Abstract 16332: ABC Transporter Genes and Risk of Type 2 Diabetes - A Study of 40,000 Individuals from the General Population

Abstract

Objective: Alterations of pancreatic β-cell cholesterol content may contribute to β-cell dysfunction. Two important determinants of intracellular cholesterol content are the ATP-Binding-Cassette transporters A1 (ABCA1) and -G1 (ABCG1). Whether genetic variation in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown.

Methods: We tested whether genetic variation in the promoter and coding regions of ABCA1 and ABCG1 associated with measures of glucose metabolism, markers of inflammation, levels of lipids and lipoproteins, and risk of type 2 diabetes in the general population. Twenty seven variants, identified by previous resequencing of both genes, were genotyped in the Copenhagen City Heart Study (CCHS, n=10,185). Two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T, n=322) and a common variant (ABCG1 g.-530A>G), were further genotyped in the Copenhagen General Population Study (CGPS, n=30,415).

Results: Only one of the variants examined, ABCG1 g.-530A>G, predicted a decreased risk of type 2 diabetes in the CCHS (P for trend=0.05). Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n=40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T) nor ABCG1 g.-530A>G associated with type 2 diabetes (P-values >0.57 and >0.30, respectively).

Conclusions: Genetic variation in ABCA1 and ABCG1 was not associated with increased risk of type 2 diabetes in the general population. These data were obtained in general population samples harboring the largest number of heterozygotes for loss-of-function mutations in ABCA1 and ABCG1.