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ABC Transporter Genes and Risk of Type 2 Diabetes a Study of 40,000 Individuals from the General Population

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ABC Transporter Genes and Risk of Type 2 Diabetes a Study of 40,000 Individuals from the General Population Cardiovascular and Metabolic Risk ORIGINAL ARTICLE ABC Transporter Genes and Risk of Type 2 Diabetes A study of 40,000 individuals from the general population 1,2 2,3,4,6 JESPER SCHOU, MSC BØRGE G. NORDESTGAARD, MD, DMSC secretion in mice (2). In humans, family 1,2,3,4 1,2,4 ANNE TYBJÆRG-HANSEN, MD, DMSC RUTH FRIKKE-SCHMIDT, MD, DMSC 5 studies and small case-control studies HOLGER J. MØLLER, MD, PHD have suggested that loss-of-function muta- tions in ABCA1 associate with decreased in- sulin secretion (8) or type 2 diabetes (9). OBJECTIVEd b b Alterations of pancreatic -cell cholesterol content may contribute to -cell Further, macrophages from diabetic mice dysfunction. Two important determinants of intracellular cholesterol content are the ATP- (10) and humans (11) display decreased binding cassette (ABC) transporters A1 (ABCA1) and -G1 (ABCG1). Whether genetic variation ABCG1 expression. Finally, we recently re- in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown. ported that two functional variants, ABCA1 RESEARCH DESIGN AND METHODSdWe tested whether genetic variation in the N1800H and ABCG1 g.-376C.T, were as- promoter and coding regions of ABCA1 and ABCG1 predicted risk of type 2 diabetes in the sociated with, respectively, substantial re- general population. Twenty-seven variants, identified by previous resequencing of both genes, ductions in levels of HDL cholesterol or were genotyped in the Copenhagen City Heart Study (CCHS) (n = 10,185). Two loss-of-function reduced ABCG1 mRNA expression levels mutations (ABCA1 N1800H and ABCG1 g.-376C.T) (n = 322) and a common variant (ABCG1 . n and increased risk of ischemic heart disease g.-530A G) were further genotyped in the Copenhagen General Population Study (CGPS) ( = and myocardial infarction (12,13)drisk 30,415). factors and disease entities closely related RESULTSdOnly one of the variants examined, ABCG1 g.-530A.G, predicted a decreased risk to diabetes. Collectively, these data suggest of type 2 diabetes in the CCHS (P for trend = 0.05). Furthermore, when validated in the CGPS or that decreased ABCA1 and ABCG1 func- in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations tion may influence normal b-cell action (ABCA1 N1800H, ABCG1 g.-376C.T) nor ABCG1 g.-530A.G were associated with type 2 and susceptibility to type 2 diabetes. For diabetes (P values .0.57 and .0.30, respectively). clarification of whether genetic variation in ABCA1 and ABCG1 contributes to risk CONCLUSIONSdGenetic variations in ABCA1 and ABCG1 were not associated with in- creased risk of type 2 diabetes in the general population. These data were obtained in general of type 2 diabetes in humans, large studies population samples harboring the largest number of heterozygotes for loss-of-function muta- of the general population are needed. tions in ABCA1 and ABCG1. We tested the following hypotheses: 1) genetic variation in ABCA1 and ABCG1 associates with measures of glucose me- tabolism, markers of inflammation, and b lipid and lipoprotein levels in the general he cellular mechanisms underlying insulin secretion in cells (2,3). The 2 pancreatic b-cell dysfunction in type question of whether genetic variation in population and ) genetic variation in T ABCA1 and ABCG1 is associated with 2 diabetes are incompletely under- ABCA1 and ABCG1 predicts risk of type 2 stood. Recent evidence suggests that al- diabetes in the general population re- risk of type 2 diabetes in the general pop- terations of b-cell cholesterol content mains unanswered. ulation. These hypotheses were tested in may contribute to islet dysfunction and Homozygosity for mutations in ABCA1 two studies of the general population, the loss of insulin secretion (1). Two impor- causes a rare HDL-deficiency syndrome, Copenhagen City Heart Study (CCHS) (n = 10,185) and the Copenhagen General tant determinants of intracellular choles- Tangier disease, a disorder characterized n terol content are the ATP-binding cassette by accumulation of cholesterol esters in pe- Population Study (CGPS) ( = 30,415), (ABC) transporters A1 (ABCA1) and -G1 ripheral tissues (4–7). Deficiency of ABCA1 harboring the largest known number of b heterozygotes for loss-of-function muta- (ABCG1), which have been suggested to in cells results in altered intracellular cho- ABCA1 ABCG1 n regulate cholesterol homeostasis and lesterol homeostasis and impaired insulin tions in and ( =322). ccccccccccccccccccccccccccccccccccccccccccccccccc RESEARCH DESIGN AND From the1Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; the 2Faculty of Health METHODSdStudies were approved by Sciences, University of Copenhagen, Copenhagen, Denmark; the 3Copenhagen City Heart Study, institutional review boards and Danish Bispebjerg Hospital, Copenhagen, Denmark; the 4Copenhagen General Population Study, Herlev Hospital, 5 ethics committees (nos. KF-100.2039/91, Copenhagen, Denmark; the Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, KF-01-144/01, and H-KF-01-144/01) and Denmark; and the 6Department of Clinical Biochemistry, Herlev Hospital, Herlev, Denmark. Corresponding author: Ruth Frikke-Schmidt, [email protected]. conducted according to the Declaration of Received 13 January 2012 and accepted 18 June 2012. Helsinki. Informed consent was obtained DOI: 10.2337/dc12-0082 from all participants. All participants were This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 white and of Danish descent. No partic- .2337/dc12-0082/-/DC1. