title: Systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with insulin clearance.
abstract: OBJECTIVE
  Insulin clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with insulin clearance.
  
  
  METHODS
  Hyperinsulinaemic-euglycaemic clamps were performed in two Hispanic-American family cohorts totalling 1329 participants in 329 families. The Metabochip was used to fine-map about 50 previously identified loci for type 2 diabetes, fasting glucose, fasting insulin, 2 h glucose or HbA1c. This resulted in 17,930 variants, which were tested for association with clamp-derived insulin clearance via meta-analysis of the two cohorts.
  
  
  RESULTS
  In the meta-analysis, 38 variants located within seven loci demonstrated association with insulin clearance (p < 0.001). The top signals for each locus were rs10241087 (DGKB/TMEM195 [TMEM195 also known as AGMO]) (p = 4.4 × 10(-5)); chr1:217605433 (LYPLAL1) (p = 3.25 × 10(-4)); rs2380949 (GLIS3) (p = 3.4 × 10(-4)); rs55903902 (FADS1) (p = 5.6 × 10(-4)); rs849334 (JAZF1) (p = 6.4 × 10(-4)); rs35749 (IGF1) (p = 6.7 × 10(-4)); and rs9460557 (CDKAL1) (p = 6.8 × 10(-4)).
  
  
  CONCLUSIONS
  While the majority of validated loci for type 2 diabetes and related traits do not appear to influence insulin clearance in Hispanics, several of these loci do show evidence of association with this trait. It is therefore possible that these loci could have pleiotropic effects on insulin secretion, insulin sensitivity and insulin clearance.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room B-131, Los Angeles, CA 90048, USA. mark.goodarzi@cshs.org
authors.forename: M O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: J
authors.initials: J
authors.lastname: Cui
authors.forename: M R
authors.initials: MR
authors.lastname: Jones
authors.forename: T
authors.initials: T
authors.lastname: Haritunians
authors.forename: A H
authors.initials: AH
authors.lastname: Xiang
authors.forename: Y-D I
authors.initials: YD
authors.lastname: Chen
authors.forename: K D
authors.initials: KD
authors.lastname: Taylor
authors.forename: T A
authors.initials: TA
authors.lastname: Buchanan
authors.forename: W A
authors.initials: WA
authors.lastname: Hsueh
authors.forename: L J
authors.initials: LJ
authors.lastname: Raffel
authors.forename: J I
authors.initials: JI
authors.lastname: Rotter
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000235:genetics; D015331:Cohort Studies; D000090943:Delta-5 Fatty Acid Desaturase; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D015309:Glucose Clamp Technique; D006442:Glycated Hemoglobin / Q000737:chemistry; D006630:Hispanic or Latino; D006801:Humans; D006943:Hyperglycemia / Q000175:diagnosis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D000090943:Delta-5 Fatty Acid Desaturase; D006442:Glycated Hemoglobin; D007328:Insulin; C000716847:FADS1 protein, human