Phospholipase A Receptor Gene Polymorphisms Alter its Functions and Present a Genetic Risk of an Increased Intima-Media Thickness of the Carotid Artery.

AIMS

Phospholipase A receptor 1 (PLAR) has multiple biological functions other than functioning as a receptor for secretory PLAs. Two nonsynonymous polymorphisms in the C-type lectin-like domains (CTLD) 1 of PLAR gene have been associated with idiopathic membranous nephropathy. This study examined whether the same PLAR polymorphisms may alter functions of PLAR in cells expressing the variant PLAR. In addition, the clinical relevance of the experiment was examined.

METHODS

Two nonsynonymous polymorphisms (T/C at rs3749117 and G/C at rs35771982) in CTLD1 of PLAR gene were completely linked. HEK293 cells expressing human wild-type PLAR (T at rs3749117 and G at rs35771982) or human mutant PLAR that had double mutations (C at rs3749117 and C at rs35771982) were constructed.

RESULTS

HEK293 cells expressing mutant PLAR had lower migratory and proliferative responses to collagen I compared with cells expressing wild-type PLAR. In 580 male patients, PLAR gene polymorphisms were associated with an increase in maximum intima-media thickness (maxIMT) of the carotid artery. The multivariate regression model showed that PLAR gene polymorphisms were a risk factor of an increased maxIMT that was independent of conventional risk factors (OR=1.93, 95% CI: 1.17-3.19, p＜0.01).

CONCLUSIONS

The nonsynonymous common variants of PLAR gene altered biological functions in cells expressing variant PLAR. PLAR gene polymorphisms present a genetic risk of an increased IMT of the carotid artery in male. The functional changes in the variant PLAR may potentially be responsible for its association with an increased IMT of the carotid artery.