized by UDP-glucuronosyltransferase 1A6 (UGT1A6), cytochrome P4502C9 (CYP2C9), and N-acetyl transferase 2 (NAT2). Variations in the activities of these enzymes may modulate adverse ASA-related symptoms such as urticaria. We examined whether polymorphisms in the UGT1A6, CYP2C9, and NAT2 genes are related to ASA-intolerant urticaria (AIU). The genotypes of 148 subjects with AIU (AIU group) and 260 normal healthy control subjects (NC group) were analyzed with respect to the following single nucleotide polymorphisms: CYP2C9 -1188T>C and CYP2C9*3A1075C; UGT1A6 T181A A>G and UGT1A6 R184S A>C; and NAT2 9796A>T, NAT2 197G>A, NAT2 286G>A, NAT2 9601A>G, and NAT2 9306A>G. There were significant differences in the allele frequencies for the CYP2C9 polymorphisms between the two groups. The frequency of the minor allele CYP2C9 -1188T>C was significantly higher in the AIU group than in the NC group (P=0.005). The frequency of the variant genotype CC was higher in the AIU group compared with the controls in both the co-dominant (P=0.007) and recessive models (P=0.012). The frequency of haplotype 2 [CA] was also significantly higher in the AIU group in both the co-dominant (P=0.006) and dominant models (P=0.012). There was no significant difference in genotype frequencies for any of the UGT1A6 or NAT2 polymorphisms between the two groups. Clinical parameters did not differ according to genotype. These results suggest that the C allele of CYP2C9 -1188T>C may be associated with AIU.

Keyword

Aspirin; Cytochrome P4502C9; Metabolizing enzyme; Urticaria

MeSH Terms

Alleles
Aspirin
Cytochromes
Gene Frequency
Genotype
Haplotypes
Idoxuridine
Salicylic Acid
Transferases
Urticaria
Aspirin
Cytochromes
Idoxuridine
Salicylic Acid
Transferases

Reference

1. Palikhe NS, Kim SH, Choi GS, Ye YM, Park HS. No evidence of association between interleukin-13 gene polymorphism in aspirin intolerant chronic urticaria. Allergy Asthma Immunol Res. 2009. 1:36–40.

2. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998. 45:525–538.

3. Ciotti M, Marrone A, Potter C, Owens IS. Genetic polymorphism in the human UGT1A6 (planar phenol) UDP-glucuronosyltransferase: pharmacological implications. Pharmacogenetics. 1997. 7:485–495.

4. Lampe JW, Bigler J, Horner NK, Potter JD. UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. Pharmacogenetics. 1999. 9:341–349.

5. Bigler J, Whitton J, Lampe JW, Fosdick L, Bostick RM, Potter JD. CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk. Cancer Res. 2001. 61:3566–3569.

6. Palikhe NS, Kim SH, Park HS. What do we know about the genetics of aspirin intolerance? J Clin Pharm Ther. 2008. 33:465–472.

7. Kim JM, Park BL, Park SM, Lee SH, Kim MO, Jung S, Lee EH, Uh ST, Park JS, Choi JS, Kim YH, Kim MK, Choi IS, Cho SH, Choi BW, Park HS, Chang HS, Shin HD, Park CS. Association analysis of N-acetyl transferase-2 polymorphisms with aspirin intolerance among asthmatics. Pharmacogenomics. 2010. 11:951–958.

8. Batra J, Sharma SK, Ghosh B. Arylamine N-acetyltransferase gene polymorphisms: markers for atopic asthma, serum IgE and blood eosinophil counts. Pharmacogenomics. 2006. 7:673–682.

9. Lee AY, Kim MJ, Chey WY, Choi J, Kim BG. Genetic polymorphism of cytochrome P450 2C9 in diphenylhydantoin-induced cutaneous adverse drug reactions. Eur J Clin Pharmacol. 2004. 60:155–159.

10. Kim SH, Kim SH, Yoon HJ, Shin DH, Park SS, Kim YS, Park JS, Jee YK. NAT2, CYP2C9, CYP2C19, and CYP2E1 genetic polymorphisms in anti-TB drug-induced maculopapular eruption. Eur J Clin Pharmacol. 2011. 67:121–127.

11. Tamer L, Calikoğlu M, Aras Ateş N, Yildirim H, Karakaş S, Atik U. Relationship between N-acetyl transferase-2 gene polymorphism and risk of bronchial asthma. Tuberk Toraks. 2006. 54:137–143.

12. Polonikov AV, Ivanov VP, Solodilova MA. Genetic variation of genes for xenobiotic-metabolizing enzymes and risk of bronchial asthma: the importance of gene-gene and gene-environment interactions for disease susceptibility. J Hum Genet. 2009. 54:440–449.