Glutamate carboxypeptidase II (GCPII) is predominantly expressed in brain, intestinal mucosa and
prostate cancer in the form of three splice variants i.e. N-acetylated-α-linked acidic
dipeptidase (
NAALADase), folyl poly-γ-
glutamate carboxypeptidase (FGCP) and prostate specific membrane
antigen (PSMA) respectively. Its inhibition was found to confer protection against certain
neurological disorders and
cancer. Despite the pivotal role of this
enzyme, the most common polymorphism i.e. H475Y has not been explored comprehensively in all its splice variants. In this study, we have determined the role of this variant in different disease conditions such as breast and
prostate cancers,
autism,
coronary artery disease (CAD) and
miscarriages (N=1561). Genotyping was done by PCR-RFLP and dideoxy sequencing. Plasma
folate levels were estimated by Axysm
folate kit. GCPII expression was studied by semi-quantitative RT-PCR. In silico model was developed using PYMOL. We observed the protective role of H475Y variant in
cancers [
breast cancer; OR (95% CI): 0.81 (0.55-1.19),
prostate cancer: OR (95% CI): 0.00 (0.00-0.66)], and in
autism (OR (95% CI): 0.47 (0.21-1.03), whereas inflated risk was observed in CAD (OR (95% CI): 1.69 (1.20-2.37) and
miscarriages [Maternal OR (95% CI): 3.26 (2.11-5.04); Paternal OR(95% CI): 1.99 (1.23-3.21)]. Further, this variant was found to impair the intestinal
folate absorption in subjects with dietary
folate intake in the lowest tertile (CC vs. CT in lowest tertile; 7.56±0.85ng/ml vs. 2.73±045ng/ml, p=0.005). In silico model of GCPII showed steric hindrance with H475Y resulting in stereochemical alteration of catalytic site, thus interfering with
ligand binding. Statistically significant association was not observed between dietary
folate levels and GCPII expression. However, a positive correlation was seen between plasma
folate levels and GCPII expression (r=0.70, p<0.05). To conclude, our data suggests that GCPII H475Y variant shows inverse association with
autism and
cancer while showing positive association with CAD and
miscarriages.