Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 May 12:5:96.
doi: 10.3389/fgene.2014.00096. eCollection 2014.

Imputation of TPMT defective alleles for the identification of patients with high-risk phenotypes

Berta Almoguera  1 , Lyam Vazquez  1 , John J Connolly  1 , Jonathan Bradfield  1 , Patrick Sleiman  2 , Brendan Keating  2 , Hakon Hakonarson  2
Affiliations

Imputation of TPMT defective alleles for the identification of patients with high-risk phenotypes

Berta Almoguera et al. Front Genet. .

Abstract

Background: The activity of thiopurine methyltransferase (TPMT) is subject to genetic variation. Loss-of-function alleles are associated with various degrees of myelosuppression after treatment with thiopurine drugs, thus genotype-based dosing recommendations currently exist. The aim of this study was to evaluate the potential utility of leveraging genomic data from large biorepositories in the identification of individuals with TPMT defective alleles.

Material and methods: TPMT variants were imputed using the 1000 Genomes Project reference panel in 87,979 samples from the biobank at The Children's Hospital of Philadelphia. Population ancestry was determined by principal component analysis using HapMap3 samples as reference. Frequencies of the TPMT imputed alleles, genotypes and the associated phenotype were determined across the different populations. A sample of 630 subjects with genotype data from Sanger sequencing (N = 59) and direct genotyping (N = 583) (12 samples overlapping in the two groups) was used to check the concordance between the imputed and observed genotypes, as well as the sensitivity, specificity and positive and negative predictive values of the imputation.

Results: Two SNPs (rs1800460 and rs1142345) that represent three TPMT alleles ((*)3A, (*)3B, and (*)3C) were imputed with adequate quality. Frequency for the associated enzyme activity varied across populations and 89.36-94.58% were predicted to have normal TPMT activity, 5.3-10.31% intermediate and 0.12-0.34% poor activities. Overall, 98.88% of individuals (623/630) were correctly imputed into carrying no risk alleles (553/553), heterozygous (45/46) and homozygous (25/31). Sensitivity, specificity and predictive values of imputation were over 90% in all cases except for the sensitivity of imputing homozygous subjects that was 80.64%.

Conclusion: Imputation of TPMT alleles from existing genomic data can be used as a first step in the screening of individuals at risk of developing serious adverse events secondary to thiopurine drugs.

Keywords: DNA biobank; Electronic Medical Records; TPMT; genotype imputation; pharmacogenetics.

PubMed Disclaimer

Figures

Figure 1
Figure 1
General schema for the study process. Hap550 is the InfiniumII HumanHap550 array, Quad is Human610-Quad version 1 array, Immunochip is the Illumina Infinium Immunochip array and Omni is the HumanOmni1-Quad version 1.
Figure 2
Figure 2
Definition of true and false positive and negative values and formulae used for the determination of the sensitivity, specificity, and predictive values of the imputation.
See this image and copyright information in PMC

References

    1. Appell M. L., Berg J., Duley J., Evans W. E., Kennedy M. A., Lennard L., et al. (2013). Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet. Genomics 23, 242–248 10.1097/FPC.0b013e32835f1cc0 - DOI - PMC - PubMed
    1. Delaneau O., Zagury J. F., Marchini J. (2013). Improved whole-chromosome phasing for disease and population genetic studies. Nat. Methods 10, 5–6 10.1038/nmeth.2307 - DOI - PubMed
    1. Dubinsky M. C. (2004). Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin. Gastroenterol. Hepatol. 2, 731–743 10.1016/S1542-3565(04)00344-1 - DOI - PubMed
    1. Gottesman O., Kuivaniemi H., Tromp G., Faucett W. A., Li R., Manolio T. A., et al. (2013). The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. Genet. Med. 15, 761–771 10.1038/gim.2013.72 - DOI - PMC - PubMed
    1. Howie B. N., Donnelly P., Marchini J. (2009). A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5:e1000529 10.1371/journal.pgen.1000529 - DOI - PMC - PubMed

LinkOut - more resources