NRAMP1 and hGPX1 gene polymorphism and response to bacillus Calmette-Guérin therapy for bladder cancer

Background

The natural resistance-associated macrophage protein 1 (NRAMP1) gene is associated with susceptibility to Mycobacterium tuberculosis in humans and to bacillus Calmette-Guérin (BCG) in mice. The detoxification enzyme, human glutathione peroxidase 1 (hGPX1), is associated with recurrence of bladder cancer (BCa).

Objective

To determine whether NRAMP1 and hGPX1 gene polymorphisms correlate with response to BCG immunotherapy for non–muscle-invasive BCa (NMIBC).

Design, setting, and participants

DNA was obtained from the peripheral blood of 99 NMIBC patients who were prospectively randomized to receive postresection intravesical BCG (81 mg [n = 50] or 27 mg [n = 19]) or BCG (27 mg) with interferon alpha (IFN-α; n = 30). The median follow-up time was 60 mo.

Intervention

Intravesical BCG or BCG–IFN-α.

Measurements

Restriction fragment length polymorphism (RFLP) analysis was performed to identify polymorphisms in the NRAMP1 promoter region (GT repeat number) and at position 543 (aspartate [D] and/or asparagine [N] expression) within the NRAMP1 protein (D543N) and position 198 (proline and/or leucine expression) within the hGPX1 protein (Pro198Leu). Data were analyzed using χ² analysis, multivariate analysis, and Kaplan-Meier curves.

Results and limitations

On univariate analysis, the NRAMP1 D543N G:G genotype had decreased cancer-specific survival (CSS; p = 0.036). The hGPX1 CT genotype (Pro-Leu) had decreased recurrence time (p = 0.03) after BCG therapy. On multivariate analysis, patients with the NRAMP1 D543N G:G genotype and allele 3 (GT)n polymorphism had decreased recurrence time (p = 0.014 and p = 0.03) after BCG therapy. The limitation of this study was its small sample size.

Conclusions

Polymorphisms of the NRAMP1 and hGPX1 genes may be associated with recurrence of BCa after BCG immunotherapy.     

Metabolic differences between Asian and Caucasian patients on clozapine treatment

OBJECTIVE: To establish if there are ethnic differences in the various metabolic disturbances that are common with clozapine treatment. METHOD: Forty subjects (20 Asians and 20 Caucasians) with a diagnosis of schizophrenia were recruited for the study. Clozapine blood levels as well as fasting blood glucose, lipid levels, and liver function tests were established. Other clinical parameters such as blood pressure and Body Mass Index (BMI) were recorded for each patient. RESULTS: The mean clozapine dose was significantly higher in the Caucasian subjects (432.5+/-194.7 mg) as compared to the Asian subjects (175.6+/-106.9 mg) (p<0.001) while the mean weight-corrected dose for Asian patients was lower (3.0+/-1.9 and 5.0+/-2.1 mg/kg, respectively, p=0.005). There were, however, no ethnic differences in the mean plasma clozapine concentration (415.3+/-185.8 ng/ml in Caucasians and 417.1+/-290.8 ng/ml in Asians). BMI were significantly higher in Caucasians, as were the number of subjects with hypertension; levels of hepatic enzymes were higher in the Asian group. CONCLUSIONS: Not only are there pharmacokinetic differences between Asian and Caucasian patients receiving clozapine, but there may also be differential emergence of certain metabolic abnormalities like hypertension and weight gain in these two ethnic groups. However, the effects of life style including diet and exercise cannot be excluded.