Assessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians

Abstract

Aims/hypothesis 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/interpretation 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.

New Aspects of Cellular Cholesterol Regulation on Blood Glucose Control—Review and Perspective on the Impact of Statin Medications on Metabolic Health

“…21 Moreover, mutation in genes for ApoA1, CETP, SR-B1, and Niemann-Pick disease, type C1 (NPC1) tend to increase a carrier's risk for T2D. [22][23][24][25][26] Loss-of-function mutations in ApoA1, CETP, and SR-B1 would negatively impact HDL functionality in accepting free cholesterol from cells with excess cholesterol. Efflux mutations in chromosome 9q31 in people with Tangier disease lead to defective ABCA1 transporters and many of these patients manifest impairments in insulin action and insulin secretion.…”

Trans-ancestry Fine Mapping and Molecular Assays Identify Regulatory Variants at the ANGPTL8 HDL-C GWAS Locus

“…To date, at least 157 loci have been associated with high-density lipoprotein cholesterol (HDL-C) in genome-wide association studies (GWAS) ( Willer et al 2013 ). Analyses of European, African American, Mexican, Pima Indian, and East Asian participants have identified four different lead variants associated with HDL-C located in or near angiopoietin-like protein 8 ( ANGPTL8 ) ( Coram et al 2013 ; Weissglas-Volkov et al 2013 ; Willer et al 2013 ; Nair et al 2016 ; Spracklen et al 2017 ). ANGPTL8 is a small protein of 198 amino acids; the gene is located on chromosome 19 within intron 14 of dedicator of cytokinesis 6 ( DOCK6 ), and is transcribed in the opposite direction of DOCK6 .…”

The role of KLF14 in multiple disease processes

“…Studies have demonstrated that changes in the vicinity of the KLF14 gene locus is close correlated with type 2 diabetes mellitus (T2DM) . On the one hand, the risk of T2DM is related to variants of single nucleotide polymorphisms of KLF14.…”

“…Studies have demonstrated that changes in the vicinity of the KLF14 gene locus is close correlated with type 2 diabetes mellitus (T2DM). [36][37][38] On the one hand, the risk of T2DM is related to variants of single nucleotide polymorphisms of KLF14. For example, the allele G of rs972283 in KLF14 gene increased the risk of diabetes 39 ; on the other hand, DNA methylation level of KLF14 has positive correlation with risk of T2DM, as significant increase DNA methylation of KLF14 among T2DM patients.…”