Paradoxical role of C1561T glutamate carboxypeptidase II (GCPII) genetic polymorphism in altering disease susceptibility

• Published in: Gene Vol. 497; no. 2; pp. 273 - 279
• Main Authors: Divyya, Shree, Naushad, Shaik Mohammad, Addlagatta, Anthony, Murthy, P.V.L.N., Reddy, Ch Ram, Digumarti, Raghunadha Rao, Gottumukkala, Suryanarayana Raju, Kumar, Ajit, Rammurti, S., Kutala, Vijay Kumar
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.04.2012
• Subjects: Abortion, Spontaneous; Abortion, Spontaneous - enzymology; Abortion, Spontaneous - genetics; absorption; antigens; Antigens, Surface; Antigens, Surface - genetics; Autism; Autistic Disorder; Autistic Disorder - enzymology; Autistic Disorder - genetics; blood; brain; breast neoplasms; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Cancer; Cohort Studies; Coronary artery disease; Coronary Artery Disease - enzymology; Coronary Artery Disease - genetics; disease resistance; enzymology; Female; folic acid; Folic Acid - blood; Genetic Predisposition to Disease; genetics; Genotype; genotyping; Glutamate Carboxypeptidase II; Glutamate Carboxypeptidase II - genetics; glutamic acid; Humans; intestinal mucosa; Male; nervous system diseases; Polymorphism; Polymorphism, Genetic; prostatic neoplasms; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; restriction fragment length polymorphism; reverse transcriptase polymerase chain reaction; risk; Glutamate carboxypeptidase II; ABC; DSM-IV; DQ; NAALADase; Coronary artery disease; FGCP; GCP II; NTDs; Autism; PSMA; TGF; NMDA; NAAG; 5-HT2A; ODS; Cancer; Polymorphism
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2012.01.055

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. ► GCPII H475Y confers protection against autism and cancer. ► GCPII H475Y inflates the risk for coronary artery disease and miscarriages. ► H475Y impairs intestinal absorption of folate when the dietary folate intake is low. ► GCPII expression correlates positively with plasma folate. ► Steric hindrance in ligand binding in H475Y variant.