title: Individual variation of human S1P₁ coding sequence leads to heterogeneity in receptor function and drug interactions.
abstract: Sphingosine 1-phosphate receptor 1 (S1P₁), 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 S1P₁ receptors on immune and neural cells to suppress neuroinflammation. However, suppression of endothelial S1P₁ receptors is associated with cardiac and vascular adverse effects. Here we report the genetic variations of the S1P₁ 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 (Arg¹²⁰ 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 (Ile⁴⁵ to Thr and Gly³⁰⁵ 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 S1P₁ can influence receptor function and, therefore, infer differential disease risks and interaction with S1P₁-targeted therapeutics.
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065.
authors.forename: Hideru
authors.initials: H
authors.lastname: Obinata
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gutkind
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Stitham
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: John
authors.initials: J
authors.lastname: Hwa
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
mesh_terms: D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D003412:Cricetulus; D004351:Drug Resistance; D004705:Endocytosis / Q000187:drug effects*; D005260:Female; D000068876:Fingolimod Hydrochloride; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011409:Propylene Glycols / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D050505:Mutant Proteins; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D011993:Recombinant Fusion Proteins; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: cell signaling; drug therapy; endocytosis; genetics; single nucleotide polymorphism; sphingosine 1-phosphate receptor; sphingosine phosphate