Influence of genetic variants of IDH1, IDH2, TET2 and DNMT3A on cytarabine cytotoxicity in different populations

Summary

What is known and objective

Cytarabine (ara-C) is the mainstay of treatment for acute myeloid leukaemia. Resistance and toxicity are common reasons for its treatment failure. Genetic variants of susceptibility genes may be involved in resistance and toxicity to ara-C. This study is aimed to explore the association between influence of genetic variants of IDH1, IDH2, TET2 and DNMT3A on cytarabine cytotoxicity in European and/or African populations.

Methods

HapMap cell lines derived from European descent (CEU) and African descent (YRI) were exposed to ara-C at different concentrations (1, 5, 40 and 80 μmol/L). The per cent survival values at each concentration were determined after 72-hour exposure to ara-C. The area under the survival curve (AUC) was calculated using the trapezoidal rule, and AUC values were log₂-transformed before statistical analysis. The 15 tagged single nucleotide polymorphism (SNPs) (rs2970357 and rs2970359 of IDH2, rs2242234 and rs1044147 of TET2, rs12999687 and rs6739187 of DNMT3A from CEU subjects, rs8040937 and rs1506941 of IDH2, rs6819857, rs7661962, rs7377314, rs6811804, rs4690309, rs4076064, rs6823876 of TET2 from YRI subjects) were selected utilizing Haploview. Minor allele frequency was more than 5% of them. Minimum pairwise r² was at least .80, and the correlation between genetic polymorphisms within IDH1, IDH2, TET2 and DNMT3A and AUC of ara-C was assessed.

Results and discussion

The genotypes of 2 SNPs in IDH2 including synonymous SNP located at 3′ UTR and 2 intrinsic SNPs in DNMT3A were significantly associated with ara-C sensitivity depicted by lower AUC in European ancestry; however, no one in DNMT3A was significant in African ancestry. Most interestingly, there was no one genotype of SNPs of IDH1 associated with sensitivity and resistance of ara-C from both CEU and YRI populations. Furthermore, 2 SNPs in IDH2 and 9 SNPs (3 in the 5′UTR, 3 in the 3′UTR, 3 in the intrinsic) of TET2 were mainly associated with ara-C resistance depicted by higher AUC in CEU and YRI populations, but, there were no genotypes of SNPs of TET2 and DNMT3A associated with ara-C sensitivity in both populations.

What is new and conclusion

These results suggest gene variations of IDH2, TET2 and DNMT3A are associated with ara-C sensitivity or resistance in European and/or African populations. Discrepancy of ara-C treatment in different populations is partly caused by distribution difference of allele frequency of IDH2, TET2 and DNMT3A in different populations. This finding may contribute to the personalization of ara-C if validated by larger studies.

CT/TT genotypes TET2 rs76619627 in African descent cell lines was associated higher area under the survival curve of Cytarabine compared with CC genotypes, indicating genetic variants of TET2 maybe involved in resistance of Cytarabine.

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