Tyrosine phosphatase 1B and leptin receptor genes and their interaction in type 2 diabetes.

OBJECTIVE

The association between three tyrosine phosphatase 1B (PTP1B) gene polymorphisms and type 2 diabetes was examined by comparing the prevalence rates of these polymorphisms in type 2 diabetic patients and healthy control subjects. Furthermore, the association of the polymorphisms and PTP1B and leptin receptor (LepR) gene-gene interactions with complications of type 2 diabetes were examined in type 2 diabetic patients.

METHODS

A total of 257 Finnish patients with type 2 diabetes and 285 nondiabetic subjects were screened. Single nucleotide polymorphisms were determined using polymerase chain reaction and restriction enzymes. The diagnosis of coronary heart disease was based on clinical and ECG criteria. The prevalences of cerebrovascular and peripheral vascular diseases were assessed on the basis of clinical criteria. Laboratory analyses were carried out in the hospital laboratory.

RESULTS

We did not find any differences in the genotype distributions or allele frequencies of IVS6 + G82A and Pro387Leu polymorphisms between the type 2 diabetics and controls. There were differences in the genotype frequencies of the Pro303Pro (C981T)-polymorphism between the two studied groups (P = 0,018); there were eight T981T subjects in the control population but none amongst the type 2 diabetics. However, there were no differences in the allele frequencies. In addition, significant associations between the IVS6 + G82A polymorphism and body mass index (BMI), albuminuria, glycohaemoglobin A1 (GHBA1) and hypertension in type 2 diabetic patients (P = 0,026-0,031) were observed. Pro387Leu and Pro303Pro did not associate with risk factors or diabetic complications. We also found a gene-gene interaction effect between PTP1B and the LepR gene with the genotype combination IVS6 + A82A and Arg223Arg having the highest BMI compared with the other genotype combinations (P = 0.0043 for trend). The interaction between these two polymorphisms explained 3% of the variation in BMI in diabetic patients when the other covariates were taken into account.

CONCLUSIONS

We conclude that the PTP1B IVS6 + G82A polymorphism was associated with BMI, albuminuria, GHBA1 and hypertension in type 2 diabetic patients. The 981T/T-genotype of the Pro303Pro- polymorphism might have some protective role against the development of type 2 diabetes. The interaction effects between the PTP1B IVS6 + A82A and LepR Arg223Arg genotypes influenced BMI, explaining 3% of its variation. A synergistic effect of PTP1B and LepR variants on the leptin signalling may be involved.