Abstract 18569: Impact of ER-Stress Affecting Variant of XBP-1 Gene on Lipids, Diabetes, Chronic Kidney Disease, and Coronary Artery Disease

Abstract

Objective: ER function is fundamentally important in all cell types, and the key transcription factor X-box binding protein 1 (XBP-1) regulates many genes of ER-stress and also hepatic lipogenesis. A functional polymorphism (-116G>C) in the promoter region of XBP1 has been identified, and -116C allele was associated with higher ER-stress in vitro . CC homozygotes are quite common in Japanese (41%) compared with European (7% in NCBI database). Even though higher ER-stress would be associated with coronary risk factors, few data exist regarding clinical importance of this polymorphism as a cardiovascular risk factor. Methods: A total of 272 patients (137 males, mean age of 57 ± 14) suspected coronary artery disease were enrolled. Genotypes were determined by PCR-RFLP, and lipid profiles with ultracentrifugation, 75gOGTT, post-heparin lipoprotein lipase activities (PHLA), and eGFR were analyzed. Coronary stenosis index (CSI) was estimated with angiography in 125 patients (69 males, mean age of 63 ± 11, Diabetes 45%). Results: No difference was observed in age and sex with genotypes. CC homozygotes showed higher BMI (CC vs. GC+GG = 24.8 ± 3.3 vs. 23.4 ± 3.2, p <0.05). CC homozygotes showed higher apoB/LDL-C ratio (0.94 ± 0.1 vs. 0.87 ± 0.1, p <0.05), and higher LDL-TG (46 ± 94 vs. 28 ± 21, p <0.05) suggesting presence of small dense-LDL. CC homozygotes showed higher hepatic transaminases, suggesting hepatic inflammation such as NAFLD. Hypertension was more frequent in CC homozygotes (79 vs. 54%, P<0.05). Also C carriers showed lower eGFR (CC+GC vs. GG = 77.3±21 vs. 83.0±24, p <0.05). Unexpectedly, CC homozygotes showed higher HOMA-beta (141 ± 178 vs. 91 ± 56, p <0.05), and lower HbA1c (5.9 ± 1.0 vs. 6.3 ± 1.3 %, p <0.05). In coronary angiography, CC homozygotes showed higher CSI in non-diabetes group (21 ± 9 vs. 11 ± 11, p <0.005), but not significant in diabetes group. Conclusion: Functional XBP1 variant showed significant impacts on advanced coronary artery disease with deteriorating lipid profile, hypertension, and chronic kidney disease.