Abstract
Sphingosine 1-phosphate receptor 1 (S1P&sub1;), an abundantly-expressed G protein-coupled receptor which regulates key vascular and immune responses, is a therapeutic target in autoimmune diseases. Fingolimod/Gilenya (FTY720), an oral medication for relapsing-remitting multiple sclerosis, targets S1P&sub1; receptors on immune and neural cells to suppress neuroinflammation. However, suppression of endothelial S1P&sub1; receptors is associated with cardiac and vascular adverse effects. Here we report the genetic variations of the S1P&sub1; coding region from exon sequencing of >12,000 individuals and their functional consequences. We conducted functional analyses of 14 nonsynonymous single nucleotide polymorphisms (SNPs) of the S1PR1 gene. One SNP mutant (Arg¹²&sup0; to Pro) failed to transmit sphingosine 1-phosphate (S1P)-induced intracellular signals such as calcium increase and activation of p44/42 MAPK and Akt. Two other mutants (Ile&sup4;&sup5; to Thr and Gly³&sup0;&sup5; to Cys) showed normal intracellular signals but impaired S1P-induced endocytosis, which made the receptor resistant to FTY720-induced degradation. Another SNP mutant (Arg¹³ to Gly) demonstrated protection from coronary artery disease in a high cardiovascular risk population. Individuals with this mutation showed a significantly lower percentage of multi-vessel coronary obstruction in a risk factor-matched case-control study. This study suggests that individual genetic variations of S1P&sub1; can influence receptor function and, therefore, infer differential disease risks and interaction with S1P&sub1;-targeted therapeutics.