title: Genome-Wide Interaction with Insulin Secretion 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 insulin secretion loci. To test this hypothesis, single nucleotide polymorphisms (SNPs) associated with acute insulin response to glucose (AIRg), a dynamic measure of first-phase insulin secretion, 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 genome-wide association study (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 LYPLAL1 (rs10746381), CHN2 (rs7796525), and EXOC1 (rs4289500). Notable AIRg GRS interactions were observed with SAMD4A (rs11627203) and UTRN (rs17074194). 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, Winston-Salem, North Carolina, United States of America.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Keaton
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Jacklyn N
authors.initials: JN
authors.lastname: Hellwege
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Maggie C Y
authors.initials: MC
authors.lastname: Ng
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: James S
authors.initials: JS
authors.lastname: Pankow
authors.affiliation: Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.affiliation: University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Correa
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Rasmussen-Torvik
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Yii-Der I
authors.initials: YD
authors.lastname: Chen
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.affiliation: Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Department of Internal Medicine - Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.affiliation: Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.|Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007328:Insulin