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