ASSOCIATION OF DIABETIC NEUROPATHY WITH NA K ATPASE GENE POLYMORPHISM/

Diabetes mellitus induces a decrease in Na/K ATpase activity in man an d animals, and this decrease plays a role in the development of diabet ic neuropathy. Na/K ATPase is encoded by various genes, of which the A TP1 A1 gene is expressed predominantly in peripheral nerves and in ery throcytes. To investigate whether a polymorphism in the Na/K ATPase ge nes could explain the predisposition of some patients with insulin-dep endent diabetes mellitus (IDDM) to develop polyneuropathy, a restricti on fragment length polymorphism (RFLP) of the ATP1 Al gene was studied together with erythrocyte Na/K ATPase activity in 81 Caucasian patien ts with more than 10 years' duration of IDDM. Associations with diabet ic neuropathy, retinopathy and nephropathy were sought. Digestion of t he first intron of the ATP1 A1 gene by the Bgl II restriction enzyme r evealed a dimorphic allelism. Frequency of the restricted allele was 0 .18 in this selected series (however, it was 0.10 in representative sa mples of IDDM patients and of normal subjects in our area). Mean eryth rocyte Na/K ATPase activity was lower in diabetic patients than in 42 control subjects (292 +/- 10, vs 402 +/- 13 nmol Pi.mg protein(-1).h(- 1), p < 0.0001) and was not related to HbA(1c) value or to diabetes du ration. It was lower in the group of the 28 patients bearing the restr icted allele (241 +/- 10 vs 319 +/- 11 nmol Pi.mg protein(-1).h(-1) p < 0.0001). Neuropathy was absent in 50 patients, mild in 15 and severe in 16. When classified accordingly the three groups of patients did n ot differ with respect to sex, age and duration of diabetes. The respe ctive frequency of the restricted allele among the groups was 10, 73 a nd 81%, (p < 0.0001) and mean erythrocyte Na/K ATPase activity was res pectively: 322 +/- 10.7 nmol Pi.mg protein(-1).h(-1), 268 +/- 15 and 2 29 +/- 17, (p < 0.001). A borderline association between renal status or retinal status and repartition of polymorphism and a borderline cor relation between renal status and Na/K ATPase activity were found, but significance disappeared after checking for the presence or absence o f neuropathy. IDDM patients bearing the ATP1 A1 variant detected by Bg l II RFLP are much more frequently affected by neuropathy (relative ri sk 6.5, with 95% CI 3.3-13). Identification of this risk factor may he lp to prevent this complication. It is suggested that the restricted a llele is in linkage disequilibrium with a genomic mutation allowing di abetes to induce a greater impairment of Na/K ATPase activity which co uld in turn favour the development of neuropathy.