{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T22:37:15Z","timestamp":1788907035792,"version":"build-2803163510"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set. Pathway analysis using European genome-wide association study data identified 100 significantly associated pathways (\n              <jats:italic>P<\/jats:italic>\n              &lt;5\u00d710\n              <jats:sup>\u2212<\/jats:sup>\n              <jats:sup>4<\/jats:sup>\n              ). Gene stability selection identified 116 single nucleotide polymorphisms in 26 genes that were responsible for driving the pathway associations, and gene ontology analysis demonstrated enrichment for calcium transport (\n              <jats:italic>P<\/jats:italic>\n              =1.05\u00d710\n              <jats:sup>\u2212<\/jats:sup>\n              <jats:sup>4<\/jats:sup>\n              ). Three single nucleotide polymorphisms in solute carrier family 8, member 1 (\n              <jats:italic>SLC8A1<\/jats:italic>\n              ), a sodium\/calcium exchanger encoding NCX1, were validated in an independent Japanese genome-wide association study data set (meta-analysis\n              <jats:italic>P<\/jats:italic>\n              =0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities (\n              <jats:italic>P<\/jats:italic>\n              =0.029). NCX1, the protein encoded by\n              <jats:italic>SLC8A1<\/jats:italic>\n              , was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of\n              <jats:italic>SLC8A1<\/jats:italic>\n              polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.116.001533","type":"journal-article","created":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T01:57:28Z","timestamp":1479866248000},"page":"559-568","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated With Susceptibility to Kawasaki Disease and Coronary Artery 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