Abstract 1085: Impact of Functional Promoter Variant of XBP1 Gene on Lipid and Glucose Metabolism in Japanese Population
Objective: The transcription factor X-box binding protein 1 (XBP1) was shown to critically regulate hepatic lipogenesis with carbohydrate feeding animal models in 2008. A polymorphism (−116G>C) in the promoter region of XBP1 has been identified, and the transcriptional activity of −116C was significantly higher than −116G in vitro. Although CC homozygotes are quite common in Japanese who have less atherosclerotic diseases, few data exist regarding clinical importance of polymorphism of this gene as a cardiovascular risk factor. XBP1 protein expression is induced with carbohydrate feeding, so high-carbohydrate diet in Japanese habit would enhance the effects of this gene. Therefore, we investigated the impact of this polymorphism on cardiovascular risk factors.
Methods and Results: A total of 265 patients (132 males, mean age of 58±14) suspected coronary artery disease were enrolled. XBP1 −116G>C genotypes were determined by PCR-RFLP, and lipid profiles with ultracentrifugation, 75gOGTT, and post-heparin lipoprotein lipase activities (PHLA) were analyzed. CC homozygotes showed lower LDL-C (CC vs. GC+GG = 141±45 vs. 159±47 mg/dl, p<0.05), lower HbA1c (5.53±1.0 vs. 5.89±1.3 %, p<0.05), and higher HOMA-beta (141±178 vs. 91±56 %, p<0.05). On the other hand, relatively small unfavorable changes were observed in CC homozygotes such as slightly higher BMI (24.8±3.3 vs. 23.4±3.2, p<0.05), higher apoB/LDL-C ratio (0.94±0.1 vs. 0.87±0.1, p<0.05), lower PHLA (0.318±0.9 vs. 0.360±0.8 U/L, p<0.05), and higher liver transaminases (AST; 30±15 vs. 24±20 IU/L, p<0.05. ALT; 39±37 vs. 24±26 IU/L, p<0.05). There were no significant differences in triglyceride (242±354 vs. 186±153 mg/dl) and HDL-C (46±13 vs. 51±18 mg/dl) levels. Among these factors, LDL-C and HbA1c were most strongly affected by XBP1 variant.
Conclusion: These results demonstrated that a functional XBP1 variant has significant impacts on clinical cardiovascular factors, such as lipid and glucose metabolism. This may partly explain the mechanism of less frequent atherosclerotic diseases in Japanese in whom CC homozygotes are more common in comparison with those in western countries (41% vs. 7%).