A Novel Val286Ala Polymorphism in the NPXXY Motif of the Sphingosine-1-Phosphate Receptor S1PR2 Associates with the Incidence and Age of Onset of Diabetes

Abstract

Aim: S1PR2 is one of five known sphingosine-1-phosphate receptors and has recently been discussed to be implicated in the development or progression of diabetes. Our aim was to identify S1PR2 polymorphisms in the coding region of the human S1PR2 gene and perform association analyses between S1PR2 polymorphisms leading to amino acid exchanges and phenotypic parameters in a clinical study cohort. Method: We screened the coding region of the S1PR2 gene for polymorphisms resulting in amino acid exchanges in the S1PR2 protein in 40 Caucasian DNA samples from a CEPH control panel. The resulting polymorphisms were then analyzed in more than 3400 patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study cohort. Results: In addition to the known Asn?Lys S1PR2 polymorphism at position 10 of the S1PR2 protein, we identified a novel polymorphism in the NPXXY motif of S1PR2, resulting in the amino acid exchange Val?Ala at position 286. The S1PR2 genotype Val286Ala showed strong association with the incidence and age at onset of diabetes in the studied patient cohort. Conclusion: With our analysis we substantiate previous reports on the possible implication of S1PR2 in the development of diabetes and identified the S1PR2 Val286Ala genotype to be significantly associated with incidence and age at onset of diabetes likely due to an altered function of S1PR2.