THE POLYMORPHIC INOSITOL POLYPHOSPHATE 1-PHOSPHATASE GENE AS A CANDIDATE FOR PHARMACOGENETIC PREDICTION OF LITHIUM-RESPONSIVE MANIC-DEPRESSIVE ILLNESS

Long-term treatment with lithium salts has been established as an effe ctive prophylactic therapy in manic-depressive (bipolar) illness. Many patients, however display a lack of (or partial) treatment response, We recently proposed that pharmacogenetic factors may influence and de termine the therapeutic efficacy of lithium in bipolar disorder. The l ithium-blockable enzyme inositol polyphosphate I-phosphatase in the ph ospholipase C signaling pathway is a putative target for the mood-stab ilizing effects of lithium. In the present study, we searched for DNA Variations in the human INPP1 gene encoding the inositol polyphosphate I-phosphatase enzyme. We report the existence of four common polymorp hisms in the coding region of the gene. The DNA alterations were all s ingle base substitutions, of which one (A682G) predicted an amino acid change (Thr228Ala), whereas the remaining three (G153T, G348A and C97 3A) were silent. In a Norwegian pilot sample, the frequencies of the f our single base substitutions were not significantly different between lithium-treated bipolar patients and healthy control individuals. Whe n subdivided with respect to drug response, however the C973A transver sion was present in six out of nine lithium responders (67%) versus on e out of nine non-responders (11%). In contrast, the C973A polymorphis m was equally common among lithium responders and non-responders in an independent sample of bipolar patients from Israel. Future studies ar e therefore needed to determine whether allelic variants of the INPP1 gene are associated with a favourable efficacy of lithium in manic-dep ressive illness. Pharmacogenetics 8:259-268 (C) 1998 Lippincott-Raven Publishers.