ITPA P32T - GET-Evidence

Curation:
Currentness:

ITPA P32T

(ITPA Pro32Thr)


Short summary

This variant is associated with inosine triphosphate pyrophosphohydrolase deficiency and may be associated with an adverse reaction to thiopurine drugs (which are used as immunosuppressants). Homozygotes have no detectable ITPase activity, individuals compound heterozygous with another less severe mutation also have severely reduced enzyme activity.

Variant evidence
Computational 2

NBLOSUM=3, gene associated with phenotype, impair secondary structure, but Polyphen 2 predicts benign effect.

See Sumi S et al. 2002 (12384777).

Functional 2

enzyme extract and yeast expression

See Stepchenkova EI et al. 2009 (19631656).

Case/Control 5

significance = 2.5 * 10^-10

See Sumi S et al. 2002 (12384777).

Familial
 
Clinical importance
Severity 3

There are conflicting reports of adverse drug reactions for ITPA deficiency

Treatability 2

Clinical treatment in development.

See unpublished research (below).

Penetrance 1

Most individuals don’t need to take azathiopurine for immunosuppression

 

Impact

Low clinical importance, pharmacogenetic

(The "low clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

Heterozygotes for this variant showed a mean ITPase activity of 22.5% while homozygotes showed complete inactivation.

Allele frequency

  • A @ chr20:3193842: 6.1% (656/10758) in EVS
  • A @ chr20:3141841: 5.5% (7/128) in GET-Evidence
  • Frequency shown in summary reports: 6.1% (656/10758)

Publications
 

Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, Thein SL, Ansari A, Sanderson J, De Abreu RA, Simmonds HA, Duley JA. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. Hum Genet. 2002 Oct;111(4-5):360-7. Epub 2002 Aug 15. PubMed PMID: 12384777.

In a study of eight families (one Chinese and the rest Caucasian?) with inosine triphosphate pyrophosphohydrolase deficiency, this variant was found in 5 out of 8 families with ITPase deficiency. The variant is expected to increase alpha-helical structure and impair dimerization of the protein. This variant is predicted increase toxicity of thiopurine drugs.

In some families multiple members were examined, and the proband (first affected member seeking medical attention) is not mentioned. To make a fair comparison with controls, we can reduce this set to single individuals by choosing the individual from each family with the most extreme ITPase deficiency (lowest ITPase activity). Doing this we get 5 homozygous for this allele, 2 heterozygous, 1 non-carrier. (Both heterozygous individuals with compound heterozygous another allele implicated, and the wild-type was homozygous for that allele.) Among 100 controls they found 10 heterozygous for this variant alone and 2 compound heterozygous for this variant and the other implicated variant.

Counting alleles, this is case+: 12, case-: 4, control+: 12, control-: 188. This is extremely significant with p=2.5 * 10^-10. All homozygous individuals have zero ITPase activity and so we can consider this as fully penetrant under a recessive hypothesis.

Marsh S, King CR, Ahluwalia R, McLeod HL. Distribution of ITPA P32T alleles in multiple world populations. J Hum Genet. 2004;49(10):579-81. Epub 2004 Aug 21. PubMed PMID: 15322947.

“Azathioprine (AZA), the pro-drug of mercaptopurine, is commonly used in organ transplant patients and for the treatment of chronic inflammatory disease, dermatologic disorders, and rheumatic diseases.”

Prior to AZA therapy, authors recommend prescreening patients for TPMT variants and ITPA P32T to further improve the chances of identifying at-risk patients.

Bierau J, Lindhout M, Bakker JA. Pharmacogenetic significance of inosine triphosphatase. Pharmacogenomics. 2007 Sep;8(9):1221-8. Review. PubMed PMID: 17924837.

The authors conclude: “The pharmacogenetic significance of inosine triphosphatase is a highly debated subject and data published are contradictory; The ITPA 94>A genotype may be associated with azathioprine-induced adverse drug reaction; Carriers of ITPA allelic variants are easily detected by measurement of ITPase activity.”

Stepchenkova EI, Tarakhovskaya ER, Spitler K, Frahm C, Menezes MR, Simone PD, Kolar C, Marky LA, Borgstahl GE, Pavlov YI. Functional study of the P32T ITPA variant associated with drug sensitivity in humans. J Mol Biol. 2009 Sep 25;392(3):602-13. Epub 2009 Jul 23. PubMed PMID: 19631656; PubMed Central PMCID: PMC2745931.

In a series of in-vitro experiments this paper proposes the method of enzyme inactivation by this variant.

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PubMed PMID: 19682085

 

Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, Little LD, Qiu P, Bertelsen AH, Watson M, Warner A, Muir AJ, Brass C, Albrecht J, Sulkowski M, McHutchison JG, Goldstein DB. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010 Feb 21. [Epub ahead of print] PubMed PMID: 20173735.

“Finally, because ITPA deficiency seems to be a benign condition, it may be possible to protect against RBV-induced anaemia by pharmacological intervention against ITPA. The identification of inosine triphosphatase deficiency as a major projective factor against RBV-induced haemolytic anaemia therefore not only provides a valuable pharmacogenetic diagnostic, but also a window into red blood cell biology and the processes governing lysis.”

Genomes
 

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het A @ chr20:3193842

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr20:3193842

 

 

 

GS06985 - var-GS06985-1100-36-ASM
het A @ chr20:3141842

 

GS12004 - var-GS12004-1100-36-ASM
het A @ chr20:3141842

 

GS18508 - var-GS18508-1100-36-ASM
het A @ chr20:3141842

 

GS19017 - var-GS19017-1100-36-ASM
het A @ chr20:3141842

 

GS19025 - var-GS19025-1100-36-ASM
het A @ chr20:3141842

 

Other external references
 

    dbSNP
  • rs1127354
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.006 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = 4
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

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