Abstract 18721: Diacylglycerol Kinase ? (DGKB) Genotype Predicts Response to Niacin Induced Flushing and Changes in Insulin in the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) Trial
Niacin has been used for decades as a lipid lowering agent but its use is limited by flushing. Stimulation of a G-protein coupled receptor (GPR109A) on immune cells of the skin by niacin results in generation of prostaglandinD2/E2 and flushing. An evoked phenotype genetic study (termed the GENE study) was undertaken to determine genes associated with flushing and the findings were validated in the AIM-HIGH cohort receiving niacin.
The GENE study recruited n=294 healthy volunteers (51% Female, 65% Caucasian (Cau)) to an IR 1 gm niacin challenge. Flushing was assessed by laser Doppler and quantified as the flux index (peak blood flow divided by baseline). In the AIM-HIGH cohort, 2100 Cau and 75 African-Americans (AA) subjects for whom DNA was available were classified as cases and controls based on flushing severity and frequency during the run-in period of the trial. Genotyping was performed on Human Cardio-Metabo BeadChip (Illumina). Insulin was assayed before and after niacin treatment was begun.
In the GENE study, two independent loci in DGKB, a downstream mediator of GPCR signaling (lead SNPs Chr7:14349921, p=1 x 10-6 and chr7:14281125, p=1.8 x10-5) were associated with the flux index. Fasting insulin levels increased after niacin 94 ± 106% (p<0.0001) at 5 hr compared to baseline. The same SNPs were also associated with the change in insulin. Subjects with the minor alleles had the greatest severity of flushing but the smallest change in insulin. DGKB SNPs were associated with flushing in the AIM-HIGH trial (lead SNP Chr7:14594540p=4 x 10-4). Subjects in the genotype group most associated with flushing had the smallest change in insulin, similar to the GENE study. SNPs in DGKB were associated with flushing in AA in both cohorts, but underpowered for significance.
Summary: SNPs in DGKB were associated with flushing and change in insulin levels following niacin and may mediate several pharmacological effects of niacin. Variation in DGKB may alter the GPR109A receptor desensitzation and response to flushing. Since GPR109A has also been found to be expressed on murine islet beta cells, variation in DGKB in this tissue type may modulate insulin production. The role of DGKB in additional pharmacological responses to niacin is currently under study.
- © 2013 by American Heart Association, Inc.