Variants of the pro-inflammatory P2X7 receptor on platelets are associated with the acute attack of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system characterized by demyelination and neuronal death. In discovery cohorts of Australasian patients with multiple sclerosis (total 2941 patients, 3008 controls) we examined the associations of twelve functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular ATP. In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a two-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, p=0.0000071). A meta-analysis of three Australasian and four European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR 0.57, p=0.0000024) [1]. In contrast a gain of function variant of P2X7, Ala348Thr was associated with an increased risk of MS (OR 1.10, p= 0.0006) [1]. Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Flow cytometric analysis of both resting and activated human platelets showed binding of the L4 mAb specific for the extracellular domain of the P2X7 receptor. Microvesicles derived from activated platelets have been shown in MS blood [2], and these may arise from the action of ATP on platelet P2X7 to induce cell blebbing. Our data show the protective effect against MS of a loss of function variant of P2RX7 and suggest a role for platelet P2X7-function in the acute MS relapse