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LETTER TO THE EDITOR

ABCC10 rs2125739 polymorphism and nevirapine-induced hepatotoxicity

lack of association in a population from Mozambique

Ciccacci, Cinziaa; Di Fusco, Davidea; Marazzi, Maria C.c; Liotta, Giuseppeb; Palombi, Leonardob; Novelli, Giusepped,e; Borgiani, Paolaa

Author Information
Pharmacogenetics and Genomics: January 2013 - Volume 23 - Issue 1 - p 38-39
doi: 10.1097/FPC.0b013e328359e951
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Recently, in their paper ‘Association of ABCC10 polymorphisms with nevirapine (NVP) plasma concentrations in the German Competence Network for HIV/AIDS’, Liptrott et al.1, described an exonic single-nucleotide polymorphism (SNP) (rs2125739) as significantly associated with the NVP plasma concentration (P=0.02) in Whites: the variant allele was significantly more frequent in those with lower NVP plasma concentrations. Moreover, they observed a prevalence of the same allele also in Blacks with a lower NVP plasma concentration even though the difference did not reach statistical significance.

In our previous paper 2, we have reported an association between a polymorphism in ABCB1, another transporter gene, and the susceptibility to hepatotoxicity in a population of Mozambique. In particular, the ABCB1 variant allele of rs1045642 showed a protective effect with respect to the development of hepatotoxicity after treatment with NVP. Considering that NVP is also a substrate for ABCC10 and that Liptrott and colleagues reported that ABCC10 genetic variability could influence the NVP plasma concentration, we decided to test whether the rs2125739 polymorphism could also influence the susceptibility/protection toward hepatotoxicity. The samples were collected in Mozambique: 78 patients who experienced hepatotoxicity and 78 controls who did not experience any adverse reaction after treatment with NVP. The characteristics of these patients have been reported previously by Ciccacci et al.2. We analysed, by direct sequencing, a DNA fragment containing the rs2125739 polymorphism. In the same fragment, the rs2125740 polymorphism was also present. The case/control association study shows no association between the two ABCC10 polymorphisms and the emergence of hepatotoxicity in our population: both genotypes and allele frequencies did not show differences between cases and controls. Moreover, from the frequencies of the two SNPs genotypes, we have inferred the frequencies of haplotypes using the Arlequin program 3. Also, this haplotype analysis did not show differences between cases and controls. We also carried out an analysis of variance to compare the distribution of transaminases’ (ALT and AST) maximum values in the three different genotypes of each SNP, considering patients altogether (cases plus controls). Also, this analysis did not show any significant difference.

In conclusion, we failed to confirm a role for the rs2125379 in the development of hepatotoxicity in our patients treated with NVP. Obviously, the small number of our sample could be a limitation of the study. Nonetheless, this result is in agreement with the negative data of Liptrott and colleagues in terms of the black population, although the ethnic origin of this population was not described. Unfortunately, no other data from African populations are available in the literature for comparison with our results. A recent paper has reported an association between ABCC10 polymorphisms and kidney tubular dysfunction in patients treated with the antiretroviral drug, Tenofovir; nonetheless, the rs2125379 only shows a low association 4. Obviously, it is possible that other ABCC10 SNPs could be involved in the response to NVP treatment in African populations. Indeed some genetic variants can result associated with a toxic effect in a certain population but could not have any toxicity role in other populations. For this purpose, it is important to carry out studies on different populations. To date, only a few polymorphisms, such as the ABCB1 C3435T and CYP2B6 G516T, have been shown to play a role in the susceptibility to severe hepatic reactions 5,6. The difficulty in the identification of new genes/polymorphisms involved in the NVP response is because of the fact that the drug response (both in terms of effectiveness and toxicity) is a multifactorial character and therefore many genetic and environmental factors contribute towards its variability, each one with a modest contribution. For this reason, further analyses are necessary to identify both other ABCC10 allelic variants and other genes involved in NVP adverse reactions.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

References

1. Liptrott NJ, Pushpakom S, Wyen C, Fätkenheuer G, Hoffmann C, Mauss S, et al. Association of ABCC10 polymorphisms with nevirapine plasma concentrations in the German Competence Network for HIV/AIDS. Pharmacogenet Genomics. 2012;22:10–19
2. Ciccacci C, Borgiani P, Ceffa S, Sirianni E, Marazzi MC, Altan AM, et al. Nevirapine-induced hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique. Pharmacogenomics. 2010;11:23–31
3. Excoffier LG, Laval, Schneider S. Arlequin ver. 3.0: an integrated software package for population genetics data analysis. Evol Bioinform Online. 2005;1:47–50
4. Pushpakom SP, Liptrott NJ, Rodríguez-Nóvoa S, Labarga P, Soriano V, Albalater M, et al. Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction. J Infect Dis. 2011;204:145–153
5. Rotger M, Colombo S, Furrer H, Bleiber G, Buclin T, Lee BL, et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics. 2005;15:1–5
6. Haas DW, Bartlett JA, Andersen JW, Sanne I, Wilkinson GR, Hinkle J, et al. Pharmacogenetics of nevirapine-associated hepatotoxicity: an Adult AIDS Clinical Trials Group collaboration. Clin Infect Dis. 2006;43:783–786
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