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly ipants appeared in more than one of the cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ two studies, permitting independent con- licenses/by-nc-nd/3.0/ for details. firmation of the findings in each group. care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online November 8, 2012 ABC transporter genes and type 2 diabetes CCHS. This was a prospective study of used to measure HDL cholesterol and tri- Events the general population initiated in 1976– glycerides (Boehringer Mannheim, Man- Informationondiagnosesoftype2di- 1978 with follow-up examinations in nheim, Germany), and LDL cholesterol abetes (World Health Organization; 1981–1983, 1991–1994, and 2001– was calculated using the Friedewald ICD-8, 250; and ICD-10, E11, E13, 2003. Individuals were selected based equation (19), when plasma triglycerides E14) was collected from the National on the National Danish Civil Registration were ,4.00 mmol/L (,354.00 mg/dL), Danish Patient Registry (94% of end System to reflect the adult Danish popu- and otherwise was measured directly points) and the National Danish Causes lation aged 20 to $80 years. Data were (Thermo Fisher Scientific, Waltham, of Death Registry (6% of end points). All obtained from a questionnaire, a physical MA). diagnoses in these registries are given by a examination, and blood samples. Blood samples for DNA extraction were avail- able on 10,185 participants attending the 1991–1994 and/or 2001–2003 examinations. CGPS. This is a prospective study of the general population initiated in 2003 with ongoing enrollment. For the current study, we used the CGPS cross-sectionally in order to include all available events oc- curring from the establishment of the National Danish Patient Registry and Na- tional Danish Causes of Death Registry in 1976 to the end of follow-up in 2010. Participants were recruited from the gen- eral population and examined as in the CCHS. At the time of genotyping, 30,415 had been included. Genotyping The ABI PRISM 7900HT Sequence De- tection System (Applied Biosystems, Fos- ter City, CA) was used to genotype the CCHS for all variants in the core promoter and nonsynonymous variants identified by previous resequencing of the ABCG1 and ABCA1 genes (12–14). Two loss-of- function mutations (ABCA1 N1800H and ABCG1 g.-376C.T),aswellasacommon variant associated with reduced risk of type 2 diabetes in the CCHS (ABCG1 g.-530A.G), were further genotyped in the CGPS. TaqMan-based assays were used. Measures of glucose metabolism, markers of inflammation, and lipid and lipoprotein levels Glucose concentrations were measured using a standard hexokinase/glucose-6- phosphate-dehydrogenease assay (15), and HbA1c was measured on a Kone analyzer (Kone-Laboratory, Helsinki, Finland). Soluble CD163, a marker of low-grade inflammation and a strong predictor of type 2 diabetes (16), was measured using an in-house sandwich enzyme-linked immunosorbent assay Figure 1dMeasures of glucose metabolism, inflammatory markers, and levels of lipids and on a BEP-2000 ELISA analyzer as previ- lipoproteins as a function of 13 ABCA1 variants. Values shown are means 6 SEM. P values by ously described (16,17). High-sensitivity Kruskal-Wallis one-way ANOVA or Mann Whitney U test. Parametric ANOVA and Student t C-reactive protein (hsCRP) was measured tests gave similar results. All calculations were performed for 10,185 individuals in CCHS except by standard nephelometric or turbidimet- for HbA1c, soluble CD163 (sCD163), and hsCRP, for which measurements were available for ric assays (18). Colorimetric assays were 5,661, 8,191, and 9,752 individuals, respectively. 2 DIABETES CARE care.diabetesjournals.org Schou and Associates hospital-employed physician on the day of their death date. In the CGPS and in the [20]), logistic regression analysis ad- discharge or death of the patient and are CCHS and CGPS combined, logistic re- justed for age in 10-year age-groups thus based on international criteria, med- gression analysis was used to estimate and sex was used to estimate odds ratios ical records, and pharmaceutical therapy. odds ratios. Multifactorial adjustment in the CCHS. Missing values were im- Follow-up ended in August 2010 and was was for age, sex, BMI, hypertension, puted. Burden testing for rare variants 100% complete; i.e., no individual was lost smoking, and physical inactivity, which (21) was performed in two ways: 1)col- to follow-up in either study.
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