title: Assessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians.
abstract: OBJECTIVE
  Epidemiological studies in Pima Indians identified elevated levels of HDL-cholesterol (HDL-C) as a protective factor against type 2 diabetes risk in women. We assessed whether HDL-C-associated single-nucleotide polymorphisms (SNPs) also associate with type 2 diabetes in female Pima Indians.
  
  
  METHODS
  Twenty-one SNPs in established HDL-C loci were initially analysed in 2,675 full-heritage Pima Indians. SNPs shown to associate with HDL-C (12 SNPs) were assessed for association with type 2 diabetes in 7,710 Pima Indians (55.6% female sex). The CETP locus provided the strongest evidence for association with HDL-C and was further interrogated by analysing tag SNPs.
  
  
  RESULTS
  Twelve of the 21 SNPs analysed had a significant association with HDL-C in Pima Indians; five SNPs representing four loci (CETP, DOCK6, PPP1R3B and ABCA1) reached genome-wide significance. Three SNPs, at CETP, KLF14 and HNF4A, associated with type 2 diabetes only in female participants with the HDL-C-lowering allele increasing diabetes risk (p values: 3.2 × 10(-4) to 7.7 × 10(-5)); the association remained significant even after adjustment for HDL-C. Additional analysis across CETP identified rs6499863 as having the strongest association with type 2 diabetes in female participants (p = 5.0 × 10(-6)) and this association remained independent of the HDL-C association.
  
  
  CONCLUSIONS
  SNPs at the CETP, HNF4A and KLF14 locus are associated with HDL-C levels and type 2 diabetes (in female participants). However, since HNF4A and KLF14 are established loci for type 2 diabetes, it is unlikely that HDL-C solely mediates these associations.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Anup K
authors.initials: AK
authors.lastname: Nair
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Piaggi
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Nellie A
authors.initials: NA
authors.lastname: McLean
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Manmeet
authors.initials: M
authors.lastname: Kaur
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 445 North 5th Street, Phoenix, AZ, 85004, USA. lbaier@phx.niddk.nih.gov.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood* / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012737:Sex Factors; D051703:Sp Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C417549:KLF14 protein, human; D051741:Kruppel-Like Transcription Factors; D051703:Sp Transcription Factors
keywords: CETP; HDL-C; HNF4A; KLF14; Lipids; Pima Indians; Type 2 diabetes