title: GENOME-WIDE INTERACTION WITH SELECTED TYPE 2 DIABETES LOCI REVEALS NOVEL LOCI FOR TYPE 2 DIABETES IN AFRICAN AMERICANS.
abstract: Type 2 diabetes (T2D) is the result of metabolic defects in insulin secretion and insulin sensitivity, yet most T2D loci identified to date influence insulin secretion. We hypothesized that T2D loci, particularly those affecting insulin sensitivity, can be identified through interaction with known T2D loci implicated in insulin secretion. To test this hypothesis, single nucleotide polymorphisms (SNPs) nominally associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, and previously associated with T2D in genome-wide association studies (GWAS) were identified in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS; n=492 subjects). These SNPs were tested for interaction, individually and jointly as a genetic risk score (GRS), using GWAS data from five cohorts (ARIC, CARDIA, JHS, MESA, WFSM; n=2,725 cases, 4,167 controls) with T2D as the outcome. In single variant analyses, suggestively significant (Pinteraction < 5×10-6) interactions were observed at several loci including DGKB (rs978989), CDK18 (rs12126276), CXCL12 (rs7921850), HCN1 (rs6895191), FAM98A (rs1900780), and MGMT (rs568530). Notable beta-cell GRS interactions included two SNPs at the DGKB locus (rs6976381; rs6962498). These data support the hypothesis that additional genetic factors contributing to T2D risk can be identified by interactions with insulin secretion loci.
authors.affiliation: Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA2Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA3Center for Diabetes Research, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Keaton
authors.forename: Jacklyn N
authors.initials: JN
authors.lastname: Hellwege
authors.forename: Maggie C Y
authors.initials: MCY
authors.lastname: Ng
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Adolfo
authors.initials: A
authors.lastname: Correa
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Rasmussen-Torvik
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Yii-DER I
authors.initials: YI
authors.lastname: Chen
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D001741:Black or African American / Q000235:genetics*; D016022:Case-Control Studies; D019295:Computational Biology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000503:physiopathology; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D012307:Risk Factors