Phospholipase A(2) Receptor Gene Polymorphisms Alter its Functions and Present a Genetic Risk of an Increased Intima-Media Thickness of the Carotid Artery

Aims: Phospholipase A(2) receptor 1 (PLA(2)R) has multiple biological functions other than functioning as a receptor for secretory PLA(2s). Two nonsynonymous polymorphisms in the C-type lectin-like domains (CTLD) 1 of PLA(2)R gene have been associated with idiopathic membranous nephropathy. This study examined whether the same PLA(2)R polymorphisms may alter functions of PLA(2)R in cells expressing the variant PLA(2)R. 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 PLA(2)R gene were completely linked. HEK293 cells expressing human wild-type PLA(2)R (T at rs3749117 and G at rs35771982) or human mutant PLA(2)R that had double mutations (C at rs3749117 and C at rs35771982) were constructed. Results: HEK293 cells expressing mutant PLA(2)R had lower migratory and proliferative responses to collagen I compared with cells expressing wild-type PLA(2)R. In 580 male patients, PLA(2)R gene polymorphisms were associated with an increase in maximum intima-media thickness (maxIMT) of the carotid artery. The multivariate regression model showed that PLA(2)R 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 PLA(2)R gene altered biological functions in cells expressing variant PLA(2)R. PLA(2)R gene polymorphisms present a genetic risk of an increased IMT of the carotid artery in male. The functional changes in the variant PLA(2)R may potentially be responsible for its association with an increased IMT of the carotid artery.