aBsTraCTs nature publishing group and increases glucose levels in humans, and that ADRA2A variation modifies these effects. METHODS: Healthy Caucasians (n=28) and African-Americans (n=32), aged 18-45 years, received 3 sequential infusions of placebo at 30 minute intervals followed by 3 infusions of DEX (0.1, 0.15, and 0.15 mcg/kg). We measured serum insulin and glucose concentrations and genotyped for ADRA2A rs553668 and rs2484516 that characterize haplotypes 4 and 4b, respectively. RESULTS: DEX decreased insulin concentrations by 27% from 8.4±6.1 μU/mL to 6.1±3.9 μU/mL (P
nature publishing group Top nsSNPs associated with Primary Outcome Based on Treatment Interaction, Analysis Presented as Risk of Event within Treatment Arm, Under an Additive Genetic Model. White (n=795). Hispanic (Hisp, n=380) White SELE Ser149Arg CCB White SELE Ser149Arg BB Hisp SELP Val209Met CCB Hisp SELP Val209Met BB White SIGLEC12 Gln29stop CCB White SIGLEC12 Gln29stop BB Hisp SIGLEC12 Gln29stop CCB Hisp SIGLEC12 Gln29stop BB S149R Interaction P=0.048 V209M Interaction P=0.<strong>00</strong>2 Q29stop Interaction P=0.033 Q29stop Interaction P=0.021 0 1 2 3 4 5 6 7 8 Odds Ratio and 95% Confidence Intervals <strong>PI</strong>-36 ALPHA ADDUCIN-1 (ADD1) SINGLE NUCLEOTIDE POLYMOR- PHISM (SNP) ASSOCIATED WITH NEW ONSET DIABETES RISK WITH HYDROCHLOROTHIAZIDE (HCTZ) THERAPY IN THE INTERNATIONAL VERAPAMIL SR TRANDOLAPRIL GENETIC SUBSTUDY (INVEST-GENES). J. H. Karnes, C. W. McDonough, Y. Gong, T. Y. Langaee, C. J. Pepine, J. A. Johnson, R. M. Cooper-DeHoff; University of Florida, Gainesville, FL. J.H. Karnes: 1. This research was sponsored by; Company/ Drug; NIH Grant TL1RR029888. C.W. McDonough: None. Y. Gong: 1. This research was sponsored by; Company/Drug; NIH grants HL074730, HL69758, HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals and the Florida Opportunity Fund. T.Y. Langaee: 1. This research was sponsored by; Company/Drug; NIH grants HL074730, HL69758, HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals and the Florida Opportunity Fund. C.J. Pepine: 1. This research was sponsored by; Company/Drug; NIH grants HL074730, HL69758, HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals and the Florida Opportunity Fund. 2. I <strong>am</strong> a paid consultant/ employee for; Company/Drug; Abbott Labs, Angioblast Systems, Athersys, Baxter Healthcare, Boehringer Ingelheim, Gilead, Medtelligence, NicOx, Pfizer, sanofi-aventis, Schering-Plough, Servier and Slack. J.A. Johnson: 1. This research was sponsored by; Company/ Drug; NIH grants HL074730, HL69758, HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals and the Florida Opportunity Fund. 2. I <strong>am</strong> a paid consultant/employee for; Company/Drug; Medco. R.M. Cooper- DeHoff: 1. This research was sponsored by; Company/Drug; NIH grants K23 HL086558, HL074730, HL69758, HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals and the Florida Opportunity Fund. BACKGROUND: The first line antihypertensive HCTZ is associated with increased new onset diabetes (NOD) risk. SNPs may help identify patients at risk for HCTZ-induced NOD and guide prescribing to reduce diabetes risk. The ADD1 SNP Gly460Trp has been associated with increased NOD risk in thiazide treated patients. Our study aimed to replicate this association and assess 31 additional ADD1 SNPs for NOD risk with HCTZ therapy in patients with hypertension and coronary artery disease. aBsTraCTs METHODS: INVEST recorded cardiovascular outcomes and NOD during a comparison of two antihypertensive strategies over a mean 2.8 years of follow up. A total of 446 NOD cases were identified and age, race and sex matched to 1,025 controls. We determined odds ratios and 95% confidence intervals for NOD in HCTZ treated versus non HCTZ treated patients using logistic regression by race/ethnicity. We calculated SNP*HCTZ treatment interaction p values adjusted for false discovery rate to determine pharmacogenetic effects. RESULTS: Gly460Trp did not increase NOD risk in HCTZ treated versus non HCTZ treated patients overall or in any race/ethnicity. The rs3775067 C allele was associated with NOD in HCTZ treated versus non HCTZ treated patients in whites, with a similar trend overall. (Figure 1) CONCLUSION: We did not replicate the previous association of Gly460Trp and thiazide induced NOD. However, the pharmacogenetic effect of rs3775067 in INVEST whites suggests that ADD1 influences HCTZ induced NOD. Replication of this association is needed. Gly460Trp (rs4691) Overall Trp/Trp Whites* Trp carriers rs3775067 Overall C/C Whites C/C SNP*HCTZ treatment Interaction p value <strong>PI</strong>-37 SULFONYLUREA RECEPTOR POLYMORPHISMS IN ABCC8 AFFECT THE RESPONSE TO SULFONYLUREA TREATMENT IN PATIENTS WITH TYPE 2 DIABETES MELLITUS. J. A. Wessels, J. J. Swen, T. Van der Straaten, T. El Hajoui, W. J. Assendelft, H. J. Guchelaar; Leiden University Medical Centre, Leiden, Netherlands. J.A. Wessels: None. J.J. Swen: None. T. Van der Straaten: None. T. El Hajoui: None. W.J. Assendelft: None. H.J. Guchelaar: None. BACKGROUND: There is significant interpatient variability in response to sulfonylureas (SUs) in patients with Type 2 Diabetes Mellitus (T2DM). We hypothesize that polymorphisms in the ABCC8 gene encoding the sulfonylurea receptor 1 influence the response to SUs. METHODS: Two hundred and seven incident SU users (tolbut<strong>am</strong>ide, glibencl<strong>am</strong>ide, glimepiride, gliclazide) with T2DM were recruited from four primary care centers. Retrospective medical and prescription data were retrieved from the electronic patient record. Haplotype analysis of the ABCC8 gene was performed by means of the fifteen most informative polymorphisms, resulting in fourteen haplotypes defined in four blocks. The association of these ABCC8 haplotypes with the achievement of stable SU CliniCal pharmaCology & TherapeuTiCs | volume 91 supplemenT 1 | marCh 2012 s21 Gly/Trp Gly/Gly Gly/Trp C/G G/G C/G G/G Decreased NOD risk with HCTZ p = 0.95 p = 0.60 p = 0.<strong>00</strong>8 p FDR = 0.27 p = 0.<strong>00</strong>2 pFDR = 0.04 0 1 2 3 4 5 6 14 15 Increased NOD risk with HCTZ Figure 1: Odds ratios and 95% confidence intervals for HCTZtreated versus non HCTZ-treated patients by genotype group. All statistics are adjusted for age, gender, body mass index, on treatment systolic blood pressure, atenolol or trandolapril treatment, and principal components one, two and three. HCTZ indicates hydrochlorothiazide, NOD new onset diabetes *Gly460Trp presented as Trp carriers due to low Trp frequency
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